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Results of a phase 2 trial of selinexor, an oral selective inhibitor of nuclear export (SINE) in 114 patients with gynaecological cancers

Date

07 Oct 2016

Session

Gynaecological cancers

Presenters

Ignace Vergote

Citation

Annals of Oncology (2016) 27 (6): 296-312. 10.1093/annonc/mdw374

Authors

I. Vergote1, B. Lund2, H. Havsteen3, Z. Ujmajuridze4, E. Van Nieuwenhuysen1, C. Haslund2, T. Juhler-Nøttrup4, P. Neven1, M. Mau-Sørensen4, P. Berteloot1, A. Kranich5, T. Rashal6, J. Meade6, Y. Landesman6, J. Saint-Martin6, G. Wright6, M. Crochiere6, S. Shacham6, M. Kauffman6, M. Raza Mirza6

Author affiliations

  • 1 Obstetrics & Gynecology, Katholieke Universiteit, 3000 - Leuven/BE
  • 2 Oncology, Aalborg University Hospital, Aalborg/DK
  • 3 Oncology, University Hospital Herlev, Herlev/DK
  • 4 Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen/DK
  • 5 Gso, GSO, Hamburg/DE
  • 6 Karyopharm, Karyopharm Therapeutics, Newton/US
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Resources

Background

The nuclear export protein Exportin 1 (XPO1) mediates the nuclear export of regulatory proteins including tumor suppressor proteins (TSP). XPO1 is expressed in aggressive ovarian carcinomas & is related to poor patient outcomes [Noske 2008]. In addition, mutations in XPO1 are common in patients (pts) with endometrial cancer [TCGA database]. Selinexor (SEL), a first-in-class inhibitor of XPO1, induces nuclear retention & activation of TSPs. This phase 2 trial evaluated the efficacy & tolerability of SEL in pts with metastatic ovarian (OC), cervical (CC) & endometrial (EC) cancers.

Methods

Eligible pts: ≥ 1 lines of prior chemotherapy, ECOG PS 0-1. In OC, pts were platin-refractory or resistant. EC & CC pts had at least one prior chemotherapy line for relapsed disease. Pts were grouped into cohorts by disease type & treated with single agent SEL. Three randomized treatment schedules (50 mg/m2 (BIW); 35 mg/m2 BIW; & 50 mg/m2 QW in 4-wk cycles) were evaluated. Responses (RECIST 1.1) were evaluated per cohort. The primary endpoint was disease-control-rate (DCR = CR + PR + SD ≥ 12weeks). Other endpoints were overall response (ORR), progression free survival (PFS), duration of response, safety, & tolerability. Blood samples were analyzed for circulating tumor cells (CTCs). Simon's 2-stage design was used.

Results

66 OC (median 6 (1–11) prior treatment regimens [PTR]), 23 EC (median 2 (1–5) PTR) & 25 CC (median 3 (1–8) PTR) pts were enrolled. DCR: OC: 49%; EC: 43%; CC: 24%. ORR: OC: 14%; EC: 14%; CC 4%. Median PFS in OC: 11 wks, EC: 12 wks & CC: 6 wks. Sixteen pts (12 OC, 2 EC, & 2 CC) were on SEL treatment >6 mos. The presence of CTCs in pts prior to treatment seem to be correlated with shorter PFS opposed to pts without CTCs. Common Grade 1/2 drug-related adverse events (AEs) for all 3 cohorts included: nausea (56%), anorexia (47%), weight loss (44%) & fatigue (42%). Grade 3 drug related AEs included: thrombocytopenia (11%), fatigue (10%), anemia (9%) & nausea (8%). Grade 4 AEs were cataract (1pt) & hyponatremia (1pt).

Conclusions

Single agent SEL has anti-tumor activity in pts with heavily pre-treated OC & EC, but was lower in CC. SEL-associated toxicity is manageable. Combination studies are ongoing & phase 3 trials in OC & EC are being planned.

Clinical trial identification

EduraCT 2013-003650-24; NCT02025985

Legal entity responsible for the study

Karyopharm Therapeutics

Funding

Karyopharm Therapeutics

Disclosure

T. Rashal, J. Meade, Y. Landesman, G. Wright, M. Crochiere: Employment Karyopharm Therapeutics Stock Ownership Karyopharm Therapeutics. J-R. Saint-Martin: Employment Karyopharm Therapeutics Stockholder Karyopharm Therapeutics. S. Shacham, M. Kauffman: Employment Karyopharm Therapeutics Stock Ownership Karyopharm Therapeutics Executive Karyopharm Therapeutics. M. Raza Mirza: Employment Karyopharm Therapeutics Stock Ownership Karyopharm Therapeutics Board of Directors Karyopharm Therapeutics. All other authors have declared no conflicts of interest.

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