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

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.