Selinexor (SXR) is a potent Exportin 1 (XPO1) inhibitor that forces nuclear retention and activation of multiple tumour suppressor proteins (TSPs) resulting in tumour cell death. The safety, tolerability, pharmacokinetics and efficacy of SXR were evaluated in the Asian population.
SXR was initially administered orally on a twice weekly continuous 28-day cycle (S1). Two additional schedules predicted to be better tolerated were explored, once a week in a 28 day cycle (S2) and twice a week for 2 weeks of a 21-day cycle (S3). Tumour biopsies were performed. Response was evaluated every two cycles (RECIST 1.1/ Cheson lymphoma criteria). Tumour nuclear localisation of XPO1 target proteins, cellular proliferation and apoptotic markers were determined.
34 patients (20M/ 14F; median age 60.5; ECOG PS 0/1: 20/14) received escalating doses of SXR across three schedules. In S1, no dose-limiting toxicity (DLT) was observed but was stopped at expanded dose-level 1 (DL1) (40 mg/m2) due to persistent ≥ G2 AEs post C1 (fatigue, hyponatriemia, anorexia). S2, 2 DLTs (fatigue, vomiting) at 70 mg/m2 continuous weekly regimen were observed. S3, 1 DLT was observed (anorexia) at DL2 (50 mg/m2) but was stopped due to multiple subsequent G3 toxicities post C1 (hyponatriemia, nausea, anorexia, anemia). Analysis of pre- and post-SXR-treated biopsy samples confirmed induction of apoptosis (increased Apoptag and cleaved caspase 3) and inhibition of tumour proliferation (reduction of Ki67). In addition, nuclear retention of TSPs (p53) were observed indicating proof of mechanism. Of 30 evaluable patients, 4 partial responses were observed in patients with DLBCL (two S2; two S3). Stable disease was noted in 7 patients (one S1; two S2; four S3). 3 colorectal cancer patients and 1 patient each with ovarian cancer, liver cancer, thymic cancer and pancreatic cancer.
Oral SXR has a manageable toxicity profile and prolonged dosing is feasible in the Asian population with preliminary signals of efficacy observed. However, tolerability differs significantly from the Caucasian population. A fourth schedule (20 mg/m2 five times a week continuous 28- day cycle) will be explored to determine the appropriate RP2D for this population.
Clinical trial identification
V.Y.M. Heong: a grant for the trial of USD$150,000 was awarded by Karyopharm. S. Friedlander, D. McCauley, C. Choe-Juliak: employee of Karyopharm. All other authors have declared no conflicts of interest.