Phase 2 study of the Exportin 1 inhibitor selinexor in patients with recurrent gynecological malignancies
Introduction
Ovarian, endometrial, and cervical malignancies lead to ∼490,000 annual deaths worldwide [1]. Patients with advanced disease that has relapsed or is refractory to platinum-based therapy or radiotherapy have limited options and short survival [2]. Therefore, novel therapies are an urgent medical need for advanced gynecological malignancies.
Exportin 1 (XPO1/CRM1) is nuclear export protein that mediates the transport of ≥200 cargo proteins through the nuclear pore complex to the cytoplasm [3]. The anti-tumor activity of TSPs requires nuclear localization, and XPO1 is the sole nuclear exporter of key tumor suppressor proteins (TSPs) such as p53, p21, BRCA1 and 2, IκB and Rb [[4], [5], [6]]. In addition, XPO1 transports eukaryotic initiation factor 4 e (eIF4E) in complex with oncogenic mRNAs, such as Cyclin D1, Myc, and MDM2 to the cytoplasm for their efficient translation [7,8]. In nearly all cancers studied to date, including ovarian cancer, XPO1 expression is elevated, leading to functional inactivation of TSPs and increased translation of oncoproteins [9]. Furthermore, the elevated levels are correlated with poor prognosis and reduced survival, including in ovarian cancer [5,10]. Advanced, heavily pretreated gynecologic cancers have disruptions in many TSP and oncogenic pathways [11]. Therefore, inhibition of XPO1 is an attractive therapeutic strategy that impacts multiple pathways required for cancer growth and survival.
Selinexor is an oral, small-molecule inhibitor of XPO1 studied as a single agent or in combination for the treatment of hematological and solid cancers. Preclinical studies using selinexor and related Selective Inhibitor of Nuclear Export (SINE) compounds, showed nuclear retention of TSPs and oncogenic mRNAs in ovarian cancer cell lines [12]. In addition, selinexor significantly reduced the growth of patient-derived, platinum-resistant ovarian cancers in vivo and dramatically improved the OS of mice compared to vehicle treated controls [12]. In a phase I trial of selinexor in advanced solid tumors, 6 of the 13 evaluable patients with heavily pretreated ovarian or cervical cancer had a reduction in target lesion size, including 2 patients with a PR and 4 with durable disease control [13]. The recommended dose of oral selinexor based on both anti-ovarian and anti-cervical cancer activity, along with other Phase 1 studies is 60 mg–80 mg on days 1 and 3 twice weekly or 80 mg–100 mg once weekly [13,14]. Based on these preliminary findings, we conducted a phase 2 trial to better characterize the efficacy and safety and to determine the optimal dosing of selinexor in advanced gynecological malignancies.
Section snippets
Study design and oversight
This was a multi-center, open-label study conducted in 2 parts. Part I evaluated selinexor in patients with ovarian, endometrial, or cervical cancer treated at 50 mg/m2 (∼80 mg) BIW in 28-day cycles (8 doses per cycle). To improve tolerability based on results from Part I, the protocol was amended to include Part II to test additional dosing schedules in a more homogenous population (patients with ovarian cancer only). In Part II, patients were randomized in a 1:1 ratio using centralized
Patient characteristics
Between October 2014 and December 2015, 116 patients were enrolled (Fig. 1). Two patients died from cardiac events prior to receiving selinexor. As a result, 114 patients with ovarian (Part I: N = 25; Part II: N = 41), endometrial (N = 23), or cervical (N = 25) cancer were evaluable. Median age was 63 years (31–80) and prior regimens for patients with ovarian, endometrial and cervical cancer were 6 (1–11), 2 (1–5), and 3 (1–6) respectively. Nearly all patients had been previously treated with a
Discussion
This is the first study to assess the efficacy of single-agent oral selinexor in a large cohort of patients with heavily pretreated, advanced gynecological malignancies. There was evidence of meaningful DCR in patients with ovarian (30%) and endometrial (35%) cancer, and to a lesser extent in patients with cervical (24%) cancer, though observed DCRs included wide confidence intervals in Part I (both below and above the prespecified 25% target). Confirmed PRs were observed in all cohorts with
Declaration of competing interest
Authors I.B.V, B. L, U. P, Z.U, A.K, E.V, C.H, T.N, S.N.H, and N.C have no conflicts of interest. M.M has received a research grant from Karyopharm Therapeutics to conduct an investigator initiated trial. Authors T.J.U, Y.C, N.A, T.R, A.J, M.C, Y.L, and J.S are employees and stockholders of Karyopharm Therapecutics. S.S and M.K are board members and stockholders of Karyopharm Therapecutics. M.R.M is a scientific advisory board member of Karyopharm Therapecutics.
Acknowledgements
We would like to thank the patients who participated in this trial and their families, the co-investigators, nurses, and study coordinators at each of the sites. This is registered at ClinicalTrials.gov (NCT02025985).
References (23)
- et al.
Atomic basis of CRM1-cargo recognition, release and inhibition
Semin. Cancer Biol.
(2014) - et al.
Comprehensive genomic profiling of recurrent endometrial cancer: implications for selection of systemic therapy
Gynecol. Oncol.
(2019) - et al.
Selective inhibition of nuclear export with selinexor in patients with non-Hodgkin lymphoma
Blood
(2017) - et al.
Decitabine priming enhances the anti-leukemic effects of exportin 1 (XPO1) selective inhibitor selinexor in acute myeloid leukemia
Blood
(2015) - et al.
Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the global burden of disease study
JAMA Oncol.
(2017) - et al.
Chemoresistance and targeted therapies in ovarian and endometrial cancers
Oncotarget
(2017) - et al.
Promising SINEs for embargoing nuclear-cytoplasmic export as an anticancer strategy
Cancer Discov.
(2014) - et al.
Nucleo-cytoplasmic transport as a therapeutic target of cancer
J. Hematol. Oncol.
(2014) - et al.
Selective inhibitors of nuclear export (SINE)--a novel class of anti-cancer agents
J. Hematol. Oncol.
(2014) - et al.
The eukaryotic translation initiation factor 4E (eIF4E) and HuR RNA operons collaboratively regulate the expression of survival and proliferative genes
Cell Cycle
(2009)
The eukaryotic translation initiation factor eIF4E in the nucleus: taking the road less traveled
Immunol. Rev.
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2023, Gynecologic OncologyCitation Excerpt :The greatest activity appeared to be in combination wiath paclitaxel [15], supporting use in this study. Single agent activity was explored in a phase II trial across all gynecologic malignancies, where modest 8% objective response and approximately 30% disease control rates were observed in a heavily pre-treated ovarian cancer population [19]. Given the role of weekly paclitaxel in the treatment of ovarian cancer \and the observed preclinical synergy, we sought to perform a phase Ib study of the combination of selinexor and weekly paclitaxel in advanced solid tumors with a planned expansion in recurrent ovarian cancer.
Advanced and recurrent endometrial cancer: State of the art and future perspectives
2022, Critical Reviews in Oncology/HematologyCitation Excerpt :Selinexor, an XPO1 inhibitor, has reported interesting signals of activity in 66 advanced EC achieving a disease control rate of 35 %, with a mPFS of 2.8 months and a mOS of 7 months were registered. The toxicity profile of the drug was predominantly hematologic (thrombocytopenia, anemia), associated with nausea and fatigue (Vergote et al., 2020b). The randomized phase 3 SIENDO trial evaluating selinexor vs placebo as maintenance treatment in chemonaive advanced/recurrent EC, not progressing during first line platinum-based chemotherapy has recently concluded the recruitment and final results are awaited (NCT03555422).
A phase I open-label study of selinexor with paclitaxel and carboplatin in patients with advanced ovarian or endometrial cancers
2021, Gynecologic OncologyCitation Excerpt :A 60 mg flat dose of selinexor weekly in combination with either dosing schedule of carboplatin/paclitaxel chemotherapy was established as the RP2D. This recommendation is based on the tolerability and preliminary efficacy of selinexor, as well as on parallel studies (NCT02025985, NCT01607892) showing similar Cmax and AUC for BSA-based (mg/m2) and flat (mg) selinexor dosing [18,20,21]. Certain treatment-related adverse events (TRAEs) of grades 1–4 occurred in all 23 patients.
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