Phase 2 study of the Exportin 1 inhibitor selinexor in patients with recurrent gynecological malignancies

doi:10.1016/j.ygyno.2019.11.012

Gynecologic Oncology

Volume 156, Issue 2, February 2020, Pages 308-314

https://doi.org/10.1016/j.ygyno.2019.11.012 Get rights and content

Highlights

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Selinexor, an oral XPO1 inhibitor, demonstrated single-agent activity in ovarian, endometrial, and cervical cancers.
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Selinexor was safe and tolerable; side effects were predominantly grade 1/2.
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Frequently reported grade 3/4 events were thrombocytopenia, fatigue, anemia, nausea, and hyponatremia.
•
These data support further development of selinexor in advanced gynecological malignancies.

Abstract

Background

Selinexor is an oral inhibitor of the nuclear export protein Exportin 1 (XPO1) with demonstrated antitumor activity in solid and hematological malignancies. We evaluated the efficacy and safety of selinexor in heavily pretreated, recurrent gynecological malignancies.

Methods

In this phase 2 trial, patients received selinexor (35 or 50 mg/m² twice-weekly [BIW] or 50 mg/m² once-weekly [QW]) in 4-week cycles. Primary endpoint was disease control rate (DCR) including complete response (CR), partial response (PR) or stable disease (SD) ≥12 weeks. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety.

Results

114 patients with ovarian (N = 66), endometrial (N = 23) or cervical (N = 25) cancer were enrolled. Median number of prior regimens for ovarian, endometrial and cervical cancer was 6 (1–11), 2 (1–5), and 3 (1–6) respectively. DCR was 30% (ovarian 30%; endometrial 35%; cervical 24%), which included confirmed PRs in 8%, 9%, and 4% of patients with ovarian, endometrial, and cervical cancer respectively. Median PFS and OS for patients with ovarian, endometrial and cervical cancer were 2.6, 2.8 and 1.4 months, and 7.3, 7.0, and 5.0 months, respectively. Common Grade 3/4 adverse events (AEs) were thrombocytopenia (17%), fatigue (14%), anemia (10%), nausea (9%) and hyponatremia (9%). Patients with ovarian cancer receiving 50 mg/m² QW had fewer high-grade AEs with similar efficacy as BIW treatment.

Conclusions

Selinexor demonstrated single-agent activity and disease control in patients with heavily pretreated ovarian and endometrial cancers. Side effects were a function of dose level and treatment frequency, similar to previous reports, reversible and mitigated with supportive care.

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).

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2023, Current Problems in Cancer
Selinexor is an oral inhibitor of the nuclear export protein called Exportin 1 (XPO1) with demonstrated antitumor activity in hematological and solid tumors. Selinexor, blocking XPO1, induces nuclear localization of tumor suppressor proteins (including p53, p73, BRCA1, and pRB), leading to the selective induction of apoptosis, and inhibition of DNA damage repair proteins. XPO1 overexpression is common in endometrial cancers. Phase I and II trials reported the antitumor activity of selinexor in patients with endometrial carcinoma. The preliminary results of the phase III Selinexor in ENDOmetrial Cancer (SIENDO/ENGOT-EN5/GOG-3055) trial supported the use of selinexor as maintenance therapy in advanced endometrial cancer patients achieving at least partial response after a minimum of 12 weeks of first-line platinum-based chemotherapy. Selinexor maintenance resulted in a (nonsignificant) 30% reduction in the risk of disease progression or death. Looking at the endometrial cancer molecular subgroup characterized by TP53 wild type, the antitumor activity of selinexor seemed more pronounced, resulting in approximately a 60% reduction in the risk of disease progression or death. The SIENDO and the XPORT-EC trials will clarify the benefits and risks of adding selinexor as a first-line chemotherapy maintenance treatment in all-comer and TP53 wild-type endometrial cancers. Preclinical data highlights the potential for selinexor to be synthetically lethal with PARP inhibitors and may also plan a role in overcoming acquired resistance to those therapies. Therefore, new possible combinations with PARP inhibitors and should be evaluated. Furthermore, the combination of selinexor plus immune checkpoint inhibitors deserves further investigation in clinical trials.
Selinexor: Changing the paradigm in patients with TP53 wild-type endometrial cancer?
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Selinexor in combination with weekly paclitaxel in patients with metastatic solid tumors: Results of an open label, single-center, multi-arm phase 1b study with expansion phase in ovarian cancer
2023, Gynecologic Oncology
Citation 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.
Selinexor is a first-in-class, oral selective inhibitor of nuclear export (SINE) compound which blocks Exportin-1 (XPO1). Our objective was to determine maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of selinexor and weekly paclitaxel.
This was an open label, single-center, multi-arm phase 1b study utilizing a “3 + 3” design and a “basket-type” expansion in recurrent solid tumors. Selinexor (60 mg or 80 mg twice weekly orally) and weekly paclitaxel (80 mg IV 2 week on, 1 week off) were one of 13 parallel arms. Efficacy was evaluated using RECIST version 1.1.
All 35 patients treated were evaluable for toxicity and 31 (88%) were evaluable for response. Patient diagnoses included platinum-resistant/refractory ovarian (n = 28), breast (n = 4), prostate (n = 2), and cervical (n = 1) cancer. Patients had a median of four prior therapies (range 1–10), and 47% had a prior taxane in the recurrent setting. There were no DLTs and 60 mg was chosen as the RP2D due to long-term tolerability. Ninety-seven percent of patients had at least one treatment-emergent adverse event (TEAE), and the most common grade ≥ 3 TEAE were neutropenia (46%), anemia (31%), and nausea (21%). Among 24 evaluable patients with ovarian cancer, response rate was 17%, CBR was 58%, and median PFS was 6.8 months (95% CI 3.7, not reached (NR)).
Oral selinexor in combination with weekly paclitaxel demonstrated promising clinical activity with manageable toxicity. This combination should be considered for further exploration in a randomized study, especially in ovarian malignancies.
Advanced and recurrent endometrial cancer: State of the art and future perspectives
2022, Critical Reviews in Oncology/Hematology
Citation 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).
Patients with primary metastatic/recurrent endometrial cancer have poor prognosis and available therapeutic options are limited. Current treatment is mainly based on platinum-based chemotherapy. Recently, the Food and Drug Administration (FDA) granted approval for the combination of pembrolizumab and lenvatinib for endometrial cancer patients without microsatellite instability (MSS) progressing on a previous line of therapy while European Medicines Agency (EMA) approved the combination for all comers patients failing previous platinum treatment. Anti programmed cell death protein-1 (PD-1) dostarlimab (TSR-042) was approved as monotherapy in patients with advanced, microsatellite instable (MSI) endometrial cancer progressing to platinum treatment. Phase II-III clinical trials in metastatic endometrial cancer are mainly focused on target therapies and immunotherapy as single agents or in combination. Unfortunately, most of these trials are lacking of predictive biomarkers of response to select patients most or at least likely to benefit from those treatments.
A phase I open-label study of selinexor with paclitaxel and carboplatin in patients with advanced ovarian or endometrial cancers
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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.
Selinexor, a selective inhibitor of nuclear export, monotherapy causes nuclear accumulation of tumor-suppressor proteins and has anti-tumor activity in ovarian and endometrial cancers. The safety and tolerability of oral selinexor plus intravenous carboplatin and paclitaxel chemotherapy (selinexor + CP) was evaluated in this population.
This phase I, 3 + 3 dose-escalation study assessed 4 selinexor + CP regimens. Patients in cohorts of 3, regardless of disease type, were administered 1 of 4 alternating regimens (selinexor at 30 mg/m² or 60 mg plus CP at AUC 5 and 175 mg/m² or 80 mg/m², respectively) for 6–10 cycles (1 cycle = 21 days), followed by selinexor maintenance. Enrolled patients with ovarian cancer had received 1 prior platinum-based therapy. Patients with endometrial cancer were chemotherapy-naive or had received 1 prior platinum-based therapy. Response was evaluated every 9 weeks.
Twenty-three patients were treated (5 serous ovarian cancer; 18 endometrial cancer, including 6 carcinosarcomas). The most common treatment-related adverse events (TRAEs) were thrombocytopenia (100%), leukopenia (91%), and hyperglycemia (87%). The most common grade 3/4 TRAEs were leukopenia (70%), neutropenia (70%), lymphopenia (61%), anemia (57%), and alanine transaminase increase (43%). One treatment-related dose-limiting toxicity (grade 3 syncope) occurred. Twelve patients achieved a partial response and 1 achieved a complete response. Responses to all four regimens were observed in ovarian and endometrial cancers.
Combination selinexor + CP was safe and tolerated in advanced ovarian and endometrial cancers.
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View all citing articles on Scopus

View full text

Phase 2 study of the Exportin 1 inhibitor selinexor in patients with recurrent gynecological malignancies

Highlights

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Study design and oversight

Patient characteristics

Discussion

Declaration of competing interest

Acknowledgements

Semin. Cancer Biol.

Gynecol. Oncol.

Blood

Blood

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.

Chemoresistance and targeted therapies in ovarian and endometrial cancers

Oncotarget

Promising SINEs for embargoing nuclear-cytoplasmic export as an anticancer strategy

Cancer Discov.

Nucleo-cytoplasmic transport as a therapeutic target of cancer

J. Hematol. Oncol.

Selective inhibitors of nuclear export (SINE)--a novel class of anti-cancer agents

J. Hematol. Oncol.

The eukaryotic translation initiation factor 4E (eIF4E) and HuR RNA operons collaboratively regulate the expression of survival and proliferative genes

Cell Cycle

The eukaryotic translation initiation factor eIF4E in the nucleus: taking the road less traveled

Immunol. Rev.