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

Vergote, Ignace; Lund, Bente; Havsteen, Hanne; Ujmajuridze, Zaza; Nieuwenhuysen, Els Van; Haslund, Charlotte Aaquist; Juhler-Nøttrup, Trine; Neven, Patrick; Mau-Sørensen, Morten; Berteloot, Patrick; Kranich, Anne L.; Rashal, Tami; Meade, Julie; Landesman, Yosef; Saint-Martin, Jean Richard; Wright, Garnett; Crochiere, Marsha; Shacham, Sharon; Kauffman, Michael; Mirza, Mansoor Raza

doi:10.1093/annonc/mdw374.01

Cited by 3 publications

(4 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Most adverse events in patients with solid tumors and hematologic malignancies were reversible grade 1 and 2, primarily nausea, anorexia, and fatigue. Among 106 patients evaluable for response, an overall disease control rate of 49% with some partial responses were observed in colorectal, melanoma, ovarian, and cervical cancer (58)(59)(60)(61). Preliminary results of an ongoing phase II clinical trial evaluating the activity of single-agent Selinexor in patients with heavily pretreated, progressive gynecologic cancers, showed promising antitumor activity across ovarian, endometrial, and cervical cancers.…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

“…Preliminary results of an ongoing phase II clinical trial evaluating the activity of single-agent Selinexor in patients with heavily pretreated, progressive gynecologic cancers, showed promising antitumor activity across ovarian, endometrial, and cervical cancers. The disease control rate was up to 52% (33 of 63 patients), with several patients remaining on study for up to 12 months (61). Durable responses and disease stabilization with single-agent Selinexor were also observed in hematologic malignancies across all disease subtypes, with some patients remaining on study for over 1 year (59,60).…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

See 1 more Smart Citation

Molecular Pathways: Anticancer Activity by Inhibition of Nucleocytoplasmic Shuttling

Conforti

Wang

Rodriguez

et al. 2015

Clinical Cancer Research

View full text Add to dashboard Cite

A dynamic distribution between nucleus and cytoplasm (nucleocytoplasmic shuttling) is one of the control mechanisms adapted by normal cells to regulate the activity of a variety of molecules. Growing evidence suggests that dysregulation of the nucleocytoplasmic shuttling is involved in promoting abnormal cell survival, tumor progression, and drug resistance, and is associated with poor cancer prognosis. Aberrant nucleocytoplasmic shuttling in cancer cells may result from a hyperactive status of diverse signal-transduction pathways, such as the PI3K-AKT and MAPK pathways, or from alterations in the general nuclear import/export machinery. Among the large number of molecules involved in the shuttling process, exportin XPO1, also known as chromosome region maintenance 1, appears to play a particularly prominent role in pathogenesis of both hematological malignancies and solid tumors. Given the importance of nucleocytoplasmic shuttling in cancer pathogenesis and the rapidly expanding knowledge in this field, attempts have been made to develop compounds able to revert the aberrant nucleocytoplasmic shuttling. A promising new drug, , which belongs to the class of XPO1 inhibitors called selective inhibitors of nuclear export, is now being tested in phase I/II clinical trials.

show abstract

Section: Clinical-translational Advancesmentioning

confidence: 99%

Section: Clinical-translational Advancesmentioning

confidence: 99%

Molecular Pathways: Anticancer Activity by Inhibition of Nucleocytoplasmic Shuttling

Conforti

Wang

Rodriguez

et al. 2015

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…Indeed, the overall frequency of weight loss and anorexia was higher in the current mCRPC study. Selinexor at doses of 50 mg/m 2 twice weekly, 35 mg/m 2 twice weekly, and 50 mg/m 2 weekly without break were also found to be relatively well tolerated in patients with advanced treatment‐refractory gynecological cancers .…”

mentioning

confidence: 98%

A Phase II Trial of Selinexor, an Oral Selective Inhibitor of Nuclear Export Compound, in Abiraterone- and/or Enzalutamide-Refractory Metastatic Castration-Resistant Prostate Cancer

et al. 2018

View full text Add to dashboard Cite

Lessons Learned. In abiraterone‐ and/or enzalutamide‐refractory metastatic castration‐resistant prostate cancer (mCRPC) patients, selinexor led to prostate‐specific antigen and/or radiographic responses in a subset of patients, indicating clinical activity in this indication.Despite twice‐a‐week dosing and maximal symptomatic management, selinexor was associated with significant anorexia, nausea, and fatigue in mCRPC patients refractory to second‐generation anti‐androgen therapies, limiting further clinical development in this patient population.This study highlights the challenge of primary endpoint selection for phase II studies in the post‐abiraterone and/or post‐enzalutamide mCRPC space.Background.Selinexor is a first‐in‐class selective inhibitor of nuclear export compound that specifically inhibits the nuclear export protein Exportin‐1 (XPO‐1), leading to nuclear accumulation of tumor suppressor proteins.Methods.This phase II study evaluated the efficacy and tolerability of selinexor in patients with metastatic castration‐resistant prostate cancer (mCRPC) refractory to abiraterone and/or enzalutamide.Results.Fourteen patients were enrolled. Selinexor was initially administered at 65 mg/m2 twice a week (days 1 and 3) and was subsequently reduced to 60 mg flat dose twice a week (days 1 and 3), 3 weeks on, 1 week off, to improve tolerability. The median treatment duration was 13 weeks. At a median follow‐up of 4 months, two patients (14%) had ≥50% prostate‐specific antigen (PSA) decline, and seven patients (50%) had any PSA decline. Of eight patients with measurable disease at baseline, two (25%) had a partial response and four (50%) had stable disease as their best radiographic response. Five patients (36%) experienced serious adverse events (SAEs; all unrelated to selinexor), and five patients (36%) experienced treatment‐related grade 3–4 AEs. The most common drug‐related adverse events (AEs) of any severity were anorexia, nausea, weight loss, fatigue, and thrombocytopenia. Three patients (21%) came off study for unacceptable tolerability.Conclusion.Selinexor demonstrated clinical activity and poor tolerability in mCRPC patients refractory to second‐line anti‐androgenic agents.

show abstract

“…Some recent trials of immuno-oncology therapies are promising. The addition of bevacizumab to carboplatin and paclitaxel improved PFS in a phase 2 trial for patients with advanced or recurrent endometrial cancer [14], and a phase 2 trial using selinexor to treat patients with gynecological cancers showed promising disease control [15]. Additional trials combining atezolizumab (NCT03603184) or dostarlimab (NCT03981796) with carboplatin and paclitaxel are underway.…”

Section: Introductionmentioning

confidence: 99%

Second-line lenvatinib in patients with recurrent endometrial cancer

Vergote

Powell

Teneriello

et al. 2020

Gynecologic Oncology

View full text Add to dashboard Cite

Objective. This study assessed the efficacy of lenvatinib, a multitargeted tyrosine kinase inhibitor, as secondline therapy in patients with unresectable endometrial cancer. The primary end point was the objective response rate (ORR) as assessed by independent radiologic review (IRR). Secondary end points included median progression-free survival (PFS), overall survival (OS), and clinical benefit rate. Exploratory end points examined the association of baseline levels of plasma biomarkers (50 circulating cytokine and/or angiogenic factors measured by immunoassays) with efficacy outcomes. Methods. An international, open-label, single-arm, multicenter, phase 2 trial was conducted. Eligible patients had histologically confirmed unresectable endometrial cancer that relapsed after 1 prior systemic platinumbased chemotherapy. Patients received once-daily oral lenvatinib 24 mg in a 28-day dosing cycle. Results. There were 133 patients in the study. By IRR, 19 patients had a confirmed objective response for an ORR of 14.3% (95% CI: 8.8-21.4). Durable stable disease (≥23 weeks) was observed in 31 patients (23.3%) and the clinical benefit rate was 37.6% (95% CI: 29.3-46.4). Median PFS was 5.6 months (95% CI: 3.7-6.3), and median OS was 10.6 months (95% CI: 8.9-14.9). The most common (any grade) treatment-related adverse events were fatigue/asthenia (48%), hypertension (49%), nausea/vomiting (32%), decreased appetite (32%), and diarrhea (31%). Lower baseline levels of angiopoietin-2 were associated with longer PFS, OS, and a higher ORR. Conclusions. Patients with recurrent endometrial cancer treated with second-line lenvatinib experienced modest antitumor activity and treatment was generally well tolerated, with a safety profile consistent with previous studies.

show abstract

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

Cited by 3 publications

References 0 publications

Molecular Pathways: Anticancer Activity by Inhibition of Nucleocytoplasmic Shuttling

Molecular Pathways: Anticancer Activity by Inhibition of Nucleocytoplasmic Shuttling

A Phase II Trial of Selinexor, an Oral Selective Inhibitor of Nuclear Export Compound, in Abiraterone- and/or Enzalutamide-Refractory Metastatic Castration-Resistant Prostate Cancer

Second-line lenvatinib in patients with recurrent endometrial cancer

Contact Info

Product

Resources

About