Xpovio (selinexor)

P2, N=50, Not yet recruiting, Navy General Hospital, Beijing

P1, N=42, Recruiting, St. Jude Children's Research Hospital | Trial completion date: Jul 2025 --> Jun 2027

This study investigates the potential of repurposing selinexor, an FDA-approved XPO1 inhibitor, as a novel therapeutic options for TNBC... XPO1 inhibitors show promise as targeted therapies for TNBC patients. New mechanistic insight into the causes leading to TNBC sensitivity to XPO1-inhibition-mediated cell death warrant further clinical trials to evaluate the safety and efficacy in TNBC.

Using complementary genetically engineered mouse (GEM) models, we demonstrated that TP53 and/or PTEN deficient TCL, and LAM within their TME, are sensitive to the selective XPO1 antagonist selinexor...We identified a novel role for eIF4E/XPO1 in exporting GATA-3 and GATA-3-dependent transcripts from the nucleus in TCL, and in the export of therapeutically relevant transcripts, including CSF-1R, from LAM. Therefore, XPO1 antagonism, by impairing oncogenic transcriptional programs in TCL and depleting LAM from their TME, is a novel approach to target two independent dependencies in a group of therapeutically challenging TCL.

Selinexor plus docetaxel was relatively well tolerated in patients with advanced KRAS mutant NSCLC. The regimen has promising efficacy in TP53 wild type cases, where selinexor monotherapy may also have activity.

P1, N=16, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Dec 2024 --> Jun 2025

P1, N=100, Recruiting, University of Chicago | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Jul 2024 --> Jul 2025

Simultaneously, the intracellular localization of FOXO3 can be monitored by a second cell line stably expressing GFP-FOXO3. Here we describe a detailed protocol on how to co-culture these reporter cell lines and use them to interrogate compound-induced FOXO3 activation in order to understand the mode of action.

P1, N=59, Active, not recruiting, Children's Oncology Group | Trial completion date: Sep 2024 --> Sep 2025

We selected 108 CLL patient samples with genetic annotation and exposed them ex-vivo to small-molecule inhibitors used clinically (ibrutinib/BTKi, duvelisib/PI3Ki, trametinib/MEKi, everolimus/mTORi, selinexor/XPO1i) or targeting key signaling pathways (compound 26/TLRi, MK2206/AKTi, nutlin-3a/MDM2i, IBET872/BETi) for 48h. In conclusion, the addition of targeted pathway perturbations to the GEP of primary CLL samples can greatly enhance the potential for molecular and functional classification of disease and subgroups. Our study provides a blueprint to use perturbed omics profiling and interaction testing to link disease drivers to pathway activation and function.

Key findings highlight the effectiveness of selinexor in preclinical studies, particularly against KRAS-mutant NSCLC and in combination with chemotherapy for SCLC. The review concludes with a discussion of future directions and underscores the potential of selinexor to improve the treatment strategies for lung cancer.

P1, N=78, Completed, Sanjay Mohan | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Sep 2024

P3, N=222, Recruiting, Stichting European Myeloma Network | Active, not recruiting --> Recruiting | N=109 --> 222

The XPO1 inhibitor selinexor suppressed HOX activation and colony formation driven by the NPM1-fusions...Thus, our study provides experimental evidence that both NPM1::MLF1 and NPM1::CCDC28A are oncogenes with functions similar to NPM1c. Inhibition of XPO1 and menin may be a promising strategy for the NPM1-rearranged AML.

P2, N=82, Not yet recruiting, Ruijin Hospital

Selinexor/KPT-185 is an allosteric degrader. We have explained how drug-induced protein degradation is mediated by a CRL5 system through an allosteric rather than a molecular glue mechanism, expanding the modes of targeted protein degradation beyond the well-known molecular glues of CRL4.

P3, N=109, Active, not recruiting, Stichting European Myeloma Network | Recruiting --> Active, not recruiting | N=222 --> 109

P1, N=39, Recruiting, Mayo Clinic | Trial completion date: Dec 2025 --> Aug 2027

P2, N=52, Active, not recruiting, Academic and Community Cancer Research United | Recruiting --> Active, not recruiting

P3, N=126, Not yet recruiting, Institute of Hematology & Blood Diseases Hospital, China

P1, N=221, Terminated, M.D. Anderson Cancer Center | Trial completion date: Dec 2024 --> Sep 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Dec 2024 --> Sep 2024; Administratively Complete

P4, N=42, Not yet recruiting, Meishan City Peoples Hospital; Meishan City Peoples Hospital

P2, N=40, Recruiting, The First Affiliated Hospital with Nanjing Medical University; The First Affiliated Hospital with Nanjing

P1/2, N=300, Recruiting, Karyopharm Therapeutics Inc | Active, not recruiting --> Recruiting

Meanwhile, the latest clinical trials have confirmed that whether it is a single agent or combined with other chemotherapy regimens, selinexor can also achieve good therapeutic effects in patients with leukemia and lymphoma. This review summarizes the results of preclinical studies and clinical trials of selinexor in treatment of non-MM hematological malignancies, aiming to explore how to choose single agent or in combination with other regimens as induction chemotherapy.

P2, N=28, Not yet recruiting, Ruijin Hospital

P2, N=18, Not yet recruiting, Ruijin Hospital

P2, N=15, Terminated, Karyopharm Therapeutics Inc | N=40 --> 15 | Trial completion date: Jan 2024 --> Sep 2023 | Active, not recruiting --> Terminated; The trial was terminated due to a lack of sufficient anti-melanoma tumor signal for the combination of selinexor + pembrolizumab.

P3, N=402, Completed, Karyopharm Therapeutics Inc | Active, not recruiting --> Completed

P1/2, N=38, Recruiting, Second Affiliated Hospital, School of Medicine, Zhejiang University

P1/2, N=37, Recruiting, Samsung Medical Center

P2, N=18, Active, not recruiting, University of Colorado, Denver | Recruiting --> Active, not recruiting

P=N/A, N=120, Recruiting, Institute of Hematology & Blood Diseases Hospital, China | Not yet recruiting --> Recruiting

After a regimen of ruxolitinib, VICLP (Vincristine, Idarubicin, Cyclophosphamide, Prednisone, Peg-asparaginase) regimen, high-dose cytarabine, and methotrexate regimens, the patient's bone marrow condition partially resolved. However, when the disease relapsed four months later, despite attempts with selinexor, venetoclax, and CAG(aclarubicin hydrochloride, Algocytidine, Granulocyte Stimulating Factor) chemotherapy, the leukocytes and peripheral blood primitive cells reduced, but the bone marrow did not achieve remission. This pathogenesis may be related to microenvironmental immune escape under prolonged inflammatory stimulation and gene disruption affecting protein function due to colony-stimulating factor 3 receptor gene (CSF3R) mutations. For this type of disease, early intervention may delay disease progression.

These findings suggest that selinexor inhibits the progression of cholangiocarcinoma by targeting XPO1 and promoting the nuclear accumulation of PEG3 protein, thereby hindering the cell cycle and inducing apoptosis.

In conclusion, this study suggests that Dasatinib/Selinexor could be a promising therapeutic strategy for CML, providing new insights for new targeted therapies.

This review summarizes current data on treatment with SINE, TCR therapy, and CELMoDs and explores their mechanism of resistance. Understanding these resistance mechanisms is critical for developing strategies to overcome treatment failure and improve therapeutic outcomes.

P2, N=42, Recruiting, Sun Yat-sen University

P=N/A, N=100, Recruiting, iOMEDICO AG | Trial completion date: Sep 2025 --> Sep 2026 | Trial primary completion date: Sep 2025 --> Sep 2026

P1/2, N=97, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting

Many structurally diverse electrophilic small molecules target exportin-1 (XPO1/CRM1) at cysteine 528, including the selective inhibitor of nuclear export (SINE) selinexor, which was FDA-approved as an anticancer agent in 2019...We observe that the electrophilic moiety of Cys528-targeting small molecules plays a decisive role in the cellular behavior observed, with subtle changes in electrophile structure being sufficient to convert XPO1-targeting probes to different pharmacological classes. This investigation represents a unique case study in which the electrophile functionality used to target a specific cysteine determines the pharmacological effect among diverse XPO1-targeting small molecules.

Clinical trials of XPO1 inhibitors, selinexor and eltanexor, in high-risk myelodysplastic neoplasms (MDS) revealed responders were enriched with SF3B1 mutations. These targets were tested in vivo using Sf3b1K700E conditional knock-in mice, which showed that the combination of eltanexor and venetoclax (BCL2 inhibitor) had a preferential sensitivity for SF3B1 mutant cells without excessive toxicity. In this study, we unveil the mechanisms underlying sensitization to XPO1 inhibition in SF3B1-mutant MDS and preclinically rationalize the combination of eltanexor and venetoclax for high-risk MDS.