Selinexor Maintenance Therapy for Endometrial Cancer

(XPORT-EC-042 Trial)

Recruiting at 202 trial locations

Overseen By Bhavana Pothuri

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Karyopharm Therapeutics Inc

Must not be taking: Systemic steroids

Disqualifiers: Uterine sarcomas, Active infection, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 28-day cycles, up to 34 months

220 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to evaluate the efficacy and safety of selinexor as a maintenance treatment in patients with p53 wt endometrial carcinoma (EC), who have achieved a partial response (PR) or complete response (CR) (per Response Evaluation Criteria in Solid Tumors version 1.1 \[RECIST v 1.1\]) after completing at least 12 weeks of platinum-based therapy. A total of 220 participants will be enrolled in the study and randomized in a 1:1 ratio to maintenance therapy with either selinexor or placebo.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, it mentions that participants should not have received any systemic anticancer therapy within 3 weeks before starting the trial. It's best to discuss your current medications with the trial team to get specific guidance.

What data supports the effectiveness of the drug Selinexor for endometrial cancer?

Research shows that Selinexor, when used as a maintenance therapy, significantly extends the time patients with advanced or recurrent endometrial cancer live without the disease getting worse, especially in those with a specific type of genetic makeup (TP53 wild-type). ^{1 2 3 4 5}

Is Selinexor safe for human use?

The safety of Selinexor, also known as Xpovio or KPT-330, has been evaluated in various clinical trials for different conditions. While specific safety data for endometrial cancer is not detailed in the provided research, Selinexor has been studied in humans, suggesting it has undergone safety assessments in clinical settings. ^{1 2 3 4 6}

How is the drug selinexor unique for treating endometrial cancer?

Selinexor is unique because it is an oral drug that works by inhibiting a protein called Exportin 1 (XPO1), which leads to the accumulation of tumor suppressor proteins in the cell nucleus, helping to fight cancer. This mechanism is different from traditional chemotherapy and shows promise as a maintenance therapy after initial treatment, especially in certain genetic subtypes of endometrial cancer. ^{2 7 8 9 10}

Eligibility Criteria

This trial is for adults with advanced or recurrent endometrial carcinoma that's p53 wild-type. They must have responded to platinum-based therapy and be able to start the study drug within 3-8 weeks after chemotherapy. Participants need good organ function, an ECOG status of 0-1, and a life expectancy over 12 weeks. Women who can bear children must test negative for pregnancy and agree to use contraception.

Inclusion Criteria

I can start the study drug 3-8 weeks after my last chemotherapy dose.

I am 18 years old or older.

My recent tests show my organs and bone marrow are working well.

Exclusion Criteria

I am taking higher than normal doses of steroids.

I do not have stomach or bowel problems affecting medicine absorption.

I have received palliative radiotherapy within the last 14 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive selinexor or placebo as maintenance therapy after achieving a response from platinum-based therapy

28-day cycles, up to 34 months

Weekly visits for dosing on Days 1, 8, 15, and 22 of each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Selinexor

Trial Overview The trial tests Selinexor as maintenance therapy against a placebo in patients who've had partial or complete response to previous treatment. It aims to see if Selinexor helps keep cancer from coming back or getting worse after initial success with chemotherapy.

Participant Groups

Group I: Selinexor Experimental Treatment 1 Intervention

Participants will receive a fixed dose of selinexor 60 milligrams (mg) oral tablets once weekly (QW) on Days 1, 8, 15, and 22 of each 28-day cycle.

Group II: Placebo Placebo Group 1 Intervention

Participants will receive matching placebo for selinexor oral tablets QW on Days 1, 8, 15, and 22 of each 28-day cycle.

Who Is Running the Clinical Trial?

Karyopharm Therapeutics Inc

Lead Sponsor

Trials

89

Recruited

7,200+

Richard Paulson

Karyopharm Therapeutics Inc

Chief Executive Officer since 2021

MBA from the University of Toronto's Rotman School of Management

Reshma Rangwala

Karyopharm Therapeutics Inc

Chief Medical Officer since 2023

MD, PhD

European Network of Gynaecological Oncological Trial Groups (ENGOT)

Collaborator

Trials

41

Recruited

19,200+

Israeli Society of Gynecologic Oncology

Collaborator

Trials

4

Recruited

1,100+

Australia New Zealand Gynaecological Oncology Group

Collaborator

Trials

16

Recruited

5,800+

Belgian Gynaecological Oncology Group

Collaborator

Trials

15

Recruited

4,000+

GOG Foundation

Collaborator

Trials

48

Recruited

18,500+

North Eastern German Society of Gynaecological Oncology

Collaborator

Trials

25

Recruited

9,000+

The GOG Foundation, Inc.

Collaborator

Trials

2

Recruited

480+

European Network of Gynaecological Oncological Trial

Collaborator

Trials

1

Recruited

220+

Belgium and Luxembourg Gynaecological Oncology Group

Collaborator

Trials

2

Recruited

480+

Findings from Research

The SIENDO trial indicated that selinexor may offer clinical benefits for patients with advanced or recurrent endometrial cancer who have a TP53 wild-type status.

Despite advancements in personalized medicine, recurrent endometrial cancer remains a challenging condition, highlighting the ongoing need for new treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selinexor: Changing the paradigm in patients with TP53 wild-type endometrial cancer? Gouda, MA., Thein, KZ.[2023]

In a phase III study involving 263 patients with advanced or recurrent endometrial cancer, selinexor showed a median progression-free survival (PFS) of 5.7 months compared to 3.8 months for placebo, although this difference did not reach statistical significance in the overall analysis.

A prespecified exploratory analysis indicated that patients with TP53 wild-type endometrial cancer experienced a significant improvement in PFS with selinexor, showing a median of 13.7 months compared to 3.7 months for placebo, suggesting potential efficacy in this specific subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral Selinexor as Maintenance Therapy After First-Line Chemotherapy for Advanced or Recurrent Endometrial Cancer. Vergote, I., Pérez-Fidalgo, JA., Hamilton, EP., et al.[2023]

Progestins are effective for treating low-grade, hormone receptor-positive endometrial cancer, with some patients experiencing prolonged survival, while combination chemotherapy regimens using platinum compounds, anthracyclines, and taxanes have shown over 50% response rates and improved overall survival beyond one year in advanced cases.

Recent advances in understanding endometrial cancer at the molecular level have led to the development of new targeted therapies, which are being investigated alongside traditional treatments, although concerns about chemotherapy-related toxicities remain significant, especially in patients with existing health issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Developments in the systemic treatment of endometrial cancer. Mountzios, G., Pectasides, D., Bournakis, E., et al.[2018]

In a phase III trial, the XPO1 inhibitor selinexor provided a significant and lasting progression-free survival benefit for women with advanced or recurrent endometrial cancer that has a TP53 wild-type status.

This benefit was observed regardless of the microsatellite stability of the cancer, indicating that selinexor may be a broadly effective maintenance therapy for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selinexor Delays Wild-type TP53 Endometrial Cancer Progression. [2023]

Class 3 semaphorins (SEMA3B and SEMA3F) are significantly downregulated in endometrial cancer cells compared to normal tissues, indicating their potential role as tumor suppressors.

Treatment with progesterone and 1,25-dihydroxyvitamin D(3) can upregulate SEMA3B and SEMA3F, leading to inhibited cancer cell growth and reduced invasiveness, suggesting that restoring these proteins could be a promising therapeutic strategy for endometrial cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progesterone and 1,25-dihydroxyvitamin D₃ inhibit endometrial cancer cell growth by upregulating semaphorin 3B and semaphorin 3F. Nguyen, H., Ivanova, VS., Kavandi, L., et al.[2013]

Progesterone therapy shows overall response rates of 11% to 25% in well-differentiated endometrioid-type tumors, but its effectiveness can be limited by the down-regulation of progesterone receptors, suggesting a need for strategies to enhance receptor expression.

Chemotherapy combinations, particularly doxorubicin and cisplatin, yield response rates of 34% to 60%, with the addition of paclitaxel improving outcomes but increasing toxicity; ongoing studies are comparing this regimen to a less toxic alternative with carboplatin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Old and new perspectives in the pharmacological treatment of advanced or recurrent endometrial cancer: Hormonal therapy, chemotherapy and molecularly targeted therapies. Gadducci, A., Cosio, S., Genazzani, AR.[2007]

In a phase 2 trial involving 114 patients with heavily pretreated recurrent gynecological cancers, selinexor showed a disease control rate of 30%, indicating its potential effectiveness as a treatment option for ovarian and endometrial cancers.

Common side effects included thrombocytopenia and fatigue, but these were manageable and reversible, with lower-grade adverse events observed in patients receiving a once-weekly dosing schedule compared to twice-weekly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 study of the Exportin 1 inhibitor selinexor in patients with recurrent gynecological malignancies. Vergote, IB., Lund, B., Peen, U., et al.[2023]

Selinexor, an inhibitor of the exportin 1 (XPO1) receptor, showed significant cytotoxic activity against various solid tumors and acute lymphoblastic leukemia (ALL) xenografts in a study involving in vitro and in vivo testing, with 76% of solid tumor models and 63% of ALL models showing improved event-free survival.

The treatment resulted in objective responses in 4 out of 38 solid tumor xenografts and 25% of ALL xenografts, indicating its potential effectiveness, particularly in tumors with specific genetic mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacodynamic and genomic markers associated with response to the XPO1/CRM1 inhibitor selinexor (KPT-330): A report from the pediatric preclinical testing program. Attiyeh, EF., Maris, JM., Lock, R., et al.[2023]

Selinexor, an oral inhibitor of the nuclear export protein XPO1, shows promising antitumor activity in advanced endometrial cancer, particularly in patients with TP53 wild-type tumors, where it may reduce the risk of disease progression or death by approximately 60%.

The ongoing SIENDO and XPORT-EC trials aim to further evaluate the safety and efficacy of selinexor as a maintenance therapy after first-line chemotherapy, and preclinical studies suggest it may work well in combination with PARP inhibitors and immune checkpoint inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selinexor in patients with advanced and recurrent endometrial cancer. Bogani, G., Monk, BJ., Coleman, RL., et al.[2023]

The combination of selinexor and carboplatin/paclitaxel chemotherapy was found to be safe and well-tolerated in patients with advanced ovarian and endometrial cancers, with 12 patients achieving a partial response and 1 achieving a complete response.

Common treatment-related adverse events included thrombocytopenia (100%) and leukopenia (91%), indicating that while the treatment is effective, it does come with significant side effects that need to be monitored.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I open-label study of selinexor with paclitaxel and carboplatin in patients with advanced ovarian or endometrial cancers. Rubinstein, MM., Grisham, RN., Cadoo, K., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

Selinexor: Changing the paradigm in patients with TP53 wild-type endometrial cancer? [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Oral Selinexor as Maintenance Therapy After First-Line Chemotherapy for Advanced or Recurrent Endometrial Cancer. [2023]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Developments in the systemic treatment of endometrial cancer. [2018]

4. United States pubmed.ncbi.nlm.nih.gov

Selinexor Delays Wild-type TP53 Endometrial Cancer Progression. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Progesterone and 1,25-dihydroxyvitamin D₃ inhibit endometrial cancer cell growth by upregulating semaphorin 3B and semaphorin 3F. [2013]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Old and new perspectives in the pharmacological treatment of advanced or recurrent endometrial cancer: Hormonal therapy, chemotherapy and molecularly targeted therapies. [2007]

7. United States pubmed.ncbi.nlm.nih.gov

Phase 2 study of the Exportin 1 inhibitor selinexor in patients with recurrent gynecological malignancies. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Pharmacodynamic and genomic markers associated with response to the XPO1/CRM1 inhibitor selinexor (KPT-330): A report from the pediatric preclinical testing program. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Selinexor in patients with advanced and recurrent endometrial cancer. [2023]

10. United States pubmed.ncbi.nlm.nih.gov

A phase I open-label study of selinexor with paclitaxel and carboplatin in patients with advanced ovarian or endometrial cancers. [2023]