Decitabine + Selinexor for Ovarian Cancer

Overseen By Patrick Stiff, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Loyola University

Must not be taking: XPO1 inhibitors, Anticoagulants

Disqualifiers: Uncontrolled hypertension, Uncontrolled diabetes, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Compensation: Varies

Number of Visits: 9

Duration: 24 weeks

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment combination for individuals with ovarian, fallopian tube, or primary peritoneal cancer that has recurred or worsened after previous treatments. Researchers aim to assess the effectiveness and safety of a combination of four drugs: decitabine, selinexor, carboplatin, and paclitaxel. This trial may suit those previously treated with platinum and taxane drugs who still have measurable disease and stable health conditions. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that participants must not have had prior chemotherapy or radiation therapy, and certain medical conditions must be controlled. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that decitabine and selinexor have been tested together in mice for ovarian cancer, but specific safety information for humans using this combination is not yet available. Selinexor alone has proven safe and tolerable in humans with ovarian and other cancers. Decitabine has also been tested with other drugs for ovarian cancer, but safety data for this specific combination in humans remains limited.

Both decitabine and selinexor have FDA approval for other uses, indicating known safety records in humans. However, using them together for ovarian cancer remains experimental and is still under study. Participants should consider this when deciding whether to join the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment for ovarian cancer because it combines decitabine and selinexor with traditional chemotherapy agents carboplatin and paclitaxel, leveraging unique mechanisms to potentially boost effectiveness. Decitabine is known for its ability to modify how genes are expressed in cancer cells, potentially making them more sensitive to chemotherapy. Selinexor, on the other hand, works by blocking a protein involved in exporting tumor suppressor proteins out of the cell nucleus, which can lead to cancer cell death. This combination aims to enhance the impact of standard chemotherapy, offering new hope for improved outcomes in ovarian cancer treatment.

What evidence suggests that this trial's treatments could be effective for ovarian cancer?

Research shows that combining decitabine and selinexor might help treat ovarian cancer. Studies in mice have found that these drugs can significantly shrink tumors and reduce fluid buildup in the abdomen. In this trial, participants will receive a combination of decitabine, selinexor, carboplatin, and paclitaxel. This combination aims to stop or reverse drug resistance, potentially enhancing the effectiveness of standard ovarian cancer treatments. Although the FDA has approved decitabine and selinexor for other uses, they are still under study for ovarian cancer. Early results are promising and suggest that these drugs might help patients stay in remission longer when used with standard chemotherapy. ^{1 2 6 7 8}

Who Is on the Research Team?

Patrick Stiff, MD

Principal Investigator

Loyola University

Are You a Good Fit for This Trial?

This trial is for adults with relapsed ovarian, fallopian tube, or primary peritoneal carcinoma who can take oral meds and have measurable disease. They must have had platinum and taxane treatments before but now show disease progression. Stable CNS metastases treated by radiotherapy are okay; active Hep B is allowed if on antivirals for 8+ weeks.

Inclusion Criteria

I can swallow and keep down pills.

My liver is functioning well.

My kidneys are working well.

Exclusion Criteria

I am not allergic or sensitive to platinum or taxane treatments.

I have never taken Selinexor or similar medications.

I do not need ongoing blood thinners for a clot related to my cancer.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive decitabine followed by carboplatin and paclitaxel for one cycle. Selinexor is added from the second cycle onwards, with treatment cycles lasting 28 days each.

24 weeks

9 visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Carboplatin
• Decitabine
• Paclitaxel
• Selinexor

Trial Overview The study tests a four-drug combo (decitabine, selinexor, carboplatin, paclitaxel) to see if it can prevent drug resistance in ovarian cancer chemotherapy. Decitabine and selinexor may help extend remission when combined with standard chemo drugs carboplatin and paclitaxel.

How Is the Trial Designed?

Group I: Decitabine / Selinexor/ Carboplatin / Paclitaxel Experimental Treatment 4 Interventions

C1: Days 1-5: Decitabine 10 mg/m2 IV daily Day 6: carboplatin AUC 5 and paclitaxel 80 mg/ m2 Days 13, 20, and 27: paclitaxel 80 mg/m2 For a single 28 day cycle Assess Response toxicities and immune effector cell changes C2-C6: Days 1-5: Decitabine 10 mg/m2 IV daily Day 6: carboplatin AUC 5 and paclitaxel 80 mg/ m2 Day 7 and weekly thereafter (day 14, 21, 28, 35…) Selinexor 60 mg PO Days 13, 20, and 27: paclitaxel 80 mg/m2 each given x five 28 day cycles Assess responses by exam, CT scan and blood tests, assess toxicities, and immune effector cell changes as well as progression and overall survival

Carboplatin is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Paraplatin for:

• Ovarian cancer
• Testicular cancer
• Lung cancer
• Head and neck cancer
• Brain cancer

Approved in European Union as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer

Approved in Canada as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer
• Testicular cancer

Who Is Running the Clinical Trial?

Loyola University

Lead Sponsor

Trials

161

Recruited

31,400+

Karyopharm Therapeutics Inc

Industry 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

Published Research Related to This Trial

In a phase 1b study involving 14 patients with advanced solid tumors, the combination of selinexor and intravenous topotecan showed preliminary efficacy, with one patient achieving an unconfirmed partial response and 46% of patients experiencing stable disease.

While the treatment was viable, it was associated with a high rate of treatment-related adverse events (86%), including significant issues like anemia and neutropenia, indicating the need for careful monitoring and management of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selinexor in combination with topotecan in patients with advanced or metastatic solid tumors: Results of an open-label, single-center, multi-arm phase Ib study. Thein, KZ., Piha-Paul, SA., Tsimberidou, A., et al.[2023]

Cytoreductive surgery followed by platinum-based chemotherapy, particularly with carboplatin, remains the standard treatment for advanced epithelial ovarian cancer, but most patients are not cured, highlighting the need for improved therapies.

Paclitaxel, a novel agent effective in platinum-resistant ovarian cancer, is being tested in combination with platinum compounds in clinical trials for previously untreated patients, aiming to enhance treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of ovarian cancer: current status. Ozols, RF.[2015]

The combination of carboplatin and paclitaxel is preferred over cisplatin and paclitaxel for treating epithelial ovarian carcinoma due to its lower side effects and suitability for outpatient use.

Current research is exploring new treatment options, including extracellular matrix breakdown inhibitors like marimastat and signal transduction inhibitors like trastuzumab, which may enhance the effectiveness of ovarian cancer therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Cytostatic treatment of ovarian carcinoma]. Neijt, JP.[2015]

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]

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]

The combination of decitabine and selinexor significantly reduced tumor size and ascites formation in murine models of high-grade serous ovarian cancer, suggesting enhanced efficacy compared to either treatment alone.

This combination therapy also improved T cell effector function and increased the release of various cytokines and chemokines, indicating a stronger anti-tumor immune response, which could lead to better treatment outcomes in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selinexor in Combination with Decitabine Attenuates Ovarian Cancer in Mice. Stiff, PJ., Mehrotra, S., Potkul, RK., et al.[2023]

In a phase Ib study involving 13 patients with advanced solid tumors, the combination of selinexor and carboplatin/paclitaxel showed some clinical activity, with 3 patients achieving unconfirmed partial responses and 5 patients having stable disease.

The most common treatment-related adverse events were severe blood-related issues, such as neutropenia and leukopenia, affecting 85% of patients, indicating that while the combination therapy has potential, it also carries significant risks that need to be managed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selinexor in combination with carboplatin and paclitaxel in patients with advanced solid tumors: Results of a single-center, multi-arm phase Ib study. Thein, KZ., Karp, DD., Tsimberidou, A., et al.[2022]

In a phase 2 trial involving 40 patients with recurrent ovarian cancer, the modified docetaxel/carboplatin regimen resulted in a significantly higher overall response rate of 80% compared to 30% for the traditional paclitaxel/carboplatin regimen.

Patients receiving the docetaxel/carboplatin treatment also had a superior 2-year survival rate of 75%, while the control group had only 35%, with no significant differences in toxicity between the two treatment groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High Efficacy and Low Toxicity of the Modified Docetaxel and Carboplatin Protocol in Patients with Recurrent Ovarian Cancer-A Phase 2 Cohort Study. Bruchim, I., Weeg, N., Alpert, Y., et al.[2018]

Panobinostat, a histone deacetylase inhibitor, shows significant synergy with gemcitabine and paclitaxel, and particularly strong synergistic effects when combined with doxorubicin and carboplatin in treating metastatic ovarian cancer cell lines.

The study utilized in vitro assays on three ovarian cancer cell lines (SK-OV3, CaOV-3, and ES-2) to identify effective drug combinations, suggesting that these combinations could enhance treatment efficacy and warrant further clinical investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The histone deacetylase inhibitor panobinostat demonstrates marked synergy with conventional chemotherapeutic agents in human ovarian cancer cell lines. Budman, DR., Tai, J., Calabro, A., et al.[2021]

The combination of carboplatin and docetaxel shows high efficacy in treating advanced ovarian cancer, with an 81% objective response rate among assessable patients in a phase II trial involving 50 participants.

While the treatment is associated with significant toxicity, particularly grade 4 neutropenia in 64% of patients, hypersensitivity reactions were common but manageable, allowing most patients to continue therapy without interruption.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination chemotherapy with carboplatin and docetaxel in the treatment of cancers of the ovary and fallopian tube and primary carcinoma of the peritoneum. Markman, M., Kennedy, A., Webster, K., et al.[2018]

In a phase I study involving 20 patients with recurrent, platinum-resistant ovarian cancer, the combination of guadecitabine and carboplatin was tolerated, with no dose-limiting toxicities observed after dose adjustments, indicating a manageable safety profile.

The treatment resulted in a partial response in 3 patients and stable disease in 6 patients for over 3 months, leading to an overall response rate of 15% and a clinical benefit rate of 45%, suggesting potential efficacy in this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase I Clinical Trial of Guadecitabine and Carboplatin in Platinum-Resistant, Recurrent Ovarian Cancer: Clinical, Pharmacokinetic, and Pharmacodynamic Analyses. Matei, D., Ghamande, S., Roman, L., et al.[2021]

Selinexor, an XPO1/CRM1 inhibitor, shows strong anti-cancer effects in ovarian carcinoma cells and enhances the sensitivity of these cells to cisplatin, particularly in cisplatin-sensitive cell lines like IGROV-1.

The study found that enriching the nuclear localization of FoxO-1 using selinexor is crucial for increasing the effectiveness of cisplatin, suggesting that treatment strategies should consider the molecular characteristics of tumors for optimal outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FoxO-1 contributes to the efficacy of the combination of the XPO1 inhibitor selinexor and cisplatin in ovarian carcinoma preclinical models. Corno, C., Stucchi, S., De Cesare, M., et al.[2023]

In a study comparing carboplatin combined with either paclitaxel or docetaxel in four ovarian carcinoma cell lines, both combinations showed a synergistic effect, enhancing the growth inhibitory impact on cancer cells.

The combination of carboplatin with paclitaxel produced a broader range of supra-additive effects across various concentrations compared to the carboplatin-docetaxel combination, suggesting that paclitaxel may be more effective in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin-paclitaxel- and carboplatin-docetaxel-induced cytotoxic effect in epithelial ovarian carcinoma in vitro. Engblom, P., Rantanen, V., Kulmala, J., et al.[2019]

Citations

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Decitabine + Selinexor for Ovarian Cancer The combination of carboplatin and docetaxel shows high efficacy in treating advanced ovarian cancer, with an 81% objective response rate among assessable ...

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The safety, efficacy, and treatment outcomes of a combination ... This trial tested the safety, efficacy, and treatment outcomes of decitabine-based chemotherapy or combined with immunotherapy in recurrent ovarian cancer ...

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Phase 2 study of the Exportin 1 inhibitor selinexor in ... Selinexor, an oral XPO1 inhibitor, demonstrated single-agent activity in ovarian, endometrial, and cervical cancers. •. Selinexor was safe and tolerable; side ...