Decitabine + Selinexor for Ovarian Cancer

Overseen By Patrick Stiff, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Loyola University

Must not be taking: XPO1 inhibitors, Anticoagulants

Disqualifiers: Uncontrolled hypertension, Uncontrolled diabetes, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial tests a combination of four drugs to treat patients whose ovarian, fallopian tube, or primary peritoneal cancer has returned. The treatment aims to kill cancer cells and prevent them from becoming resistant. The drugs are administered in a specific sequence to maximize effectiveness.

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.

What data supports the effectiveness of the drug combination Decitabine + Selinexor for ovarian cancer?

Research shows that carboplatin and paclitaxel, which are part of the treatment, are standard and effective drugs for ovarian cancer, often used together due to their effectiveness and fewer side effects. Additionally, paclitaxel is known to be highly active in patients with platinum-resistant ovarian cancer, suggesting potential benefits when combined with other agents like Decitabine and Selinexor. ^{1 2 3 4 5}

Is the combination of Decitabine and Selinexor safe for treating ovarian cancer?

The combination of Decitabine and Selinexor has been studied in mice for ovarian cancer, but specific human safety data for this combination is not provided in the available research. However, a related study on Guadecitabine (a similar agent to Decitabine) and Carboplatin in humans showed that the treatment was generally tolerated, with some patients experiencing side effects like low blood cell counts, nausea, and vomiting. ^{1 5 6 7 8}

What makes the drug combination of Decitabine and Selinexor unique for treating ovarian cancer?

This drug combination is unique because Selinexor, a selective inhibitor of nuclear export, works by trapping tumor-suppressor proteins inside the cell nucleus, enhancing the effectiveness of chemotherapy drugs like Carboplatin and Paclitaxel. This approach is novel as it targets the cancer cells' ability to export proteins that regulate cell growth and death, potentially improving treatment outcomes for ovarian cancer. ^{9 10 11 12 13}

Research Team

Patrick Stiff, MD

Principal Investigator

Loyola University

Eligibility Criteria

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 am 18 years old or older.

I can swallow and keep down pills.

My liver is functioning 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.

Trial Timeline

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

Treatment Details

Interventions

• Carboplatin (Alkylating agents)
• Decitabine (Anti-metabolites)
• Paclitaxel (Anti-tumor antibiotic)
• Selinexor (Other)

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.

Participant Groups

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 Canada for the following indications:

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

Findings from Research

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]

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]

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 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]

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]

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 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]

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]

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]

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]

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]

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 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]

References

1. United States 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. [2018]

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

Treatment of ovarian cancer: current status. [2015]

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

The histone deacetylase inhibitor panobinostat demonstrates marked synergy with conventional chemotherapeutic agents in human ovarian cancer cell lines. [2021]

4. Netherlands pubmed.ncbi.nlm.nih.gov

[Cytostatic treatment of ovarian carcinoma]. [2015]

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

Carboplatin-paclitaxel- and carboplatin-docetaxel-induced cytotoxic effect in epithelial ovarian carcinoma in vitro. [2019]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Selinexor in Combination with Decitabine Attenuates Ovarian Cancer in Mice. [2023]

7. United States 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. [2021]

8. England 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. [2018]

9. 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]

10. United States 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. [2023]

11. United States 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. [2022]

12. 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]

13. England 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. [2023]