Eltanexor + Inqovi for Myelodysplastic Syndrome

Overseen By Alain Mina, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Myeloid growth factors

Disqualifiers: Thrombocytopenia, Neutropenia, Cardiac conditions, others

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

Compensation: Varies

Number of Visits: 2

Duration: 6 cycles (approximately 6 months)

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment approach for individuals with myelodysplastic syndromes (MDS), diseases that disrupt blood cell production in the bone marrow and can lead to leukemia. The study examines the effectiveness of a drug called KPT-8602 (Eltanexor) when combined with Inqovi, a medication already used for MDS. Participants will take these drugs in cycles at home and visit the clinic regularly for check-ups. The trial seeks individuals with high-risk MDS that hasn't responded to previous treatments. As a Phase 1, Phase 2 trial, the research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking research.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, any prior therapy must be completed more than 4 weeks before starting the trial, except for Inqovi. Please consult with the trial team for specific guidance.

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

Research has shown that Eltanexor (KPT-8602) and Inqovi have promising safety results from earlier studies. Eltanexor, when used alone, has proven to be safe, generally well-tolerated, and may extend patient survival.

Inqovi, a combination of decitabine and cedazuridine, has undergone safety studies for treating myelodysplastic syndromes. A common serious side effect is low blood cell counts, which can weaken the body's ability to fight infections and requires careful monitoring. However, such side effects are typical in treatments for similar conditions and are closely monitored in clinical settings.

Overall, early findings suggest that patients tolerate the combination of Eltanexor and Inqovi. Like any treatment, it can cause side effects, but clinical trial participants will be closely monitored to manage these effects and ensure safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Eltanexor combined with Inqovi for treating Myelodysplastic Syndrome (MDS) because it offers a fresh approach compared to traditional therapies like hypomethylating agents. Eltanexor, also known as KPT-8602, is a selective inhibitor of nuclear export, which means it works by blocking certain proteins from leaving the cell nucleus, potentially disrupting cancer cell survival. In combination with Inqovi, which is already used to treat MDS, this treatment aims to enhance the anti-cancer effects. Unlike most existing treatments that may take weeks to show results, this combination has the potential to work faster by targeting cancer cells more precisely and effectively. Researchers are hopeful that this dual-action strategy will improve outcomes for patients with high-risk MDS.

What evidence suggests that this trial's treatments could be effective for myelodysplastic syndrome?

This trial will evaluate the combination of Eltanexor (KPT-8602) and Inqovi for higher-risk Myelodysplastic Syndrome (MDS). Research has shown that Eltanexor may help treat higher-risk MDS. In studies, patients with MDS that returned or didn't respond to treatment lived an average of 8.7 months after taking Eltanexor, which is significant given the typically low survival rates in these cases. Early results suggest that Eltanexor works and is generally well-tolerated.

For Inqovi, studies have shown it to be effective in treating MDS, with about 70% of patients experiencing some improvement, including complete or partial recovery and healthier bone marrow. The average survival time for patients using Inqovi was reported to be 31.7 months, indicating its potential benefit in managing MDS. Participants in this trial will receive Inqovi followed by Eltanexor, with the trial exploring different dosing strategies. ^{2 6 7 8 9}

Who Is on the Research Team?

Alain Mina, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

Adults over 18 with high-risk Myelodysplastic Syndromes (MDS) that didn't improve after treatment can join. They need to be fairly active, have good organ function, and not pregnant or breastfeeding. Participants must agree to use birth control and have no recent growth factor treatments or uncontrolled illnesses.

Inclusion Criteria

I have high-risk MDS and my previous treatment with HMA didn't work well.

- AST(SGOT)/ALT(SGPT) <= 3 X institutional upper limit of normal OR <= 5 X institutional upper limit of normal if related to MDS-specific cause

My organs and bone marrow work well.

Exclusion Criteria

I have not had any other cancer in the last 2 years.

I have active or uncontrolled Hepatitis C.

My low platelet count does not improve with transfusions.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive KPT-8602 and Inqovi in 28-day cycles, with Inqovi taken daily on days 1-5 and KPT-8602 on a schedule assigned by the researcher

6 cycles (approximately 6 months)

At least 1 visit per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

8 years

Follow-up visits at the clinic

Extension

Participants may continue taking the drugs if their disease improves after 6 cycles

What Are the Treatments Tested in This Trial?

Interventions

• Inqovi
• KPT-8602

Trial Overview The trial is testing Eltanexor (KPT-8602) combined with Inqovi (Decitabine-Cedazuridine), both oral tablets for MDS. Over at least six 28-day cycles, participants take these drugs at home and visit the clinic regularly for exams and tests like blood work and bone marrow biopsies.

How Is the Trial Designed?

Group I: Phase II- Dose expansion for HR-MDS Experimental Treatment 2 Interventions

Inqovi for 5 days, followed by RP2D/Phase II dose of KPT-8602

Group II: Phase I- Dose escalation of KPT-8602 for HR-MDS Experimental Treatment 2 Interventions

Inqovi for 5 days, followed by escalating doses of KPT-8602

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

Approved in United States as Inqovi for:

• Myelodysplastic syndromes (MDS)

Approved in European Union as Inqovi for:

• Myelodysplastic syndromes (MDS)

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a phase 1/2 clinical trial involving 20 patients with higher-risk myelodysplastic syndromes (MDS) who were refractory to hypomethylating agents, the investigational drug eltanexor demonstrated a 53.3% overall response rate, with 46.7% of patients achieving complete remission.

Eltanexor was found to be safe and well tolerated, with the most common side effects being nausea, diarrhea, and fatigue, while the median overall survival for patients evaluated for efficacy was approximately 9.86 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral eltanexor treatment of patients with higher-risk myelodysplastic syndrome refractory to hypomethylating agents. Lee, S., Mohan, S., Knupp, J., et al.[2022]

In a study of 99 patients with myelodysplastic syndromes (MDS), decitabine administered at a higher dose of 20 mg/m² daily for 5 days every 4 weeks resulted in a 32% overall response rate, indicating significant efficacy in treating MDS.

The outpatient regimen of decitabine not only provided comparable efficacy to the FDA-approved inpatient schedule but also allowed for more than half of the patients to show clinical improvement, suggesting a safe and effective alternative treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter study of decitabine administered daily for 5 days every 4 weeks to adults with myelodysplastic syndromes: the alternative dosing for outpatient treatment (ADOPT) trial. Steensma, DP., Baer, MR., Slack, JL., et al.[2023]

Inqovi, a combination of decitabine and cedazuridine, was approved by the FDA for treating myelodysplastic syndromes (MDS) based on a phase III study involving 133 adults, showing similar effectiveness to intravenous decitabine.

The treatment demonstrated a complete remission rate of 21% in one study and 18% in another, with a median duration of remission lasting around 7.5 to 8.7 months, while adverse reactions were consistent with those seen in IV decitabine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Decitabine and Cedazuridine Tablets for Myelodysplastic Syndromes. Kim, N., Norsworthy, KJ., Subramaniam, S., et al.[2023]

The fixed-dose oral combination of decitabine and cedazuridine (Inqovi®) has been approved for treating myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML), enhancing the oral bioavailability of decitabine through the inhibition of cytidine deaminase by cedazuridine.

Decitabine is already an established treatment for MDS and CMML, and the combination therapy has shown promise in ongoing clinical studies for other cancers like acute myeloid leukaemia (AML), glioma, and solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine/Cedazuridine: First Approval. Dhillon, S.[2021]

Luspatercept has shown significant efficacy in treating low-risk myelodysplastic syndromes (MDS), with 63% of patients experiencing hematological improvement and 38% achieving transfusion independence in clinical trials.

Oral decitabine combined with oral cedazuridine has demonstrated pharmacological equivalence to intravenous decitabine, achieving overall response rates of 60% and 43% in phase 2 and 3 trials for high-risk MDS, respectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[New treatment for myelodysplastic syndromes: luspatercept and oral hypomethylating agents]. Usuki, K.[2022]

A new oral drug combination, DEC-cedazuridine (C-DEC), has been developed to provide a more convenient treatment option for patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML), which traditionally required lengthy parenteral therapies.

C-DEC has been approved by major health authorities, including the US FDA, for patients with newly diagnosed or previously treated intermediate or high-risk MDS and CMML, indicating its safety and potential efficacy in managing these complex disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of cedazuridine/decitabine in the management of myelodysplastic syndrome and chronic myelomonocytic leukemia. Thota, S., Oganesian, A., Azab, M., et al.[2021]

The phase 2 study found that oral cedazuridine/decitabine (100 mg/35 mg) provided similar systemic exposure and DNA demethylation compared to standard IV decitabine (20 mg/m2) in patients with myelodysplastic syndromes or chronic myelomonocytic leukemia, indicating comparable efficacy.

Clinical responses were observed in 60% of patients, with 21% achieving a complete response, while the most common serious side effects included neutropenia (46%) and thrombocytopenia (38%), highlighting the treatment's safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. Garcia-Manero, G., Griffiths, EA., Steensma, DP., et al.[2021]

Citations

1. ashpublications.org ashpublications.org/blood/article/134/Supplement_1/2997/423507/Eltanexor-KPT-8602-a-Second-Generation-Selective

Eltanexor (KPT-8602), a Second-Generation Selective ... Eltanexor (KPT-8602), a Second-Generation Selective Inhibitor of Nuclear Export (SINE) Compound, in Patients with Higher-Risk Myelodysplastic Syndrome

2. clinicaltrials.gov clinicaltrials.gov/study/NCT02649790

NCT02649790 | Study of the Safety, Tolerability and ... Life expectancy of ≥ 4 months. RR High-risk Myelodysplastic Syndrome (Part F Phase 2):. Documented diagnosis of MDS with 5% to 19% myeloblasts in the bone ...

3. investors.karyopharm.com investors.karyopharm.com/2023-05-03-Karyopharm-Announces-Presentation-of-Interim-Data-from-Phase-2-Study-of-Single-Agent-Eltanexor-in-Relapsed-Refractory-R-R-Higher-Risk-Myelodysplastic-Neoplasms-MDS-at-17th-International-Congress-on-MDS

May 3, 2023 Relapsed/Refractory MDS Patients Achieved Median Overall Survival of 8.7 months –. – Historically, Median Overall Survival in this Hard to ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35922861/

Oral eltanexor treatment of patients with higher-risk ... Single-agent oral eltanexor was active, safe, and well tolerated in patients with higher-risk, primary HMA-refractory MDS.

5. jhoonline.biomedcentral.com jhoonline.biomedcentral.com/articles/10.1186/s13045-022-01319-y

Oral eltanexor treatment of patients with higher-risk ... Single-agent oral eltanexor was active, safe, and well tolerated in patients with higher-risk, primary HMA-refractory MDS.

6. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-05256

Eltanexor (KPT-8602) With Inqovi (Decitabine- ... People with high-risk MDS have a low survival rate. Better treatments are needed. Objective: To test a study drug (KPT-8602), combined with another drug (Inqovi) ...

7. clin.larvol.com clin.larvol.com/trial-detail/NCT05918055

Eltanexor (KPT-8602) With Inqovi (Decitabine- ... Phase 2: To further evaluate the PK properties and safety of KPT-8602 in combination with Inqovi in MDS participants, The grades and types of toxicity noted ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12411709/

Novel small-molecule therapies for myelodysplastic ... Therefore, eltanexor demonstrates encouraging efficacy as a promising single agent with a positive safety record and survival benefit, ...

9. withpower.com withpower.com/trial/phase-2-preleukemia-6-2023-14fa5

Eltanexor + Inqovi for Myelodysplastic Syndrome Inqovi, a combination of decitabine and cedazuridine, has been studied for safety in treating myelodysplastic syndromes. Common serious side effects include low ...