NCT05918055

Eltanexor (KPT-8602) With Inqovi (Decitabine-Cedazuridine) in High-Risk Myelodysplastic Syndromes

A Phase I/II Trial of Eltanexor (KPT-8602) With Inqovi (Decitabine-Cedazuridine) in High-Risk Myelodysplastic Syndromes

• Status: Terminated
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 3 (actual)
• Sponsor: National Cancer Institute (NCI) · NIH
• Sex: All
• Age: 18 Years – 120 Years
• Healthy volunteers: Not accepted

Summary

Background: Myelodysplastic syndromes (MDS) are diseases that affect the bone marrow. They can inhibit the blood formation process and reduce blood cell counts. High-risk MDS can lead to leukemia. People with high-risk MDS have a low survival rate. Better treatments are needed. Objective: To test a study drug Eltanexor (KPT-8602), combined with another drug (Inqovi), in people with MDS. Eligibility: Adults aged 18 years and older with high-risk MDS that did not respond to treatment. Design: Participants will be screened. They will have a physical exam. They will have blood and urine tests and tests of their heart function. They may have a bone marrow biopsy: Their hip will be numbed; then a needle will be inserted to draw out a sample of soft tissue from inside the bone. They will answer questions about their quality of life. Genetic tests may be performed. KPT-8602 and Inqovi are both tablets taken by mouth. Participants will take these drugs at home on a 28-day cycle. They will take Inqovi once a day on days 1 to 5. They will take KPT-8602 on a schedule assigned by the researcher. Participants will be given a drug diary to record each dose. Participants will visit the clinic for an exam at least once in each cycle. Some tests, including the bone marrow biopsy, may be repeated. Participants will continue treatment for at least 6 cycles. If their disease improves, they may continue taking the drugs after 6 cycles. Participants will have follow-up visits at the clinic for about 8 years.

Detailed description

Background: * The myelodysplastic syndromes (MDS) are a group of clonal bone marrow neoplasms characterized by ineffective hematopoiesis, cytopenia, and high risk of transformation to acute myeloid leukemia (AML). * The median survival of patients with newly diagnosed higher-risk MDS (HR-MDS) according to the Revised International Prognostic Scoring System (IPSS-R) is 1.5 years. * Hypomethylating agents (HMAs), such as azacitidine and decitabine, are the standard of care therapy for HR-MDS. However, less than half of patients respond to HMAs, and even the best responses are transient and non-curative. * The only curative treatment for patients with MDS is allogeneic hematopoietic stem cell transplantation (HSCT); however, only a small portion are eligible for transplant. * More effective therapies are needed for patients with HR-MDS. * A promising approach for improving HMA efficacy in the treatment of MDS is by exploiting therapeutic synergism in combinatorial approaches. * Inqovi (decitabine-cedazuridine) is an oral formulation of decitabine plus cytidine deaminase inhibitor that was recently Food and Drug Administration (FDA)-approved for MDS, based on a similar safety and efficacy profile to decitabine for injection. * KPT-8602 (eltanexor) is an orally available, second-generation selective inhibitor of nuclear export (SINE) that covalently binds to exportin 1 (XPO1). * XPO1 is a protein that mediates the nuclear export of molecules from the nucleus to the cytoplasm of the cell. Among affected molecules are tumor suppressor genes, messenger ribonucleic acid (mRNAs) encoding oncogenes (including cellular myelocytomatosis oncogene (c-MYC), and newly assembled ribosomal subunits. * By interfering with c-MYC translation, KPT-8602 may diminish rebound methylation after decitabine cessation and improve treatment responses in patients with MDS. * Preliminary reports from a Phase 1/2 trial of KPT-8602 monotherapy in patients with higher-risk MDS who have failed HMAs show anti-tumor activity and an acceptable toxicity profile. * Sequential addition of KPT-8602 to Inqovi may improve treatment responses in patients with MDS by acting synergistically to inhibit further DNA methylation. Objective: * Phase I: To determine the recommended phase 2 dose (RP2D) of KPT-8602 in combination with Inqovi in adult participants with higher-risk MDS * Phase II: To determine overall response rate (ORR) of KPT-8602 in combination with Inqovi in adult participants with higher- risk MDS Eligibility: * Participants must have histologically or cytologically confirmed MDS according to 2016 World Health Organization (WHO) criteria, and for both Phase I and II: * have HR-MDS (Revised International Prognostic Scoring System (IPSS-R) \> 3.5) with inadequate response to hypomethylating agent (HMA) therapy (received \>= 4 cycles of the standard dose (35 mg decitabine and 100 mg cedazuridine) without prior dose-reductions, with failure to achieve at least a PR or experienced disease progression prior to completing 4 cycles) * Age \>= 18 years * Eastern Cooperative Oncology Group (ECOG) performance status \<= 2 (KPS \>= 60) Design: * Participants with HR-MDS will be enrolled in both Phase I and II. * Participants will be treated with Inqovi at a fixed dose of 1 tablet (35 mg decitabine and 100 mg cedazuridine) daily on Days 1-5 of each 28-day cycle, followed by KPT-8602 at escalating doses (Phase I) or the RP2D (Phase II). * In Phase I, KPT-8602 will be dose-escalated following a standard 3+3 design, with a starting dose level of 10 mg for 10 days (staggered) within a cycle. If tolerated, the dose will be escalated to 14 days per cycle, or dose de-escalated to 5 mg at 14 or 10 days. * This study will be done at the National Institutes of Health (NIH) Center with an enrollment of up to 80 planned participants.

Conditions

• Myelodysplastic Syndromes

Interventions

Type	Name	Description
DRUG	KPT-8602	5-10 mg by mouth (PO) daily for 10-14 days based on dose level
DRUG	Inqovi	Inqovi will be administered via oral route once daily on Days 1-5 of each treatment cycle, according to guidelines outlined in the Food and Drug Administration (FDA) product label.
PROCEDURE	Bone marrow aspirate	Screening (if necessary), baseline (30 days prior to treatment start), and Cycle 1, Day 28 (phase I only).
PROCEDURE	Bone marrow biopsy	Screening (if necessary), baseline (30 days prior to treatment start), and Cycle 1, Day 28 (phase I only).
DIAGNOSTIC_TEST	ECG	Screening and baseline. Cycle 1, Day 1 and Cycle 1, Day 15 (2 hours post dose that day +/- 20 minutes).

Timeline

• Start date: 2023-11-14
• Primary completion: 2025-03-10
• Completion: 2025-03-12
• First posted: 2023-06-26
• Last updated: 2025-12-02
• Results posted: 2025-12-02

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study