Eltanexor (KPT-8602) With Inqovi (Decitabine-Cedazuridine) in High-Risk Myelodysplastic Syndromes
- Registration Number
- NCT05918055
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief 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 (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.
Participant 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 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, mRNAs encoding oncogenes (including 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 WHO criteria, and for both Phase I and II:
* have HR-MDS (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
* 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 NIH Clincal Center with an enrollment of up to 80 planned participants.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 3
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Phase II- Dose expansion for HR-MDS KPT-8602 Inqovi for 5 days, followed by RP2D/Phase II dose of KPT-8602 Phase II- Dose expansion for HR-MDS Inqovi Inqovi for 5 days, followed by RP2D/Phase II dose of KPT-8602 Phase I- Dose escalation of KPT-8602 for HR-MDS KPT-8602 Inqovi for 5 days, followed by escalating doses of KPT-8602 Phase I- Dose escalation of KPT-8602 for HR-MDS Inqovi Inqovi for 5 days, followed by escalating doses of KPT-8602
- Primary Outcome Measures
Name Time Method Phase 2: To determine the overall response rate (ORR) of KPT-8602 in combination with Inqovi in adult participants with with higher-MDS each cycle (bloods), cycle 2 and 6 during treatment and every 3-6 months (bloods and bone marrow) Participants evaluated in phase II will have the fraction with clinical responses reported, with a 95% confidence interval.
Phase 1: To determine the recommended phase 2 dose (RP2D) of KPT-8602 in combination with Inqovi in adult participants with with higher-MDS from day 1 of study drug through 28 days after the first dose Participants enrolled in phase I will have the grades and types of toxicity reported at each dose level. The overall estimate of the fraction of participants who have a DLT at the RP2D will be reported.
- Secondary Outcome Measures
Name Time Method Phase 2: To further evaluate the PK properties and safety of KPT-8602 in combination with Inqovi in MDS participants assessed at least weekly through cycle 3 and then at the start and and every cycle after that The grades and types of toxicity noted for the agent at each dose level and reported descriptively.
Phase 1: To characterize the PK properties of KPT-8602 in combination with Inqovi in MDS participants 1, 2, 3, 4, 8, 24 and 48 hours after the product administration on days 8 and 21 of cycle one The AUC, half-life, and Css of KPT-8602 will be evaluated in participants, by dose level using descriptive statistics.
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States