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.
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
3
5-10 mg by mouth (PO) daily for 10-14 days based on dose level
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.
Screening (if necessary), baseline (30 days prior to treatment start), and Cycle 1, Day 28 (phase I only).
Screening (if necessary), baseline (30 days prior to treatment start), and Cycle 1, Day 28 (phase I only).
Screening and baseline. Cycle 1, Day 1 and Cycle 1, Day 15 (2 hours post dose that day +/- 20 minutes).
National Institutes of Health Clinical Center
Bethesda, Maryland, United States
Phase 1: Recommended Phase 2 Dose (RP2D) of Eltanexor (KPT-8602) in Combination With Inqovi (Decitabine-Cedazuridine) in Adult Participants With Higher-Myelodysplastic Syndromes (MDS)
If no DLTs are observed at the highest planned dose level for evaluation (dose level 2), dose escalation will stop, and this will be considered the recommended phase 2 dose (RP2D) of Eltanexor (KPT-8602). A DLT is defined as a treatment-related toxicity based on Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.
Time frame: From day 1 of study drug through 28 days after the first dose
Phase 1: Number of Participants Who Have Grades 3 and/or 4 Dose-limiting Toxicity (DLT) at the Recommended Phase 2 Dose (RP2D)
Participants enrolled in phase I will have the grades and types of toxicity reported at each dose level to determine the RP2D. Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to adverse event. Toxicity was assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0).
Time frame: First 28 days of study treatment
Phase 2: Overall Response Rate (ORR) of Eltanexor (KPT-8602) in Combination With Inqovi (Decitabine-Cedazuridine) Reported With a 95% Confidence Interval in Adult Participants With Higher-Myelodysplastic Syndromes (MDS)
Participants evaluated in phase II will have the fraction with clinical responses reported, with a 95% confidence interval. ORR is defined as Complete Remission (CR)+Partial Remission (PR)+marrow (mCR) with hematologic improvement (HI) per each cohort and assessed by the 2006 International Working Group Response Criteria with Modified Definitions for Hematologic Improvement by the 2018 International Working Group Response Criteria. Complete Remission (CR) is bone marrow: ≤5% myeloblasts with normal maturation of all cell lines. Partial Remission (PR) is all CR criteria if abnormal before treatment except bone marrow blasts decreased by ≥50% over pretreatment but still \>5%; and cellularity and morphology not relevant. Marrow Complete Remission is bone marrow: ≤5% myeloblasts and decrease by ≥50% over pretreatment.
Time frame: Each cycle (bloods), cycle 2 and 6 during treatment and every 3-6 months (bloods and bone marrow)
Phase 1: AUC Under the Concentration Time Curve (AUC 0-48h) of Eltanexor (KPT-8602) in Combination With Inqovi (Decitabine-Cedazuridine) in Participants With Myelodysplastic Syndromes (MDS)
AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption.
Time frame: 1, 2, 3, 4, 8, 24 and 48 hours after the product administration on days 8 and 21 of cycle one
Phase 1: Half-life of Eltanexor (KPT-8602) in Combination With Inqovi (Decitabine-Cedazuridine) in Participants With Myelodysplastic Syndromes (MDS)
The half-life of Eltanexor (KPT-8602) will be evaluated in participants, by dose level when given in combination with Inqovi. Plasma decay half-life is the time measured for the plasma concentration of the drug to decrease by one half.
Time frame: 1, 2, 3, 4, 8, 24 and 48 hours after the product administration on days 8 and 21 of cycle one
Phase 1: Calculating Steady State (Css) Concentration of Eltanexor (KPT-8602) When Given in Combination With Inqovi (Decitabine-Cedazuridine)
Steady state concentration, measured by the Eltanexor (KPT-8602) blood concentration will be evaluated in participants, by dose level when given in combination with Inqovi (Decitabine-Cedazuridine). Steady state is defined as consistent drug concentration in the body.
Time frame: 1, 2, 3, 4, 8, 24 and 48 hours after the product administration on days 8 and 21 of cycle one
Phase 2: Number of Grades 1, 2, 3, 4, and/or 5 Toxicity of Eltanexor (KPT-8602) and Inqovi (Decitabine-Cedazuridine) at Each Dose Level in Participants With Myelodysplastic Syndromes (MDS)
The grades and types of toxicity noted for the agent at each dose level will be reported. Toxicity was assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to adverse event.
Time frame: At least weekly through cycle 3 and then at the start and every cycle after that
Phase 2: Number of Serious Adverse Events Leading to Discontinuation, Death, and Laboratory Abnormalities
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. Serious adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0).
Time frame: At least weekly through cycle 3 and then at the start and every cycle after that