Eltanexor (KPT-8602) With Inqovi (Decitabine-Cedazuridine) in High-Risk Myelodysplastic Syndromes
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ClinicalTrials.gov Identifier: NCT05918055 |
Recruitment Status :
Recruiting
First Posted : June 26, 2023
Last Update Posted : May 16, 2024
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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.
Condition or disease | Intervention/treatment | Phase |
---|---|---|
Myelodysplastic Syndromes | Drug: KPT-8602 Drug: Inqovi | Phase 1 Phase 2 |
Study Type : | Interventional (Clinical Trial) |
Estimated Enrollment : | 80 participants |
Allocation: | Non-Randomized |
Intervention Model: | Sequential Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
Official Title: | A Phase I/II Trial of Eltanexor (KPT-8602) With Inqovi (Decitabine-Cedazuridine) in High-Risk Myelodysplastic Syndromes |
Actual Study Start Date : | November 14, 2023 |
Estimated Primary Completion Date : | April 5, 2027 |
Estimated Study Completion Date : | July 5, 2027 |
Arm | Intervention/treatment |
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Experimental: Phase I- Dose escalation of KPT-8602 for HR-MDS
Inqovi for 5 days, followed by escalating doses of KPT-8602
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Drug: KPT-8602
5-10 mg 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 FDA product label. |
Experimental: Phase II- Dose expansion for HR-MDS
Inqovi for 5 days, followed by RP2D/Phase II dose of KPT-8602
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Drug: KPT-8602
5-10 mg 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 FDA product label. |
- Phase 2: To determine the overall response rate (ORR) of KPT-8602 in combination with Inqovi in adult participants with with higher-MDS [ Time Frame: 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 [ Time Frame: 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.
- Phase 2: To further evaluate the PK properties and safety of KPT-8602 in combination with Inqovi in MDS participants [ Time Frame: 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 [ Time Frame: 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.
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Ages Eligible for Study: | 18 Years to 120 Years (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
-INCLUSION CRITERIA:
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Participants must have histologically or cytologically confirmed MDS by the Laboratory of Pathology, NCI- according to 2016 WHO criteria AND:
-Cohort 1 (Phase 1) & 2 (Phase 2): 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 (Karnofsky >= 60%,)
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Participants must have adequate organ and marrow function as defined below:
-total bilirubin <= 1.5 X institutional upper limit of normal
OR
<= 3 X institutional upper limit of normal in participants with Gilbert s syndrome (except for participants with increased bilirubin levels attributed to intramedullary hemolysis, which will be allowable)
-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
- creatinine clearance >= 60 mL/min
- QTc(F) <= 470 ms
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Females of child-bearing potential (FOCP) must have a negative serum test at screening. FOCP is defined as the following:
- Has not undergone a hysterectomy, tubal ligation, or bilateral oophorectomy
- Has not been naturally postmenopausal for at least 24 consecutive months (i.e.,has had menses at any time in the preceding 24 consecutive months).
- Females of childbearing potential (FOCP) and males of child-fathering potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) unless they have had a prior vasectomy, hysterectomy, or bilateral oophorectomy, prior to study entry, for the duration of study participation, and for at least 6 months after last dose of HMA.
- Breastfeeding participants must be willing to discontinue breastfeeding from study treatment initiation through 30 days after the last administration of study drug
- Any prior therapy must have been completed >4 weeks or, if known, >= 5 half-lives of the prior agent (whichever is shorter) prior to treatment (with a minimum of 1 week between prior therapy and study treatment). Note: This does not apply to prior HMA therapy if that therapy involves Inqovi
- Ability to understand and the willingness to sign a written informed consent document.
EXCLUSION CRITERIA:
- Participants with platelet transfusion-refractory thrombocytopenia, with inability to keep platelet threshold above 10K/mcL with transfusions or those with ongoing or uncontrolled hemorrhagic complications.
- Participants with clinically significant neutropenia, defined as ANC <100 cells/mcL with frequent hospitalizations for infection (average > 1 hospitalization per month in the past 6 months).
- Participants on treatment with a myeloid growth factor (e.g., G-CSF) within 14 days prior to initiation of study treatment.
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to HMAs or other agents used in study.
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Uncontrolled intercurrent illness evaluated by history, physical exam, and chemistries or
situations that would limit compliance with study requirements, interpretation of results or that could increase risk to the participant
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Participants with the following cardiac conditions: symptomatic congestive heart failure,
unstable angina pectoris, or cardiac arrhythmia as assessed by electrocardiogram (ECG).
- Pregnancy (confirmed with Beta-HCG serum or urine pregnancy test performed in females of childbearing potential at screening)
- Presence of any other malignancy (except basal and squamous cell carcinoma of the skin, or stable chronic cancers on hormone or targeted therapy) for which participant received systemic anticancer treatment (except maintenance therapy) within 24 months prior to treatment.
- Participants with active/uncontrolled Hepatitis B
- Participants with active/uncontrolled Hepatitis C
- Participants with active/uncontrolled HIV infection or AIDS.
- Participants currently taking contraindicated medications for HIV, Hepatitis B, or Hepatitis C disease control
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05918055
Contact: Rebecca Alexander | (240) 781-4037 | rebecca.alexander@nih.gov | |
Contact: Steven Z Pavletic, M.D. | (240) 760-6174 | sp326h@nih.gov |
United States, Maryland | |
National Institutes of Health Clinical Center | Recruiting |
Bethesda, Maryland, United States, 20892 | |
Contact: National Cancer Institute Referral Office 888-624-1937 |
Principal Investigator: | Steven Z Pavletic, M.D. | National Cancer Institute (NCI) |
Responsible Party: | National Cancer Institute (NCI) |
ClinicalTrials.gov Identifier: | NCT05918055 |
Other Study ID Numbers: |
10001541 001541-C |
First Posted: | June 26, 2023 Key Record Dates |
Last Update Posted: | May 16, 2024 |
Last Verified: | May 10, 2024 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | Yes |
Plan Description: | .All collected IPD will be shared. In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP. |
Supporting Materials: |
Study Protocol Statistical Analysis Plan (SAP) Informed Consent Form (ICF) |
Time Frame: | Clinical data available during the study and indefinitely. |
Access Criteria: | Data from this study may be requested by contacting the PI. |
Studies a U.S. FDA-regulated Drug Product: | Yes |
Studies a U.S. FDA-regulated Device Product: | No |
Acute Myeloid Leukemia hypomethylating agents Allogeneic Hematopoietic Stem Cell Transplantation |
Preleukemia Myelodysplastic Syndromes Syndrome Disease Pathologic Processes Bone Marrow Diseases Hematologic Diseases |
Precancerous Conditions Neoplasms Decitabine and cedazuridine drug combination Antimetabolites, Antineoplastic Antimetabolites Molecular Mechanisms of Pharmacological Action Antineoplastic Agents |