Ignite Creation Date:
2024-05-06 @ 7:09 PM
Last Modification Date:
2024-10-26 @ 3:01 PM
Study NCT ID:
NCT05918055
Status:
RECRUITING
Last Update Posted:
2024-07-10
First Post:
2023-06-23
Brief Title:
Eltanexor KPT-8602 With Inqovi Decitabine-Cedazuridine in High-Risk Myelodysplastic Syndromes
Sponsor:
National Cancer Institute NCI
Organization:
National Institutes of Health Clinical Center CC
Study Overview
Official Title:
A Phase III Trial of Eltanexor KPT-8602 With Inqovi Decitabine-Cedazuridine in High-Risk Myelodysplastic Syndromes
Status:
RECRUITING
Status Verified Date:
2024-09-26
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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
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 15 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 12 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 35 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 33 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
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 15 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 12 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 35 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 33 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 001541-C | None | None | None |