Phase 1-2 Study of Low Dose ASTX727 (ASTX727 LD) in Lower Risk MDS
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| ClinicalTrials.gov Identifier: NCT03502668 |
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Recruitment Status :
Active, not recruiting
First Posted : April 19, 2018
Last Update Posted : April 14, 2023
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Sponsor:
Astex Pharmaceuticals, Inc.
Information provided by (Responsible Party):
Astex Pharmaceuticals, Inc.
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Brief Summary:
Multicenter, open-label study of various ASTX727 LD doses and schedules to assess safety, pharmacodynamics, pharmacokinetics, and hematologic response in subjects with International Prognostic Scoring System (IPSS) risk category of low-risk or Intermediate-1 MDS. This study will be conducted in two phases. In phase 1 subjects will be randomized into 3 cohorts in a 28-day cycles. Phase 2, 80 new subjects will be randomized in a 1:1 ratio into 2 doses/schedules.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Myelodysplastic Syndromes | Drug: ASTX727 LD Drug: ASTX727 SD | Phase 1 Phase 2 |
A Phase 1-2, multicenter, open-label study of various ASTX727 LD doses and schedules to assess the safety, pharmacodynamics (PD), pharmacokinetics (PK), and hematologic response in subjects with IPSS risk category of low-risk or Intermediate-1 MDS. The study will be conducted in 2 phases.
Phase 1: In Stage A, subjects will be randomized into 3 cohorts of 6 subjects each testing different doses of oral decitabine with cedazuridine in 28-day cycles. When safety has been established in Phase 1 Stage A, Phase 1 Stage B will open, wherein additional 30 subjects will be randomized in a 1:1:1 ratio into 3 cohorts of 10 subjects.
Phase 2: Using 2 doses/schedules one of which will be selected from Phase 1, 40 additional subjects per dose/schedule will be randomized in a 1:1 ratio. The selected doses/schedules will be evaluated for safety (drug-related AEs), efficacy (including hematologic response), PD (long interspersed nucleotide element-1 (LINE-1 methylation, and fetal hemoglobin as fraction of total hemoglobin), and PK.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 160 participants |
| Allocation: | Randomized |
| Intervention Model: | Sequential Assignment |
| Intervention Model Description: | Multicenter, open label |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | A Randomized, Open-Label, Phase 1-2 Study of ASTX727 Low Dose (ASTX727 LD) Extended Schedule in Subjects With Lower Risk (IPSS Low or Intermediate-1) Myelodysplastic Syndromes (MDS) |
| Actual Study Start Date : | July 27, 2018 |
| Estimated Primary Completion Date : | June 2023 |
| Estimated Study Completion Date : | June 2023 |
Resource links provided by the National Library of Medicine
MedlinePlus related topics:
Myelodysplastic Syndromes
Drug Information available for:
Decitabine
| Arm | Intervention/treatment |
|---|---|
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Experimental: Phase 1 Stage A
3 cohorts of 6 subjects each in a schedule in 28-day cycles of ASTX727 LD
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Drug: ASTX727 LD
oral decitabine (LD) + cedazuridine (E7727)
Other Name: oral decitabine (LD) + cedazuridine (E7727) |
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Experimental: Phase 1 Stage B
3 cohorts of 10 subjects each in 28-day cycles of ASTX727 LD
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Drug: ASTX727 LD
oral decitabine (LD) + cedazuridine (E7727)
Other Name: oral decitabine (LD) + cedazuridine (E7727) |
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Experimental: Phase 2
80 additional subjects randomized in a 1:1 ratio studying two different doses
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Drug: ASTX727 LD
oral decitabine (LD) + cedazuridine (E7727)
Other Name: oral decitabine (LD) + cedazuridine (E7727) Drug: ASTX727 SD oral decitabine (SD) + cedazuridine (E7727)
Other Name: oral decitabine (SD) + cedazuridine (E7727) |
Primary Outcome Measures :
- Incidence of drug-related Grade ≥3 Adverse Events (AEs) or dose-limiting toxicities (DLTs) (if any) for each cohort dose/schedule [ Time Frame: 18-24 months ]Phase 1: Safety
- Hematologic response based on normalization of conversion of any baseline cytopenia or anemia (hemoglobin response, neutrophil response, platelet response, transfusion independence) [ Time Frame: 18-24 months ]Phase 2: Efficacy
Secondary Outcome Measures :
- %LINE-1 methylation change from baseline [ Time Frame: 18-24 months ]pharmacodynamics
- Area under the curve (AUC) [ Time Frame: 18-24 months ]pharmacokinetics parameter
- Maximum plasma concentration (Cmax) [ Time Frame: 18-24 months ]pharmacokinetics parameter
- Time to reach maximum concentration (Tmax) [ Time Frame: 18-24 months ]pharmacokinetics parameter
- Half life (t1/2) [ Time Frame: 18-24 months ]pharmacokinetics parameter
- Hematologic response (Phase 1 only) based on normalization of conversion of any baseline cytopenia or anemia (hemoglobin response, neutrophil response, platelet response, transfusion independence) [ Time Frame: 18-24 months ]Phase 1: Efficacy
- Time to bone marrow blasts >5% [ Time Frame: 18-24 months ]Number of days from the date of randomization to the date when bone marrow blasts are >5% and increased by ≥50%.
- Leukemia-free survival [ Time Frame: 18-24 months ]Number of days from the date of randomization to the date when bone marrow or peripheral blood blasts reach ≥20%, or death from any cause
- Overall survival [ Time Frame: 18-24 months ]Number of days from the date of randomization to the date of death from any cause
Information from the National Library of Medicine
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
- Able to understand and comply with the study procedures, understand the risks involved in the study, and provide written informed consent before the first study-specific procedure.
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Men or women ≥18 years with IPSS low risk or Int-1 MDS (all subjects). Subjects must have had at least 1 of the following disease-related criteria during the 8 weeks before randomization:
- Red blood cell (RBC) transfusion dependence of 2 or more units of RBC transfusions (RBC transfusion administered for hemoglobin (Hb) levels ≤9.0 g/dL are counted).
- Hb of <9.0 g/dL in at least 2 blood counts prior to randomization or in 1 blood count if RBC transfusion was received.
- Absolute Neutrophil Count (ANC) of <0.5 × 10^9/L in at least 2 blood counts prior to randomization.
- Platelet counts of <50 × 10^9/L in at least 2 blood counts prior to randomization.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
- Adequate organ function.
- Women of child-bearing potential (according to recommendations of the Clinical Trial Facilitation Group [CTFG]) must not be pregnant or breastfeeding and must have a negative pregnancy test at screening.
- Women of child-bearing potential must agree to use contraceptive measures of birth control for 6 months after completing treatment; men must use contraceptive measures and agree not to father a child for at least 3 months after completing treatment.
Exclusion Criteria:
- Treatment with any investigational drug or therapy within 2 weeks before study treatment.
- Treatments for MDS must be concluded 1 month prior to study treatment.
- Prior treatment with azacitidine, decitabine, or guadecitabine.
- Diagnosis of chronic myelomonocytic leukemia (CMML).
- Poor medical risk because of other conditions such as uncontrolled systemic diseases or active uncontrolled infections.
- Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, prostate cancer or breast cancer under control with hormone therapy, or other cancer from which the subject has been disease free for at least 1 year.
- Known active infection with human immunodeficiency virus or hepatitis viruses.
Information from the National Library of Medicine
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): NCT03502668
Locations
Show 31 study locations
Sponsors and Collaborators
Astex Pharmaceuticals, Inc.
| Responsible Party: | Astex Pharmaceuticals, Inc. |
| ClinicalTrials.gov Identifier: | NCT03502668 |
| Other Study ID Numbers: |
ASTX727-03 |
| First Posted: | April 19, 2018 Key Record Dates |
| Last Update Posted: | April 14, 2023 |
| Last Verified: | April 2023 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Keywords provided by Astex Pharmaceuticals, Inc.:
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low risk myelodysplastic syndromes, MDS, ASTX727 |
Additional relevant MeSH terms:
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Preleukemia Myelodysplastic Syndromes Syndrome Disease Pathologic Processes Bone Marrow Diseases Hematologic Diseases Precancerous Conditions |
Neoplasms Decitabine Decitabine and cedazuridine drug combination Antimetabolites, Antineoplastic Antimetabolites Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Enzyme Inhibitors |