TriangleNCT02103478 · CITED IN SOURCE DOCUMENTS
Pharmacokinetic Guided Dose Escalation and Dose Confirmation With Oral Decitabine and Oral Cytidine Deaminase Inhibitor (CDAi) in Patients With Myelodysplastic Syndromes (MDS)
An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.
- Phase
- PHASE1, PHASE2
- Status at capture
- COMPLETED
- Registry last update
- 2024-08-27
This first-in-human, 3-stage, open-label study evaluated the safety and pharmacokinetics of ASTX727, as well as determined the dose for later stages.
Open the original ClinicalTrials.gov record → · Download preserved record
What did the study report?
Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.
Participant flow
Baseline characteristics
Mean Decitabine Area Under the Concentration Versus Time Curve (AUC0-t) on Day 5 by Cohort in Phase 1
Mean Decitabine Area Under the Plasma Concentration Versus Time Curve Ratio (5-day AUC0-t) in Phase 2
Number of Participants With Dose-limiting Toxicity in Phase 1
Mean Maximum %LINE Demethylation in Phase 2
Number of Participants With Overall Response in Phase 2
Area Under the Concentration Versus Time Curve of Cedazuridine (E7727) and Cedazuridine-epimer
Maximum Observed Plasma Concentration (Cmax) of Cedazuridine (E7727) and Cedazuridine-epimer
Time to Maximum Observed Plasma Concentration (Tmax) of Cedazuridine (E7727) and Cedazuridine-epimer
Maximum Observed Plasma Concentration (Cmax) of Decitabine
Time to Maximum Observed Plasma Concentration (Tmax) of Decitabine in Phase 2
Duration of Complete Response in Phase 1
Duration of Complete Response in Phase 2 - Kaplan-Meier Estimate
Mean Maximum %LINE Demethylation in Phase 1
Number of Participants With Overall Response in Phase 1
Number of Participants With Adverse Events
Number of Participants With Hematological Improvement
Number of Participants With Transfusion Independence
Number of Participants to Reach Acute Myeloid Leukemia (AML) or Death
Number of Participants With Overall Survival
Adverse events
Limitations, agreements, and source contact
Who could take part
- eligibility Criteria
- Inclusion Criteria: * International Prognostic Scoring System (IPSS) low, intermediate -1, intermediate-2, or high risk MDS (including chronic myelomonocytic leukemia; CMML) in Dose Escalation and Dose Confirmation-Randomization; only intermediate-2, or high risk MDS in Dose Confirmation-Open Label * Eastern Cooperative Oncology Group (ECOG) 0 to 2 * No major surgery within 2 weeks of starting study treatment * No cytotoxic chemotherapy within 2 weeks of starting study treatment * Able to swallow pills Exclusion Criteria: * Previous treatment with 2 or more courses of decitabine (all stages) or azacitidine (Dose Confirmation stage only) * Treatment with investigational therapy within 2 weeks of study treatment * Uncontrolled medical disease(s) or active, uncontrolled infection * Diagnosed with acute myeloid leukemia (AML) * Active uncontrolled gastric or duodenal ulcer * Known history of HIV or hepatitis C or B
- healthy Volunteers
- false
- minimum Age
- 18 Years
- sex
- ALL
- std Ages
- ADULT
- OLDER_ADULT
Treatment arms and interventions
- arm Groups
- description
- Starting cohort was administered 40 mg oral cedazuridine and 20 mg oral decitabine. Participants were enrolled into successive cohorts in which either the cedazuridine or decitabine oral dose was varied in Course 1 Day 2 through Course 1 Day 5 for comparison with a single dose of IV decitabine at 20 mg/m\^2 administered on Day 1 by continuous IV infusion over 1 hour (28 days per course).
- intervention Names
- Drug: ASTX727 Dose Escalation
- label
- Phase 1 Dose Escalation
- type
- EXPERIMENTAL
- description
- Participants were randomized in a 1:1 ratio to receive either oral cedazuridine (E7727) (100 mg) + decitabine (35 mg) capsules Dailyx5 in Course 1 followed by IV decitabine (20 mg/m\^2) Dailyx5 in Course 2 (28 days per course) or the converse. In Courses ≥ 3, participants received cedazuridine and decitabine capsules Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study.
- intervention Names
- Drug: ASTX727 Dose Confirmation
- label
- Phase 2 Dose Confirmation
- type
- EXPERIMENTAL
- description
- Participants were randomized in a 1:1 ratio to receive either the fixed-dose combination (FDC) tablet (100 mg cedazuridine (E7727)/35 mg decitabine) Dailyx5 in Course 1 followed by IV decitabine (20 mg/m\^2) Dailyx5 in Course 2 (28 days per course) or the converse. In Courses ≥ 3, all participants received the FDC tablet Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study.
- intervention Names
- Drug: ASTX727 Fixed-Dose Combination
- label
- Phase 2 Fixed-Dose Combination
- type
- EXPERIMENTAL
- interventions
- arm Group Labels
- Phase 1 Dose Escalation
- description
- Oral investigational product and approved IV decitabine
- name
- ASTX727 Dose Escalation
- other Names
- cedazuridine (E7727)
- oral decitabine
- IV decitabine
- type
- DRUG
- arm Group Labels
- Phase 2 Dose Confirmation
- description
- Randomization cross over design for courses 1 and 2
- name
- ASTX727 Dose Confirmation
- other Names
- ASTX727 oral (combination of oral E7727 and oral decitabine)
- IV decitabine
- type
- DRUG
- arm Group Labels
- Phase 2 Fixed-Dose Combination
- description
- Fixed-dose investigational product
- name
- ASTX727 Fixed-Dose Combination
- other Names
- ASTX727 oral (combination of oral E7727 and oral decitabine)
- type
- DRUG
Study design
- allocation
- RANDOMIZED
- intervention Model
- SEQUENTIAL
- masking Info
- masking
- NONE
- primary Purpose
- TREATMENT
Enrollment
- count
- 130
- type
- ACTUAL
Registered outcome plans (not posted results)
- primary Outcomes
- description
- Mean AUC0-t of oral decitabine given with cedazuridine (E7727) following IV decitabine 20 mg/m\^2 infusion on Day 5. AUCs were calculated by the linear up/log down method using the measured concentration-time values above the BQL (below the limit of quantification).
- measure
- Mean Decitabine Area Under the Concentration Versus Time Curve (AUC0-t) on Day 5 by Cohort in Phase 1
- time Frame
- Day 5
- description
- Decitabine 5-day AUC ratio following IV decitabine 20 mg/m\^2 infusion versus concomitant oral administration of decitabine + cedazuridine (E7727) or ASTX727 in the dose combination and fixed-dose combination stages, respectively. AUC0-t (the area under the concentration-time curve from time zero to the time of the last (tlast) quantifiable concentration (Ct)) by dose/cohort and course/days was used for estimating decitabine cumulative 5-day AUC0-t exposures.
- measure
- Mean Decitabine Area Under the Plasma Concentration Versus Time Curve Ratio (5-day AUC0-t) in Phase 2
- time Frame
- Pre-dose to Day 5
- description
- Number of participants with protocol-specified dose-limiting toxicities (DLTs) in the dose escalation stage. DLTs were defined using the Common Terminology Criteria for Adverse Events Version 4.0 (CTCAEv4.0), specifically ≥ Grade 3 non-hematologic toxicity (except Grade 3 nausea, vomiting, or diarrhea that is controllable by anti-emetics or optimal therapy or related to underlying disease or disease progression), specific Grade 3 laboratory tests, related prolonged Grade 4 thrombocytopenia or neutropenia that was not present prior to dosing, does not resolve within 14 days, and is not related to underlying disease, or any toxicity related to study treatment that results in treatment delays of \>4 weeks after Day 28.
- measure
- Number of Participants With Dose-limiting Toxicity in Phase 1
- time Frame
- Up to Day 28 in Course 1 (28 days per course)
- description
- Mean maximum % long interspread nuclear element-1 (LINE-1) demethylation after oral decitabine + cedazuridine (E7727) or ASTX727 (Course 1 or Course 2 - Treatment) compared with IV decitabine 20 mg/m\^2 (Course 1 or Course 2 - IV Decitabine) in the dose confirmation and fixed-dose combination stages, respectively. Least squares mean of maximum %LINE-1 methylation change from baseline.
- measure
- Mean Maximum %LINE Demethylation in Phase 2
- time Frame
- Pre-dose to Day 28 in Course 2 (28 days per course)
- description
- The evaluation of response was based on International Working Group (IWG) 2006 MDS Response Criteria, with overall response calculated as number of participants with complete response+partial response+marrow complete response+hematological improvement (CR+PR+mCR+HI).
- measure
- Number of Participants With Overall Response in Phase 2
- time Frame
- Up to approximately 29 months
- secondary Outcomes
- description
- AUC is a measure of the plasma concentration of the drug over time (AUC0-8). PK parameters are reported for the dose escalation stage by cohort in Phase 1 and dose confirmation and fixed-dose combination stages in Phase 2.
- measure
- Area Under the Concentration Versus Time Curve of Cedazuridine (E7727) and Cedazuridine-epimer
- time Frame
- At specified timepoints from 0 to 24 hours post-dose
- description
- Cmax is the maximum observed plasma concentration. PK parameters are reported for the dose escalation stage by cohort in Phase 1 and dose confirmation and fixed-dose combination stages in Phase 2.
- measure
- Maximum Observed Plasma Concentration (Cmax) of Cedazuridine (E7727) and Cedazuridine-epimer
- time Frame
- At specific timepoints from 0 to 24 hours post-dose
- description
- Tmax is the time to maximum observed plasma concentration. PK parameters are reported for the dose escalation stage by cohort in Phase 1 and the dose confirmation and fixed-dose combination stages in Phase 2.
- measure
- Time to Maximum Observed Plasma Concentration (Tmax) of Cedazuridine (E7727) and Cedazuridine-epimer
- time Frame
- At specific timepoints from 0 to 24 hours post-dose
- description
- Cmax is the maximum observed plasma concentration. PK parameters for plasma decitabine are reported for the dose escalation stage by cohort in Phase 1 and dose confirmation and fixed-dose combination stages in Phase 2.
- measure
- Maximum Observed Plasma Concentration (Cmax) of Decitabine
- time Frame
- At specific timepoints from 0 to 24 hours post-dose
- description
- Tmax is the time to reach maximum plasma concentration for decitabine. PK parameters for plasma decitabine are reported for the dose confirmation and fixed-dose combination stages.
- measure
- Time to Maximum Observed Plasma Concentration (Tmax) of Decitabine in Phase 2
- time Frame
- At specific timepoints from 0 to 24 hours post-dose
- description
- Duration of response (in number of days) was calculated from the first time the response was observed to time of relapse or last time point in the study.
- measure
- Duration of Complete Response in Phase 1
- time Frame
- Up to 32 Months
- description
- Duration of response (in number of days) was calculated from the first time the response was observed to time of relapse or last time point in the study. Kaplan-Meier estimate for complete response is shown.
- measure
- Duration of Complete Response in Phase 2 - Kaplan-Meier Estimate
- time Frame
- Up to approximately 29 months
- description
- Mean maximum % long interspread nuclear element-1 (LINE-1) demethylation decrease from baseline after oral decitabine + cedazuridine (E7727) or ASTX727 compared with IV decitabine 20 mg/m\^2 in the dose escalation stage.
- measure
- Mean Maximum %LINE Demethylation in Phase 1
- time Frame
- Pre-dose to Day 28 in Course 2 (28 days per course)
- description
- The evaluation of response was based on International Working Group 2006 MDS Response Criteria, with overall response calculated as number of participants with complete response+partial response+marrow complete response+hematological improvement (CR+PR+mCR+HI).
- measure
- Number of Participants With Overall Response in Phase 1
- time Frame
- Up to 32 months
- description
- Number of participants with any treatment-emergent adverse event (AE) and any AE graded ≥3 using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
- measure
- Number of Participants With Adverse Events
- time Frame
- Up to 5 years
- description
- Hematological improvement was calculated as defined by the IWG 2006 MDS Response Criteria.
- measure
- Number of Participants With Hematological Improvement
- time Frame
- Up to 32 months
- description
- Transfusion independence was calculated based on the number of transfusion-dependent participants at baseline who had no red blood cell or platelet transfusions for 56 consecutive days or more after treatment.
- measure
- Number of Participants With Transfusion Independence
- time Frame
- Up to 32 months
Full study description
- brief Summary
- This first-in-human, 3-stage, open-label study evaluated the safety and pharmacokinetics of ASTX727, as well as determined the dose for later stages.
- detailed Description
- The trial was designed to define daily doses of the individual components (cedazuridine \[E7727\] or decitabine) so that decitabine exposure after oral administration would be comparable to exposure after IV decitabine at the approved daily dose of 20 mg/m\^2. The main objective of Phases 1 and 2 was to establish and confirm the doses of the 2 components to be used in the final fixed-dose combination (FDC) product (ASTX727) using mainly pharmacokinetics and pharmacodynamics as endpoints.
Source references
- references
- citation
- Garcia-Manero G, Griffiths EA, Steensma DP, Roboz GJ, Wells R, McCloskey J, Odenike O, DeZern AE, Yee K, Busque L, O'Connell C, Michaelis LC, Brandwein J, Kantarjian H, Oganesian A, Azab M, Savona MR. Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. Blood. 2020 Aug 6;136(6):674-683. doi: 10.1182/blood.2019004143.
- pmid
- 32285126
- type
- DERIVED
- citation
- Savona MR, Odenike O, Amrein PC, Steensma DP, DeZern AE, Michaelis LC, Faderl S, Harb W, Kantarjian H, Lowder J, Oganesian A, Azab M, Garcia-Manero G. An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study. Lancet Haematol. 2019 Apr;6(4):e194-e203. doi: 10.1016/S2352-3026(19)30030-4.
- pmid
- 30926081
- type
- DERIVED
Source notices and limitations
Discovery and provenance
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Preserved source evidence · Not medical advice