Pharmacokinetic Guided Dose Escalation and Dose Confirmation With Oral Decitabine and Oral Cytidine Deaminase Inhibitor (CDAi) in Patients With Myelodysplastic Syndromes (MDS)

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase1-2 Pharmacokinetic Guided Dose-Escalation and Dose-Confirmation Study of ASTX727, a Combination of the Oral Cytidine Deaminase Inhibitor (CDAi) E7727 With Oral Decitabine in Subjects With Myelodysplastic Syndromes (MDS)

Conditions
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MDS, Myelodysplastic Syndrome

Intervention / Treatment
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* Drug: ASTX727 Dose Escalation
* Drug: ASTX727 Dose Confirmation
* Drug: ASTX727 Fixed-Dose Combination


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 Dose Escalation<br>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). | Drug: ASTX727 Dose Escalation<br>* Oral investigational product and approved IV decitabine<br>* Other names: IV decitabine;|
| Experimental: Phase 2 Dose Confirmation<br>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. | Drug: ASTX727 Dose Confirmation<br>* Randomization cross over design for courses 1 and 2<br>* Other names: IV decitabine;|
| Experimental: Phase 2 Fixed-Dose Combination<br>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. | Drug: ASTX727 Fixed-Dose Combination<br>* Fixed-dose investigational product<br>* Other names: ASTX727 oral (combination of oral E7727 and oral decitabine);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Decitabine Area Under the Concentration Versus Time Curve (AUC0-t) on Day 5 by Cohort in Phase 1 | 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). | Day 5 | 
| Mean Decitabine Area Under the Plasma Concentration Versus Time Curve Ratio (5-day AUC0-t) in Phase 2 | 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. | Pre-dose to Day 5 | 
| Number of Participants With Dose-limiting Toxicity in Phase 1 | 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. | Up to Day 28 in Course 1 (28 days per course) | 
| Mean Maximum %LINE Demethylation in Phase 2 | 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. | Pre-dose to Day 28 in Course 2 (28 days per course) | 
| Number of Participants With Overall Response in Phase 2 | 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). | Up to approximately 29 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration Versus Time Curve of Cedazuridine (E7727) and Cedazuridine-epimer | 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. | At specified timepoints from 0 to 24 hours post-dose | 
| Maximum Observed Plasma Concentration (Cmax) of Cedazuridine (E7727) and Cedazuridine-epimer | 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. | At specific timepoints from 0 to 24 hours post-dose | 
| Time to Maximum Observed Plasma Concentration (Tmax) of Cedazuridine (E7727) and Cedazuridine-epimer | 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. | At specific timepoints from 0 to 24 hours post-dose | 
| Maximum Observed Plasma Concentration (Cmax) of Decitabine | 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. | At specific timepoints from 0 to 24 hours post-dose | 
| Time to Maximum Observed Plasma Concentration (Tmax) of Decitabine in Phase 2 | 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. | At specific timepoints from 0 to 24 hours post-dose | 
| Duration of Complete Response in Phase 1 | 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. | Up to 32 Months | 
| Duration of Complete Response in Phase 2 - Kaplan-Meier Estimate | 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. | Up to approximately 29 months | 
| Mean Maximum %LINE Demethylation in Phase 1 | 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. | Pre-dose to Day 28 in Course 2 (28 days per course) | 
| Number of Participants With Overall Response in Phase 1 | 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). | Up to 32 months | 
| Number of Participants With Adverse Events | 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. | Up to 5 years | 
| Number of Participants With Hematological Improvement | Hematological improvement was calculated as defined by the IWG 2006 MDS Response Criteria. | Up to 32 months | 
| Number of Participants With Transfusion Independence | 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. | Up to 32 months | 
| Number of Participants to Reach Acute Myeloid Leukemia (AML) or Death | Number of participants to reach the event (AML or death), where time to reach AML was calculated as the number of days from the day the participant received the first dose of IV decitabine, oral decitabine + E7727, or the FDC tablet to the date of death or the date of MDS progression to AML as defined by ≥20% blasts in bone marrow or peripheral blood using the World Health Organization classification. Time to AML or death was censored on the last date of contact if a participant was lost to follow up prior to reaching a time-to-event endpoint. | Up to 32 months | 
| Number of Participants With Overall Survival | Overall survival was defined as the number of days from the day the participant received the first dose of IV decitabine, oral decitabine + E7727, or the FDC tablet to the date of death, regardless of cause. | Up to 32 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MDS, Myelodysplastic Syndrome