MDS, Myelodysplastic Syndrome
Conditions
Keywords
Myelodysplastic Syndrome, MDS
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.
Interventions
DRUGASTX727 Dose Escalation
Oral investigational product and approved IV decitabine
DRUGASTX727 Dose Confirmation
Randomization cross over design for courses 1 and 2
DRUGASTX727 Fixed-Dose Combination
Fixed-dose investigational product
Sponsors
Astex Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Decitabine Area Under the Concentration Versus Time Curve (AUC0-t) on Day 5 by Cohort in Phase 1 | Day 5 | 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). |
| Mean Decitabine Area Under the Plasma Concentration Versus Time Curve Ratio (5-day AUC0-t) in Phase 2 | Pre-dose to Day 5 | 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. |
| Number of Participants With Dose-limiting Toxicity in Phase 1 | Up to Day 28 in Course 1 (28 days per course) | 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. |
| Mean Maximum %LINE Demethylation in Phase 2 | Pre-dose to Day 28 in Course 2 (28 days per course) | 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. |
| Number of Participants With Overall Response in Phase 2 | Up to approximately 29 months | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Complete Response in Phase 1 | Up to 32 Months | 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. |
| Duration of Complete Response in Phase 2 - Kaplan-Meier Estimate | Up to approximately 29 months | 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. |
| Mean Maximum %LINE Demethylation in Phase 1 | Pre-dose to Day 28 in Course 2 (28 days per course) | 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. |
| Number of Participants With Overall Response in Phase 1 | Up to 32 months | 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). |
| Area Under the Concentration Versus Time Curve of Cedazuridine (E7727) and Cedazuridine-epimer | At specified timepoints from 0 to 24 hours post-dose | 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. |
| Number of Participants With Hematological Improvement | Up to 32 months | Hematological improvement was calculated as defined by the IWG 2006 MDS Response Criteria. |
| Number of Participants With Transfusion Independence | Up to 32 months | 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. |
| Number of Participants to Reach Acute Myeloid Leukemia (AML) or Death | Up to 32 months | 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. |
| Number of Participants With Overall Survival | Up to 32 months | 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. |
| Number of Participants With Adverse Events | Up to 5 years | 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. |
| Maximum Observed Plasma Concentration (Cmax) of Cedazuridine (E7727) and Cedazuridine-epimer | At specific timepoints from 0 to 24 hours post-dose | 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. |
| Time to Maximum Observed Plasma Concentration (Tmax) of Cedazuridine (E7727) and Cedazuridine-epimer | At specific timepoints from 0 to 24 hours post-dose | 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. |
| Maximum Observed Plasma Concentration (Cmax) of Decitabine | At specific timepoints from 0 to 24 hours post-dose | 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. |
| Time to Maximum Observed Plasma Concentration (Tmax) of Decitabine in Phase 2 | At specific timepoints from 0 to 24 hours post-dose | 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. |
Countries
Canada, United States
Participant flow
Recruitment details
In Phase 1, 127 participants were screened and 44 were randomized and received at least one treatment. In Phase 2, a total of 138 were screened, 86 were randomized, and 80 received at least one treatment.
Pre-assignment details
Response data for Phase 1 per June 2017 data cut and for Phase 2 per June 2018 data cut. Median follow up in Phase 1 was 1915.5 days (range: 1771-2213) and 1563.0 days in Phase 2 (range: 1199-1710).
Participants by arm
| Arm | Count |
|---|---|
| Phase 1 Dose Escalation Cohort 1 Cohort 1 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). | 7 |
| Phase 1 Dose Escalation Cohort 2 Cohort 2 was administered 60 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). | 6 |
| Phase 1 Dose Escalation Cohort 3 Cohort 3 was administered 100 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). | 6 |
| Phase 1 Dose Escalation Cohort 4 Cohort 4 was administered 100 mg oral cedazuridine and 40 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). | 6 |
| Phase 1 Dose Escalation Cohort 5 Cohort 5 was administered 100 mg oral cedazuridine and 30 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). | 19 |
| Phase 2 Dose Confirmation Participants were randomized in a 1:1 ratio to receive either oral cedazuridine (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, all participants received cedazuridine and decitabine capsules Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study. | 50 |
| Phase 2 Fixed-Dose Combination Participants were randomized in a 1:1 ratio to receive either the fixed-dose combination (FDC) tablet (100 mg cedazuridine/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. | 30 |
| Total | 124 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 1 | 2 | 1 | 0 | 0 | 0 |
| Overall Study | Death | 2 | 2 | 1 | 1 | 5 | 15 | 14 | 10 | 11 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Other | 1 | 3 | 2 | 0 | 3 | 8 | 8 | 4 | 2 |
| Overall Study | Progressive Disease | 2 | 1 | 2 | 0 | 9 | 1 | 2 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 0 | 0 | 4 | 0 | 0 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Phase 1 Dose Escalation Cohort 1 | Total | Phase 2 Fixed-Dose Combination | Phase 2 Dose Confirmation | Phase 1 Dose Escalation Cohort 5 | Phase 1 Dose Escalation Cohort 4 | Phase 1 Dose Escalation Cohort 3 | Phase 1 Dose Escalation Cohort 2 |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 69.6 years STANDARD_DEVIATION 8.1 | 70.6 years STANDARD_DEVIATION 9.67 | 69.6 years STANDARD_DEVIATION 10.57 | 69.7 years STANDARD_DEVIATION 10.72 | 71.6 years STANDARD_DEVIATION 8.8 | 75.2 years STANDARD_DEVIATION 7.1 | 74 years STANDARD_DEVIATION 4.8 | 72 years STANDARD_DEVIATION 6.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 6 Participants | 3 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 113 Participants | 26 Participants | 46 Participants | 18 Participants | 5 Participants | 5 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 5 Participants | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 5 Participants | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 4 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 114 Participants | 28 Participants | 46 Participants | 18 Participants | 5 Participants | 5 Participants | 6 Participants |
| Region of Enrollment Canada | 0 participants | 16 participants | 8 participants | 8 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Region of Enrollment United States | 7 participants | 108 participants | 22 participants | 42 participants | 19 participants | 6 participants | 6 participants | 6 participants |
| Sex: Female, Male Female | 4 Participants | 33 Participants | 10 Participants | 9 Participants | 4 Participants | 2 Participants | 3 Participants | 1 Participants |
| Sex: Female, Male Male | 3 Participants | 91 Participants | 20 Participants | 41 Participants | 15 Participants | 4 Participants | 3 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 7 | 2 / 6 | 1 / 6 | 1 / 6 | 5 / 19 | 29 / 50 | 21 / 30 |
| other Total, other adverse events | 6 / 7 | 6 / 6 | 6 / 6 | 6 / 6 | 18 / 19 | 48 / 50 | 30 / 30 |
| serious Total, serious adverse events | 2 / 7 | 4 / 6 | 2 / 6 | 6 / 6 | 14 / 19 | 39 / 50 | 25 / 30 |
Outcome results
Primary
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).
Time frame: Day 5
Population: Participants who were successfully dosed according to criteria for both ASTX727 and IV decitabine dosing and with evaluable pharmacokinetic (PK) measurements are included.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 Dose Escalation Cohort 1 | Mean Decitabine Area Under the Concentration Versus Time Curve (AUC0-t) on Day 5 by Cohort in Phase 1 | 53.6 ng*h/mL | Geometric Coefficient of Variation 40 |
| Phase 1 Dose Escalation Cohort 2 | Mean Decitabine Area Under the Concentration Versus Time Curve (AUC0-t) on Day 5 by Cohort in Phase 1 | 68.9 ng*h/mL | Geometric Coefficient of Variation 44 |
| Phase 1 Dose Escalation Cohort 3 | Mean Decitabine Area Under the Concentration Versus Time Curve (AUC0-t) on Day 5 by Cohort in Phase 1 | 94.8 ng*h/mL | Geometric Coefficient of Variation 46 |
| Phase 1 Dose Escalation Cohort 4 | Mean Decitabine Area Under the Concentration Versus Time Curve (AUC0-t) on Day 5 by Cohort in Phase 1 | 221 ng*h/mL | Geometric Coefficient of Variation 74 |
| Phase 1 Dose Escalation Cohort 5 | Mean Decitabine Area Under the Concentration Versus Time Curve (AUC0-t) on Day 5 by Cohort in Phase 1 | 146 ng*h/mL | Geometric Coefficient of Variation 50 |
Primary
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.
Time frame: Pre-dose to Day 5
Population: Participants with evaluable PK measurements are included. Phase 2 crossover design was used to compare AUC ratio for oral and IV administration.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Phase 1 Dose Escalation Cohort 1 | Mean Decitabine Area Under the Plasma Concentration Versus Time Curve Ratio (5-day AUC0-t) in Phase 2 | 93.52 Ratio of Geometric LSM |
| Phase 1 Dose Escalation Cohort 2 | Mean Decitabine Area Under the Plasma Concentration Versus Time Curve Ratio (5-day AUC0-t) in Phase 2 | 97.59 Ratio of Geometric LSM |
Primary
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.
Time frame: Pre-dose to Day 28 in Course 2 (28 days per course)
Population: The pharmacodynamic population includes all participants with evaluable data who received at least one dose of investigational product.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Phase 1 Dose Escalation Cohort 1 | Mean Maximum %LINE Demethylation in Phase 2 | Course 1 - IV Decitabine | 11.303 Percent |
| Phase 1 Dose Escalation Cohort 1 | Mean Maximum %LINE Demethylation in Phase 2 | Course 2 - IV Decitabine | 9.920 Percent |
| Phase 1 Dose Escalation Cohort 1 | Mean Maximum %LINE Demethylation in Phase 2 | Course 1 - Treatment | 11.159 Percent |
| Phase 1 Dose Escalation Cohort 1 | Mean Maximum %LINE Demethylation in Phase 2 | Course 2 - Treatment | 9.833 Percent |
| Phase 1 Dose Escalation Cohort 2 | Mean Maximum %LINE Demethylation in Phase 2 | Course 2 - Treatment | 8.134 Percent |
| Phase 1 Dose Escalation Cohort 2 | Mean Maximum %LINE Demethylation in Phase 2 | Course 1 - IV Decitabine | 12.665 Percent |
| Phase 1 Dose Escalation Cohort 2 | Mean Maximum %LINE Demethylation in Phase 2 | Course 1 - Treatment | 10.077 Percent |
| Phase 1 Dose Escalation Cohort 2 | Mean Maximum %LINE Demethylation in Phase 2 | Course 2 - IV Decitabine | 8.230 Percent |
95% CI: [-3.165, 2.876]
95% CI: [-3.463, 3.288]
95% CI: [-6.074, 0.899]
95% CI: [-5.08, 4.888]
Primary
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.
Time frame: Up to Day 28 in Course 1 (28 days per course)
Population: The safety population includes participants in Phase 1 who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1 Dose Escalation Cohort 1 | Number of Participants With Dose-limiting Toxicity in Phase 1 | 0 Participants |
| Phase 1 Dose Escalation Cohort 2 | Number of Participants With Dose-limiting Toxicity in Phase 1 | 0 Participants |
| Phase 1 Dose Escalation Cohort 3 | Number of Participants With Dose-limiting Toxicity in Phase 1 | 0 Participants |
| Phase 1 Dose Escalation Cohort 4 | Number of Participants With Dose-limiting Toxicity in Phase 1 | 0 Participants |
| Phase 1 Dose Escalation Cohort 5 | Number of Participants With Dose-limiting Toxicity in Phase 1 | 1 Participants |
Primary
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).
Time frame: Up to approximately 29 months
Population: The efficacy population includes all participants in Phase 2 who received at least one dose of investigational product.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1 Dose Escalation Cohort 1 | Number of Participants With Overall Response in Phase 2 | 29 Participants |
| Phase 1 Dose Escalation Cohort 2 | Number of Participants With Overall Response in Phase 2 | 19 Participants |
Secondary
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.
Time frame: At specified timepoints from 0 to 24 hours post-dose
Population: Participants with evaluable PK measurements are included.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1 Dose Escalation Cohort 1 | Area Under the Concentration Versus Time Curve of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine-epimer | 503 ng*h/mL | Geometric Coefficient of Variation 20 |
| Phase 1 Dose Escalation Cohort 1 | Area Under the Concentration Versus Time Curve of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine | 1650 ng*h/mL | Geometric Coefficient of Variation 43 |
| Phase 1 Dose Escalation Cohort 2 | Area Under the Concentration Versus Time Curve of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine | 1990 ng*h/mL | Geometric Coefficient of Variation 64 |
| Phase 1 Dose Escalation Cohort 2 | Area Under the Concentration Versus Time Curve of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine-epimer | 917 ng*h/mL | Geometric Coefficient of Variation 64 |
| Phase 1 Dose Escalation Cohort 3 | Area Under the Concentration Versus Time Curve of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine-epimer | 1670 ng*h/mL | Geometric Coefficient of Variation 48 |
| Phase 1 Dose Escalation Cohort 3 | Area Under the Concentration Versus Time Curve of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine | 3190 ng*h/mL | Geometric Coefficient of Variation 53 |
| Phase 1 Dose Escalation Cohort 4 | Area Under the Concentration Versus Time Curve of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine | 4830 ng*h/mL | Geometric Coefficient of Variation 51 |
| Phase 1 Dose Escalation Cohort 4 | Area Under the Concentration Versus Time Curve of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine-epimer | 2180 ng*h/mL | Geometric Coefficient of Variation 34 |
| Phase 1 Dose Escalation Cohort 5 | Area Under the Concentration Versus Time Curve of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine-epimer | 1560 ng*h/mL | Geometric Coefficient of Variation 56 |
| Phase 1 Dose Escalation Cohort 5 | Area Under the Concentration Versus Time Curve of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine | 3490 ng*h/mL | Geometric Coefficient of Variation 46 |
| Phase 2 Dose Confirmation | Area Under the Concentration Versus Time Curve of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine | 2370 ng*h/mL | Geometric Coefficient of Variation 56.8 |
| Phase 2 Dose Confirmation | Area Under the Concentration Versus Time Curve of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine-epimer | 1190 ng*h/mL | Geometric Coefficient of Variation 48.3 |
| Phase 2 Fixed-Dose Combination | Area Under the Concentration Versus Time Curve of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine-epimer | 710 ng*h/mL | Geometric Coefficient of Variation 38 |
| Phase 2 Fixed-Dose Combination | Area Under the Concentration Versus Time Curve of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine | 1510 ng*h/mL | Geometric Coefficient of Variation 49.4 |
Secondary
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.
Time frame: Up to 32 Months
Population: The efficacy population includes all participants in Phase 1 who received at least one dose of investigational product.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Dose Escalation Cohort 1 | Duration of Complete Response in Phase 1 | 546.00 days |
| Phase 1 Dose Escalation Cohort 2 | Duration of Complete Response in Phase 1 | 364.00 days |
| Phase 1 Dose Escalation Cohort 3 | Duration of Complete Response in Phase 1 | 470.00 days |
| Phase 1 Dose Escalation Cohort 4 | Duration of Complete Response in Phase 1 | 29.00 days |
| Phase 1 Dose Escalation Cohort 5 | Duration of Complete Response in Phase 1 | 399.0 days |
Secondary
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.
Time frame: Up to approximately 29 months
Population: The efficacy population includes all participants in Phase 2 who received at least one dose of investigational product.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Dose Escalation Cohort 1 | Duration of Complete Response in Phase 2 - Kaplan-Meier Estimate | 413.0 days |
| Phase 1 Dose Escalation Cohort 2 | Duration of Complete Response in Phase 2 - Kaplan-Meier Estimate | 155.0 days |
Secondary
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.
Time frame: At specific timepoints from 0 to 24 hours post-dose
Population: Participants with evaluable PK measurements are included.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1 Dose Escalation Cohort 1 | Maximum Observed Plasma Concentration (Cmax) of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine | 309 ng/mL | Geometric Coefficient of Variation 50 |
| Phase 1 Dose Escalation Cohort 1 | Maximum Observed Plasma Concentration (Cmax) of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine-epimer | 96 ng/mL | Geometric Coefficient of Variation 22 |
| Phase 1 Dose Escalation Cohort 2 | Maximum Observed Plasma Concentration (Cmax) of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine-epimer | 184 ng/mL | Geometric Coefficient of Variation 70 |
| Phase 1 Dose Escalation Cohort 2 | Maximum Observed Plasma Concentration (Cmax) of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine | 376 ng/mL | Geometric Coefficient of Variation 67 |
| Phase 1 Dose Escalation Cohort 3 | Maximum Observed Plasma Concentration (Cmax) of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine | 636 ng/mL | Geometric Coefficient of Variation 50 |
| Phase 1 Dose Escalation Cohort 3 | Maximum Observed Plasma Concentration (Cmax) of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine-epimer | 343 ng/mL | Geometric Coefficient of Variation 44 |
| Phase 1 Dose Escalation Cohort 4 | Maximum Observed Plasma Concentration (Cmax) of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine | 697 ng/mL | Geometric Coefficient of Variation 75 |
| Phase 1 Dose Escalation Cohort 4 | Maximum Observed Plasma Concentration (Cmax) of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine-epimer | 321 ng/mL | Geometric Coefficient of Variation 47 |
| Phase 1 Dose Escalation Cohort 5 | Maximum Observed Plasma Concentration (Cmax) of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine | 570 ng/mL | Geometric Coefficient of Variation 51 |
| Phase 1 Dose Escalation Cohort 5 | Maximum Observed Plasma Concentration (Cmax) of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine-epimer | 291 ng/mL | Geometric Coefficient of Variation 54 |
| Phase 2 Dose Confirmation | Maximum Observed Plasma Concentration (Cmax) of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine | 451 ng/mL | Geometric Coefficient of Variation 51.4 |
| Phase 2 Dose Confirmation | Maximum Observed Plasma Concentration (Cmax) of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine-epimer | 235 ng/mL | Geometric Coefficient of Variation 49 |
| Phase 2 Fixed-Dose Combination | Maximum Observed Plasma Concentration (Cmax) of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine | 293 ng/mL | Geometric Coefficient of Variation 43.1 |
| Phase 2 Fixed-Dose Combination | Maximum Observed Plasma Concentration (Cmax) of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine-epimer | 154 ng/mL | Geometric Coefficient of Variation 44.6 |
Secondary
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.
Time frame: At specific timepoints from 0 to 24 hours post-dose
Population: Participants with evaluable PK measurements are included.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 Dose Escalation Cohort 1 | Maximum Observed Plasma Concentration (Cmax) of Decitabine | 54.0 ng/mL | Geometric Coefficient of Variation 36 |
| Phase 1 Dose Escalation Cohort 2 | Maximum Observed Plasma Concentration (Cmax) of Decitabine | 76.5 ng/mL | Geometric Coefficient of Variation 42 |
| Phase 1 Dose Escalation Cohort 3 | Maximum Observed Plasma Concentration (Cmax) of Decitabine | 80.9 ng/mL | Geometric Coefficient of Variation 41 |
| Phase 1 Dose Escalation Cohort 4 | Maximum Observed Plasma Concentration (Cmax) of Decitabine | 161 ng/mL | Geometric Coefficient of Variation 51 |
| Phase 1 Dose Escalation Cohort 5 | Maximum Observed Plasma Concentration (Cmax) of Decitabine | 138 ng/mL | Geometric Coefficient of Variation 55 |
| Phase 2 Dose Confirmation | Maximum Observed Plasma Concentration (Cmax) of Decitabine | 126 ng/mL | Geometric Coefficient of Variation 70.9 |
| Phase 2 Fixed-Dose Combination | Maximum Observed Plasma Concentration (Cmax) of Decitabine | 126 ng/mL | Geometric Coefficient of Variation 76.2 |
Secondary
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.
Time frame: Pre-dose to Day 28 in Course 2 (28 days per course)
Population: The pharmacodynamic population includes all participants in Phase 1 with evaluable data who received at least one dose of investigational product.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1 Dose Escalation Cohort 1 | Mean Maximum %LINE Demethylation in Phase 1 | Course 2 | -8.0 Percent change | Standard Deviation 3.56 |
| Phase 1 Dose Escalation Cohort 1 | Mean Maximum %LINE Demethylation in Phase 1 | Course 1 | -8.3 Percent change | Standard Deviation 5.28 |
| Phase 1 Dose Escalation Cohort 2 | Mean Maximum %LINE Demethylation in Phase 1 | Course 1 | -9.2 Percent change | Standard Deviation 5.84 |
| Phase 1 Dose Escalation Cohort 2 | Mean Maximum %LINE Demethylation in Phase 1 | Course 2 | -7.1 Percent change | Standard Deviation 2.92 |
| Phase 1 Dose Escalation Cohort 3 | Mean Maximum %LINE Demethylation in Phase 1 | Course 1 | -10.5 Percent change | Standard Deviation 7.55 |
| Phase 1 Dose Escalation Cohort 3 | Mean Maximum %LINE Demethylation in Phase 1 | Course 2 | -8.9 Percent change | Standard Deviation 5.42 |
| Phase 1 Dose Escalation Cohort 4 | Mean Maximum %LINE Demethylation in Phase 1 | Course 1 | -12.1 Percent change | Standard Deviation 7.82 |
| Phase 1 Dose Escalation Cohort 4 | Mean Maximum %LINE Demethylation in Phase 1 | Course 2 | -8.6 Percent change | Standard Deviation 3.24 |
| Phase 1 Dose Escalation Cohort 5 | Mean Maximum %LINE Demethylation in Phase 1 | Course 1 | -11.7 Percent change | Standard Deviation 5.67 |
| Phase 1 Dose Escalation Cohort 5 | Mean Maximum %LINE Demethylation in Phase 1 | Course 2 | -7.5 Percent change | Standard Deviation 5.47 |
Secondary
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.
Time frame: Up to 32 months
Population: The efficacy population includes all participants in Phase 1 and Phase 2 who received at least one dose of investigational product.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1 Dose Escalation Cohort 1 | Number of Participants to Reach Acute Myeloid Leukemia (AML) or Death | Event | 3 Participants |
| Phase 1 Dose Escalation Cohort 1 | Number of Participants to Reach Acute Myeloid Leukemia (AML) or Death | Censored | 4 Participants |
| Phase 1 Dose Escalation Cohort 2 | Number of Participants to Reach Acute Myeloid Leukemia (AML) or Death | Event | 1 Participants |
| Phase 1 Dose Escalation Cohort 2 | Number of Participants to Reach Acute Myeloid Leukemia (AML) or Death | Censored | 5 Participants |
| Phase 1 Dose Escalation Cohort 3 | Number of Participants to Reach Acute Myeloid Leukemia (AML) or Death | Censored | 6 Participants |
| Phase 1 Dose Escalation Cohort 3 | Number of Participants to Reach Acute Myeloid Leukemia (AML) or Death | Event | 0 Participants |
| Phase 1 Dose Escalation Cohort 4 | Number of Participants to Reach Acute Myeloid Leukemia (AML) or Death | Event | 1 Participants |
| Phase 1 Dose Escalation Cohort 4 | Number of Participants to Reach Acute Myeloid Leukemia (AML) or Death | Censored | 5 Participants |
| Phase 1 Dose Escalation Cohort 5 | Number of Participants to Reach Acute Myeloid Leukemia (AML) or Death | Event | 8 Participants |
| Phase 1 Dose Escalation Cohort 5 | Number of Participants to Reach Acute Myeloid Leukemia (AML) or Death | Censored | 11 Participants |
| Phase 2 Dose Confirmation | Number of Participants to Reach Acute Myeloid Leukemia (AML) or Death | Censored | 22 Participants |
| Phase 2 Dose Confirmation | Number of Participants to Reach Acute Myeloid Leukemia (AML) or Death | Event | 28 Participants |
| Phase 2 Fixed-Dose Combination | Number of Participants to Reach Acute Myeloid Leukemia (AML) or Death | Event | 19 Participants |
| Phase 2 Fixed-Dose Combination | Number of Participants to Reach Acute Myeloid Leukemia (AML) or Death | Censored | 11 Participants |
Secondary
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.
Time frame: Up to 5 years
Population: The safety population includes all participants in Phase 1 and Phase 2 who received at least one dose of investigational product.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1 Dose Escalation Cohort 1 | Number of Participants With Adverse Events | Any Adverse Event | 6 Participants |
| Phase 1 Dose Escalation Cohort 1 | Number of Participants With Adverse Events | Any Grade ≥3 Adverse Event | 5 Participants |
| Phase 1 Dose Escalation Cohort 2 | Number of Participants With Adverse Events | Any Adverse Event | 6 Participants |
| Phase 1 Dose Escalation Cohort 2 | Number of Participants With Adverse Events | Any Grade ≥3 Adverse Event | 6 Participants |
| Phase 1 Dose Escalation Cohort 3 | Number of Participants With Adverse Events | Any Adverse Event | 6 Participants |
| Phase 1 Dose Escalation Cohort 3 | Number of Participants With Adverse Events | Any Grade ≥3 Adverse Event | 5 Participants |
| Phase 1 Dose Escalation Cohort 4 | Number of Participants With Adverse Events | Any Adverse Event | 6 Participants |
| Phase 1 Dose Escalation Cohort 4 | Number of Participants With Adverse Events | Any Grade ≥3 Adverse Event | 6 Participants |
| Phase 1 Dose Escalation Cohort 5 | Number of Participants With Adverse Events | Any Adverse Event | 19 Participants |
| Phase 1 Dose Escalation Cohort 5 | Number of Participants With Adverse Events | Any Grade ≥3 Adverse Event | 18 Participants |
| Phase 2 Dose Confirmation | Number of Participants With Adverse Events | Any Adverse Event | 50 Participants |
| Phase 2 Dose Confirmation | Number of Participants With Adverse Events | Any Grade ≥3 Adverse Event | 48 Participants |
| Phase 2 Fixed-Dose Combination | Number of Participants With Adverse Events | Any Grade ≥3 Adverse Event | 28 Participants |
| Phase 2 Fixed-Dose Combination | Number of Participants With Adverse Events | Any Adverse Event | 30 Participants |
Secondary
Number of Participants With Hematological Improvement
Hematological improvement was calculated as defined by the IWG 2006 MDS Response Criteria.
Time frame: Up to 32 months
Population: The efficacy population includes all participants in Phase 1 and Phase 2 who received at least one dose of investigational product.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1 Dose Escalation Cohort 1 | Number of Participants With Hematological Improvement | 4 Participants |
| Phase 1 Dose Escalation Cohort 2 | Number of Participants With Hematological Improvement | 3 Participants |
| Phase 1 Dose Escalation Cohort 3 | Number of Participants With Hematological Improvement | 2 Participants |
| Phase 1 Dose Escalation Cohort 4 | Number of Participants With Hematological Improvement | 0 Participants |
| Phase 1 Dose Escalation Cohort 5 | Number of Participants With Hematological Improvement | 3 Participants |
| Phase 2 Dose Confirmation | Number of Participants With Hematological Improvement | 8 Participants |
| Phase 2 Fixed-Dose Combination | Number of Participants With Hematological Improvement | 7 Participants |
Secondary
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).
Time frame: Up to 32 months
Population: The efficacy population includes all participants in Phase 1 who received at least one dose of investigational product.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1 Dose Escalation Cohort 1 | Number of Participants With Overall Response in Phase 1 | 4 Participants |
| Phase 1 Dose Escalation Cohort 2 | Number of Participants With Overall Response in Phase 1 | 3 Participants |
| Phase 1 Dose Escalation Cohort 3 | Number of Participants With Overall Response in Phase 1 | 2 Participants |
| Phase 1 Dose Escalation Cohort 4 | Number of Participants With Overall Response in Phase 1 | 1 Participants |
| Phase 1 Dose Escalation Cohort 5 | Number of Participants With Overall Response in Phase 1 | 3 Participants |
Secondary
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.
Time frame: Up to 32 months
Population: The efficacy population includes all participants in Phase 1 and Phase 2 who received at least one dose of investigational product.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1 Dose Escalation Cohort 1 | Number of Participants With Overall Survival | Censored | 6 Participants |
| Phase 1 Dose Escalation Cohort 1 | Number of Participants With Overall Survival | Event | 1 Participants |
| Phase 1 Dose Escalation Cohort 2 | Number of Participants With Overall Survival | Censored | 5 Participants |
| Phase 1 Dose Escalation Cohort 2 | Number of Participants With Overall Survival | Event | 1 Participants |
| Phase 1 Dose Escalation Cohort 3 | Number of Participants With Overall Survival | Censored | 6 Participants |
| Phase 1 Dose Escalation Cohort 3 | Number of Participants With Overall Survival | Event | 0 Participants |
| Phase 1 Dose Escalation Cohort 4 | Number of Participants With Overall Survival | Censored | 5 Participants |
| Phase 1 Dose Escalation Cohort 4 | Number of Participants With Overall Survival | Event | 1 Participants |
| Phase 1 Dose Escalation Cohort 5 | Number of Participants With Overall Survival | Censored | 15 Participants |
| Phase 1 Dose Escalation Cohort 5 | Number of Participants With Overall Survival | Event | 4 Participants |
| Phase 2 Dose Confirmation | Number of Participants With Overall Survival | Censored | 26 Participants |
| Phase 2 Dose Confirmation | Number of Participants With Overall Survival | Event | 24 Participants |
| Phase 2 Fixed-Dose Combination | Number of Participants With Overall Survival | Censored | 14 Participants |
| Phase 2 Fixed-Dose Combination | Number of Participants With Overall Survival | Event | 16 Participants |
Secondary
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.
Time frame: Up to 32 months
Population: The efficacy population includes all participants in Phase 1 and Phase 2 who received at least one dose of investigational product and were transfusion-dependent at baseline. Number analyzed is the number of participants who were transfusion-dependent at baseline.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1 Dose Escalation Cohort 1 | Number of Participants With Transfusion Independence | Red Blood Cell | 2 Participants |
| Phase 1 Dose Escalation Cohort 1 | Number of Participants With Transfusion Independence | Platelet | 0 Participants |
| Phase 1 Dose Escalation Cohort 2 | Number of Participants With Transfusion Independence | Red Blood Cell | 0 Participants |
| Phase 1 Dose Escalation Cohort 2 | Number of Participants With Transfusion Independence | Platelet | 0 Participants |
| Phase 1 Dose Escalation Cohort 3 | Number of Participants With Transfusion Independence | Red Blood Cell | 3 Participants |
| Phase 1 Dose Escalation Cohort 3 | Number of Participants With Transfusion Independence | Platelet | 1 Participants |
| Phase 1 Dose Escalation Cohort 4 | Number of Participants With Transfusion Independence | Red Blood Cell | 0 Participants |
| Phase 1 Dose Escalation Cohort 4 | Number of Participants With Transfusion Independence | Platelet | 0 Participants |
| Phase 1 Dose Escalation Cohort 5 | Number of Participants With Transfusion Independence | Red Blood Cell | 2 Participants |
| Phase 1 Dose Escalation Cohort 5 | Number of Participants With Transfusion Independence | Platelet | 1 Participants |
| Phase 2 Dose Confirmation | Number of Participants With Transfusion Independence | Red Blood Cell | 11 Participants |
| Phase 2 Dose Confirmation | Number of Participants With Transfusion Independence | Platelet | 3 Participants |
| Phase 2 Fixed-Dose Combination | Number of Participants With Transfusion Independence | Red Blood Cell | 8 Participants |
| Phase 2 Fixed-Dose Combination | Number of Participants With Transfusion Independence | Platelet | 3 Participants |
Secondary
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.
Time frame: At specific timepoints from 0 to 24 hours post-dose
Population: Participants with evaluable PK measurements are included.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1 Dose Escalation Cohort 1 | Time to Maximum Observed Plasma Concentration (Tmax) of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine | 3 hours |
| Phase 1 Dose Escalation Cohort 1 | Time to Maximum Observed Plasma Concentration (Tmax) of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine-epimer | 3 hours |
| Phase 1 Dose Escalation Cohort 2 | Time to Maximum Observed Plasma Concentration (Tmax) of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine | 3 hours |
| Phase 1 Dose Escalation Cohort 2 | Time to Maximum Observed Plasma Concentration (Tmax) of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine-epimer | 3 hours |
| Phase 1 Dose Escalation Cohort 3 | Time to Maximum Observed Plasma Concentration (Tmax) of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine | 3 hours |
| Phase 1 Dose Escalation Cohort 3 | Time to Maximum Observed Plasma Concentration (Tmax) of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine-epimer | 3 hours |
| Phase 1 Dose Escalation Cohort 4 | Time to Maximum Observed Plasma Concentration (Tmax) of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine | 3 hours |
| Phase 1 Dose Escalation Cohort 4 | Time to Maximum Observed Plasma Concentration (Tmax) of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine-epimer | 3 hours |
| Phase 1 Dose Escalation Cohort 5 | Time to Maximum Observed Plasma Concentration (Tmax) of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine | 3 hours |
| Phase 1 Dose Escalation Cohort 5 | Time to Maximum Observed Plasma Concentration (Tmax) of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine-epimer | 3 hours |
| Phase 2 Dose Confirmation | Time to Maximum Observed Plasma Concentration (Tmax) of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine | 3 hours |
| Phase 2 Dose Confirmation | Time to Maximum Observed Plasma Concentration (Tmax) of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine-epimer | 3 hours |
| Phase 2 Fixed-Dose Combination | Time to Maximum Observed Plasma Concentration (Tmax) of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine | 3 hours |
| Phase 2 Fixed-Dose Combination | Time to Maximum Observed Plasma Concentration (Tmax) of Cedazuridine (E7727) and Cedazuridine-epimer | Cedazuridine-epimer | 3.05 hours |
Secondary
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.
Time frame: At specific timepoints from 0 to 24 hours post-dose
Population: Participants with evaluable PK measurements are included.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 Dose Escalation Cohort 1 | Time to Maximum Observed Plasma Concentration (Tmax) of Decitabine in Phase 2 | 1.00 hours |
| Phase 1 Dose Escalation Cohort 2 | Time to Maximum Observed Plasma Concentration (Tmax) of Decitabine in Phase 2 | 0.95 hours |