A Phase 1/2 interventional study of ASTX727 Dose Escalation and ASTX727 Dose Confirmation in Myelodysplastic Syndrome and MDS, sponsored by Astex Pharmaceuticals, Inc.. Completed at 17 sites in 2 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2024-08-27.
Sponsored by Astex Pharmaceuticals, Inc. (part of Otsuka Holdings Co., Ltd.) · Phase 1/2, Interventional, and Treatment
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.
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.
2,165 studies on the registry are indexed under Myelodysplastic Syndromes; 322 are open to participants now.
This study's enrollment of 130 is above the median of 39 across 1,771 interventional studies indexed under Myelodysplastic Syndromes.
Browse Myelodysplastic Syndromes studies →Astex Pharmaceuticals, Inc. is the lead sponsor of 45 studies on the registry; none are open to participants now.
Of its 13 completed or terminated interventional studies of FDA-regulated products, 6 (46%) have results posted.
First submitted after Astex Pharmaceuticals, Inc. became part of Otsuka Holdings Co., Ltd..
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Exclusion Criteria:
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
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
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
Oral investigational product and approved IV decitabine
Also known as: cedazuridine (E7727), oral decitabine, IV decitabine
Randomization cross over design for courses 1 and 2
Also known as: ASTX727 oral (combination of oral E7727 and oral decitabine), IV decitabine
Fixed-dose investigational product
Also known as: ASTX727 oral (combination of oral E7727 and oral decitabine)
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
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
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)
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)
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
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
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
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
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
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
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
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
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)
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
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
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
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
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
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
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.
| Milestone | Phase 1 Dose Escalation Cohort 1 | Phase 1 Dose Escalation Cohort 2 | Phase 1 Dose Escalation Cohort 3 | Phase 1 Dose Escalation Cohort 4 | Phase 1 Dose Escalation Cohort 5 | Phase 2 Dose Confirmation Sequence A | Phase 2 Dose Confirmation Sequence B | Phase 2 Fixed-Dose Combination Sequence A | Phase 2 Fixed-Dose Combination Sequence B |
|---|---|---|---|---|---|---|---|---|---|
| Started | 7 | 6 | 6 | 6 | 19 | 25 | 25 | 16 | 14 |
| Completed | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Not completed | 7 | 6 | 6 | 6 | 19 | 25 | 25 | 16 | 14 |
| Withdrew: Adverse event | 0 | 0 | 1 | 1 | 2 | 1 | 0 | 0 | 0 |
| Withdrew: Death | 2 | 2 | 1 | 1 | 5 | 15 | 14 | 10 | 11 |
| Withdrew: Progressive disease | 2 | 1 | 2 | 0 | 9 | 1 | 2 | 0 | 1 |
| Withdrew: Withdrawal by subject | 2 | 0 | 0 | 4 | 0 | 0 | 1 | 1 | 0 |
| Withdrew: Lost to follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Withdrew: Other | 1 | 3 | 2 | 0 | 3 | 8 | 8 | 4 | 2 |
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).
| ng*h/mL | Phase 1 Dose Escalation Cohort 1 | Phase 1 Dose Escalation Cohort 2 | Phase 1 Dose Escalation Cohort 3 | Phase 1 Dose Escalation Cohort 4 | 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 | 53.6 ± 40 | 68.9 ± 44 | 94.8 ± 46 | 221 ± 74 | 146 ± 50 |
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.
| Ratio of Geometric LSM | Phase 2 Dose Confirmation | Phase 2 Fixed-Dose Combination |
|---|---|---|
| Mean Decitabine Area Under the Plasma Concentration Versus Time Curve Ratio (5-day AUC0-t) in Phase 2 | 93.52 (82.10 to 106.50) | 97.59 (80.48 to 118.30) |
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.
| Participants | Phase 1 Dose Escalation Cohort 1 | Phase 1 Dose Escalation Cohort 2 | Phase 1 Dose Escalation Cohort 3 | Phase 1 Dose Escalation Cohort 4 | Phase 1 Dose Escalation Cohort 5 |
|---|---|---|---|---|---|
| Number of Participants With Dose-limiting Toxicity in Phase 1 | 0 | 0 | 0 | 0 | 1 |
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.
| Percent | Phase 2 Dose Confirmation | Phase 2 Fixed-Dose Combination |
|---|---|---|
| Course 1 - Treatment | 11.159 (9.023 to 13.294) | 10.077 (7.696 to 12.459) |
| Course 1 - IV Decitabine | 11.303 (9.167 to 13.439) | 12.665 (10.12 to 15.211) |
| Course 2 - Treatment | 9.833 (7.446 to 12.219) | 8.134 (4.438 to 11.830) |
| Course 2 - IV Decitabine | 9.920 (7.534 to 12.307) | 8.230 (4.887 to 11.574) |
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).
| Participants | Phase 2 Dose Confirmation | Phase 2 Fixed-Dose Combination |
|---|---|---|
| Number of Participants With Overall Response in Phase 2 | 29 | 19 |
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.
| ng*h/mL | Phase 1 Dose Escalation Cohort 1 | Phase 1 Dose Escalation Cohort 2 | Phase 1 Dose Escalation Cohort 3 | Phase 1 Dose Escalation Cohort 4 | Phase 1 Dose Escalation Cohort 5 | Phase 2 Dose Confirmation | Phase 2 Fixed-Dose Combination |
|---|---|---|---|---|---|---|---|
| Cedazuridine | 1650 ± 43 | 1990 ± 64 | 3190 ± 53 | 4830 ± 51 | 3490 ± 46 | 2370 ± 56.8 | 1510 ± 49.4 |
| Cedazuridine-epimer | 503 ± 20 | 917 ± 64 | 1670 ± 48 | 2180 ± 34 | 1560 ± 56 | 1190 ± 48.3 | 710 ± 38 |
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.
| ng/mL | Phase 1 Dose Escalation Cohort 1 | Phase 1 Dose Escalation Cohort 2 | Phase 1 Dose Escalation Cohort 3 | Phase 1 Dose Escalation Cohort 4 | Phase 1 Dose Escalation Cohort 5 | Phase 2 Dose Confirmation | Phase 2 Fixed-Dose Combination |
|---|---|---|---|---|---|---|---|
| Cedazuridine | 309 ± 50 | 376 ± 67 | 636 ± 50 | 697 ± 75 | 570 ± 51 | 451 ± 51.4 | 293 ± 43.1 |
| Cedazuridine-epimer | 96 ± 22 | 184 ± 70 | 343 ± 44 | 321 ± 47 | 291 ± 54 | 235 ± 49 | 154 ± 44.6 |
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.
| hours | Phase 1 Dose Escalation Cohort 1 | Phase 1 Dose Escalation Cohort 2 | Phase 1 Dose Escalation Cohort 3 | Phase 1 Dose Escalation Cohort 4 | Phase 1 Dose Escalation Cohort 5 | Phase 2 Dose Confirmation | Phase 2 Fixed-Dose Combination |
|---|---|---|---|---|---|---|---|
| Cedazuridine | 3 (2 to 4) | 3 (2 to 4) | 3 (3 to 4) | 3 (2 to 6) | 3 (2 to 6) | 3 (1.50 to 4.08) | 3 (2.00 to 7.18) |
| Cedazuridine-epimer | 3 (2 to 4) | 3 (2 to 3) | 3 (3 to 4) | 3 (2 to 6) | 3 (2 to 6) | 3 (1.50 to 6.17) | 3.05 (2.00 to 7.20) |
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.
| ng/mL | Phase 1 Dose Escalation Cohort 1 | Phase 1 Dose Escalation Cohort 2 | Phase 1 Dose Escalation Cohort 3 | Phase 1 Dose Escalation Cohort 4 | Phase 1 Dose Escalation Cohort 5 | Phase 2 Dose Confirmation | Phase 2 Fixed-Dose Combination |
|---|---|---|---|---|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) of Decitabine | 54.0 ± 36 | 76.5 ± 42 | 80.9 ± 41 | 161 ± 51 | 138 ± 55 | 126 ± 70.9 | 126 ± 76.2 |
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.
| hours | Phase 2 Dose Confirmation | Phase 2 Fixed-Dose Combination |
|---|---|---|
| Time to Maximum Observed Plasma Concentration (Tmax) of Decitabine in Phase 2 | 1.00 (0.47 to 3.00) | 0.95 (0.47 to 2.12) |
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.
| days | Phase 1 Dose Escalation Cohort 1 | Phase 1 Dose Escalation Cohort 2 | Phase 1 Dose Escalation Cohort 3 | Phase 1 Dose Escalation Cohort 4 | Phase 1 Dose Escalation Cohort 5 |
|---|---|---|---|---|---|
| Duration of Complete Response in Phase 1 | 546.00 (546.0 to 546.0) | 364.00 (56.0 to 672.0) | 470.00 (470.0 to 470.0) | 29.00 (29.0 to 29.0) | 399.0 (202.0 to 420.0) |
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.
| days | Phase 2 Dose Confirmation | Phase 2 Fixed-Dose Combination |
|---|---|---|
| Duration of Complete Response in Phase 2 - Kaplan-Meier Estimate | 413.0 (180.0 to 553.0) | 155.0 (35.0 to 285.0) |
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.
| Percent change | Phase 1 Dose Escalation Cohort 1 | Phase 1 Dose Escalation Cohort 2 | Phase 1 Dose Escalation Cohort 3 | Phase 1 Dose Escalation Cohort 4 | Phase 1 Dose Escalation Cohort 5 |
|---|---|---|---|---|---|
| Course 1 | -8.3 ± 5.28 | -9.2 ± 5.84 | -10.5 ± 7.55 | -12.1 ± 7.82 | -11.7 ± 5.67 |
| Course 2 | -8.0 ± 3.56 | -7.1 ± 2.92 | -8.9 ± 5.42 | -8.6 ± 3.24 | -7.5 ± 5.47 |
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).
| Participants | Phase 1 Dose Escalation Cohort 1 | Phase 1 Dose Escalation Cohort 2 | Phase 1 Dose Escalation Cohort 3 | Phase 1 Dose Escalation Cohort 4 | Phase 1 Dose Escalation Cohort 5 |
|---|---|---|---|---|---|
| Number of Participants With Overall Response in Phase 1 | 4 | 3 | 2 | 1 | 3 |
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.
| Participants | Phase 1 Dose Escalation Cohort 1 | Phase 1 Dose Escalation Cohort 2 | Phase 1 Dose Escalation Cohort 3 | Phase 1 Dose Escalation Cohort 4 | Phase 1 Dose Escalation Cohort 5 | Phase 2 Dose Confirmation | Phase 2 Fixed-Dose Combination |
|---|---|---|---|---|---|---|---|
| Any Adverse Event | 6 | 6 | 6 | 6 | 19 | 50 | 30 |
| Any Grade ≥3 Adverse Event | 5 | 6 | 5 | 6 | 18 | 48 | 28 |
Hematological improvement was calculated as defined by the IWG 2006 MDS Response Criteria.
| Participants | Phase 1 Dose Escalation Cohort 1 | Phase 1 Dose Escalation Cohort 2 | Phase 1 Dose Escalation Cohort 3 | Phase 1 Dose Escalation Cohort 4 | Phase 1 Dose Escalation Cohort 5 | Phase 2 Dose Confirmation | Phase 2 Fixed-Dose Combination |
|---|---|---|---|---|---|---|---|
| Number of Participants With Hematological Improvement | 4 | 3 | 2 | 0 | 3 | 8 | 7 |
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.
| Participants | Phase 1 Dose Escalation Cohort 1 | Phase 1 Dose Escalation Cohort 2 | Phase 1 Dose Escalation Cohort 3 | Phase 1 Dose Escalation Cohort 4 | Phase 1 Dose Escalation Cohort 5 | Phase 2 Dose Confirmation | Phase 2 Fixed-Dose Combination |
|---|---|---|---|---|---|---|---|
| Red Blood Cell | 2 | 0 | 3 | 0 | 2 | 11 | 8 |
| Platelet | 0 | 0 | 1 | 0 | 1 | 3 | 3 |
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.
| Participants | Phase 1 Dose Escalation Cohort 1 | Phase 1 Dose Escalation Cohort 2 | Phase 1 Dose Escalation Cohort 3 | Phase 1 Dose Escalation Cohort 4 | Phase 1 Dose Escalation Cohort 5 | Phase 2 Dose Confirmation | Phase 2 Fixed-Dose Combination |
|---|---|---|---|---|---|---|---|
| Censored | 4 | 5 | 6 | 5 | 11 | 22 | 11 |
| Event | 3 | 1 | 0 | 1 | 8 | 28 | 19 |
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.
| Participants | Phase 1 Dose Escalation Cohort 1 | Phase 1 Dose Escalation Cohort 2 | Phase 1 Dose Escalation Cohort 3 | Phase 1 Dose Escalation Cohort 4 | Phase 1 Dose Escalation Cohort 5 | Phase 2 Dose Confirmation | Phase 2 Fixed-Dose Combination |
|---|---|---|---|---|---|---|---|
| Censored | 6 | 5 | 6 | 5 | 15 | 26 | 14 |
| Event | 1 | 1 | 0 | 1 | 4 | 24 | 16 |
Collected over Up to 5 years. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Phase 1 Dose Escalation Cohort 1 | 2/7 (28.6%) | 2/7 (28.6%) | 6/7 (85.7%) |
| Phase 1 Dose Escalation Cohort 2 | 2/6 (33.3%) | 4/6 (66.7%) | 6/6 (100%) |
| Phase 1 Dose Escalation Cohort 3 | 1/6 (16.7%) | 2/6 (33.3%) | 6/6 (100%) |
| Phase 1 Dose Escalation Cohort 4 | 1/6 (16.7%) | 6/6 (100%) | 6/6 (100%) |
| Phase 1 Dose Escalation Cohort 5 | 5/19 (26.3%) | 14/19 (73.7%) | 18/19 (94.7%) |
| Phase 2 Dose Confirmation | 29/50 (58%) | 39/50 (78%) | 48/50 (96%) |
| Phase 2 Fixed-Dose Combination | 21/30 (70%) | 25/30 (83.3%) | 30/30 (100%) |
| Event | Phase 1 Dose Escalation Cohort 1 | Phase 1 Dose Escalation Cohort 2 | Phase 1 Dose Escalation Cohort 3 | Phase 1 Dose Escalation Cohort 4 | Phase 1 Dose Escalation Cohort 5 | Phase 2 Dose Confirmation | Phase 2 Fixed-Dose Combination |
|---|---|---|---|---|---|---|---|
| Febrile neutropeniaBlood and lymphatic system disorders | 1/7 | 1/6 | 1/6 | 2/6 | 2/19 | 17/50 | 7/30 |
| PneumoniaInfections and infestations | 0/7 | 1/6 | 0/6 | 2/6 | 3/19 | 8/50 | 5/30 |
| SepsisInfections and infestations | 0/7 | 0/6 | 0/6 | 2/6 | 2/19 | 5/50 | 8/30 |
| AnemiaBlood and lymphatic system disorders | 0/7 | 0/6 | 1/6 | 0/6 | 1/19 | 1/50 | 0/30 |
| Abdominal painGastrointestinal disorders | 0/7 | 1/6 | 0/6 | 0/6 | 0/19 | 1/50 | 0/30 |
| Gastrointestinal hemorrhageGastrointestinal disorders | 0/7 | 0/6 | 1/6 | 0/6 | 0/19 | 2/50 | 1/30 |
| DiarrheaGastrointestinal disorders | 0/7 | 1/6 | 0/6 | 0/6 | 1/19 | 0/50 | 0/30 |
| Multiple organ dysfunction syndromeGeneral disorders | 0/7 | 1/6 | 0/6 | 0/6 | 0/19 | 0/50 | 1/30 |
| PyrexiaGeneral disorders | 0/7 | 0/6 | 0/6 | 1/6 | 0/19 | 3/50 | 1/30 |
| BacteremiaInfections and infestations | 0/7 | 0/6 | 0/6 | 1/6 | 1/19 | 3/50 | 0/30 |
| Event | Phase 1 Dose Escalation Cohort 1 | Phase 1 Dose Escalation Cohort 2 | Phase 1 Dose Escalation Cohort 3 | Phase 1 Dose Escalation Cohort 4 | Phase 1 Dose Escalation Cohort 5 | Phase 2 Dose Confirmation | Phase 2 Fixed-Dose Combination |
|---|---|---|---|---|---|---|---|
| ConstipationGastrointestinal disorders | 2/7 | 5/6 | 1/6 | 2/6 | 7/19 | 17/50 | 12/30 |
| FatigueGeneral disorders | 2/7 | 5/6 | 3/6 | 5/6 | 6/19 | 23/50 | 12/30 |
| ThrombocytopeniaBlood and lymphatic system disorders | 4/7 | 3/6 | 4/6 | 3/6 | 10/19 | 27/50 | 15/30 |
| NeutropeniaBlood and lymphatic system disorders | 3/7 | 2/6 | 4/6 | 1/6 | 6/19 | 28/50 | 12/30 |
| NauseaGastrointestinal disorders | 1/7 | 4/6 | 3/6 | 3/6 | 5/19 | 13/50 | 14/30 |
| AnemiaBlood and lymphatic system disorders | 4/7 | 1/6 | 2/6 | 3/6 | 5/19 | 16/50 | 8/30 |
| Abdominal painGastrointestinal disorders | 0/7 | 0/6 | 1/6 | 3/6 | 2/19 | 3/50 | 3/30 |
| Edema peripheralGeneral disorders | 0/7 | 3/6 | 1/6 | 2/6 | 4/19 | 13/50 | 3/30 |
| HypomagnesemiaMetabolism and nutrition disorders | 2/7 | 1/6 | 1/6 | 3/6 | 2/19 | 12/50 | 5/30 |
| Acute kidney injuryRenal and urinary disorders | 0/7 | 3/6 | 0/6 | 1/6 | 2/19 | 2/50 | 3/30 |
Demographic and baseline characteristics are shown for participants who received at least one dose of study drug.
| Age, Continuous(years) | Phase 1 Dose Escalation Cohort 1 | Phase 1 Dose Escalation Cohort 2 | Phase 1 Dose Escalation Cohort 3 | Phase 1 Dose Escalation Cohort 4 | Phase 1 Dose Escalation Cohort 5 | Phase 2 Dose Confirmation | Phase 2 Fixed-Dose Combination | Total |
|---|---|---|---|---|---|---|---|---|
| Mean | 69.6 ± 8.1 | 72 ± 6.2 | 74 ± 4.8 | 75.2 ± 7.1 | 71.6 ± 8.8 | 69.7 ± 10.72 | 69.6 ± 10.57 | 70.6 ± 9.67 |
| Sex: Female, Male(Participants) | Phase 1 Dose Escalation Cohort 1 | Phase 1 Dose Escalation Cohort 2 | Phase 1 Dose Escalation Cohort 3 | Phase 1 Dose Escalation Cohort 4 | Phase 1 Dose Escalation Cohort 5 | Phase 2 Dose Confirmation | Phase 2 Fixed-Dose Combination | Total |
|---|---|---|---|---|---|---|---|---|
| Female | 4 | 1 | 3 | 2 | 4 | 9 | 10 | 33 |
| Male | 3 | 5 | 3 | 4 | 15 | 41 | 20 | 91 |
| Ethnicity (NIH/OMB)(Participants) | Phase 1 Dose Escalation Cohort 1 | Phase 1 Dose Escalation Cohort 2 | Phase 1 Dose Escalation Cohort 3 | Phase 1 Dose Escalation Cohort 4 | Phase 1 Dose Escalation Cohort 5 | Phase 2 Dose Confirmation | Phase 2 Fixed-Dose Combination | Total |
|---|---|---|---|---|---|---|---|---|
| Hispanic or Latino | 0 | 0 | 0 | 1 | 0 | 2 | 3 | 6 |
| Not Hispanic or Latino | 7 | 6 | 5 | 5 | 18 | 46 | 26 | 113 |
| Unknown or Not Reported | 0 | 0 | 1 | 0 | 1 | 2 | 1 | 5 |
| Race (NIH/OMB)(Participants) | Phase 1 Dose Escalation Cohort 1 | Phase 1 Dose Escalation Cohort 2 | Phase 1 Dose Escalation Cohort 3 | Phase 1 Dose Escalation Cohort 4 | Phase 1 Dose Escalation Cohort 5 | Phase 2 Dose Confirmation | Phase 2 Fixed-Dose Combination | Total |
|---|---|---|---|---|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Asian | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Black or African American | 1 | 0 | 0 | 1 | 1 | 2 | 0 | 5 |
| White | 6 | 6 | 5 | 5 | 18 | 46 | 28 | 114 |
| More than one race | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 1 | 0 | 0 | 1 | 2 | 4 |
| Region of Enrollment(participants) | Phase 1 Dose Escalation Cohort 1 | Phase 1 Dose Escalation Cohort 2 | Phase 1 Dose Escalation Cohort 3 | Phase 1 Dose Escalation Cohort 4 | Phase 1 Dose Escalation Cohort 5 | Phase 2 Dose Confirmation | Phase 2 Fixed-Dose Combination | Total |
|---|---|---|---|---|---|---|---|---|
| Canada | 0 | 0 | 0 | 0 | 0 | 8 | 8 | 16 |
| United States | 7 | 6 | 6 | 6 | 19 | 42 | 22 | 108 |
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Studies of the drug tested here: Decitabine