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

1. Trial at a Glance

This page covers the registry results for Pharmacokinetic Guided Dose Escalation and Dose Confirmation With Oral Decitabine and Oral Cytidine Deaminase Inhibitor (CDAi) in Patients With Myelodysplastic Syndromes (MDS) (NCT02103478), a randomized phase 1, phase 2 study. The primary outcome is Mean Decitabine Area Under the Concentration Versus Time Curve (AUC0-t) on Day 5 by Cohort in Phase 1.

2. Clinical Question

The study was described as a first-in-human, three-stage, open-label investigation of ASTX727. Its stated aims included evaluating safety and pharmacokinetics and determining a dose for later stages. The primary result is cohort-based: it reports a geometric mean AUC0-t for each Phase 1 dose-escalation cohort, with geometric coefficient of variation (GCV) as the measure of dispersion.

The clinical context is MDS, but the primary endpoint does not measure disease response, symptom improvement, or survival. It quantifies decitabine exposure after oral dosing with cedazuridine, with the record describing IV decitabine dosing as part of the measurement context. Dose escalation and dose confirmation address different study-stage questions, so the cohort results should not be treated as if they came from a single parallel-group efficacy comparison.

3. Trial Design

This completed study had Phase 1 and Phase 2 components and was described as randomized overall, with no masking. The registry record reports enrollment of 130 and dates of 2014-10-28 for study start and 2018-06-05 for primary completion. Its brief description characterizes the investigation as first-in-human, open-label, and conducted in three stages.

In Phase 1 dose escalation, participants entered successive cohorts. The starting cohort received 40 mg oral cedazuridine and 20 mg oral decitabine. The registry description says that in later cohorts either the cedazuridine or decitabine oral dose was varied in Course 1 Day 2 through Course 1 Day 5 for comparison with a single IV decitabine dose. The description ends before giving complete dosing details, so the full dose sequence and the dose used in every cohort are not reported in the registry record.

Phase 2 included dose confirmation and fixed-dose combination stages. Participants in each stage were randomized in a 1:1 ratio to treatment sequences involving oral treatment in Course 1 and IV decitabine in Course 2, or the converse. The dose-confirmation description specifies oral cedazuridine 100 mg with decitabine 35 mg, while the fixed-dose description specifies a tablet containing 100 mg cedazuridine and 35 mg decitabine. The descriptions state that courses lasted 28 days and that treatment in later courses was given, but those details are truncated; the complete later-course schedules are not reported in the registry record.

The registry record's randomized allocation label therefore describes the study overall, while the primary endpoint analyzed belongs to the sequential Phase 1 dose-escalation cohorts. The design is not a single randomized comparison for that endpoint. The record does not report the randomization method, allocation concealment, or the rationale for the cohort sequence.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: 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).

Only the first 6 of 9 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Participants who were successfully dosed according to criteria for both ASTX727 and IV decitabine dosing and with evaluable pharmacokinetic (PK) measurements are included.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: Demographic and baseline characteristics are shown for participants who received at least one dose of study drug.

Only the first 6 of 8 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Mean Decitabine Area Under the Concentration Versus Time Curve (AUC0-t) on Day 5 by Cohort in Phase 1, measured over Day 5.

The primary endpoint is the mean decitabine AUC0-t on Day 5 by cohort in Phase 1. AUC0-t represents the area under the measured plasma concentration-versus-time curve from the start of observation to the last measured time point. As a general pharmacokinetic concept, this area summarizes drug exposure over the measurement interval: it reflects concentrations across time rather than a concentration at only one moment.

The registry defines the reported mean as a geometric mean and reports dispersion using the geometric coefficient of variation. It describes AUC calculation by the linear up/log down method, using measured concentration-time values above the limit of quantification. Values below the limit of quantification were not included in those calculations, according to the endpoint description.

Exposure is relevant to a dose-escalation study because the investigators were assessing pharmacokinetics while varying oral doses and determining a dose for later stages. AUC can help characterize whether exposure differs across dose cohorts, but the endpoint alone does not establish clinical efficacy, safety, or an optimal regimen. Those questions require other outcome information and an appropriate analysis.

The endpoint population was restricted to participants successfully dosed according to criteria for both ASTX727 and IV decitabine and with evaluable pharmacokinetic measurements. The criteria themselves, and the number of participants excluded from the primary analysis, are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is summarized with a geometric mean and geometric coefficient of variation, and the registry describes how the AUC was calculated. Those choices affect how the results should be read. They do not, by themselves, specify a hypothesis test or provide uncertainty intervals.

Why report a geometric mean?

As a general statistical concept, a geometric mean is useful for positive measurements that may be multiplicative in nature or have a right-skewed distribution. It is calculated on a logarithmic scale and then expressed back on the original measurement scale. This makes it different from an arithmetic mean: it summarizes values in a way that is sensitive to relative rather than purely additive changes. The registry identifies the primary summary as a geometric mean but does not report the distribution of individual AUC measurements or the rationale for choosing this summary.

A geometric mean should not be interpreted as the value observed in a typical participant without qualification. It is a group-level summary calculated from the set of observations used in the analysis. The registry population is restricted to participants with qualifying dosing and evaluable pharmacokinetic measurements. The record does not report the individual values, the number of missing measurements, or the rules used to determine whether a measurement was evaluable.

What does the GCV describe?

As a general statistical concept, the geometric coefficient of variation expresses relative dispersion around a geometric mean. It helps convey how variable measurements are in relation to their scale. A GCV is not a confidence interval and does not directly quantify how uncertain the estimated geometric mean is. Estimation uncertainty would ordinarily require an interval or another inferential result; those are not reported for the primary cohort estimates in the registry record.

Relative dispersion can be important in pharmacokinetic analyses because exposure measurements may vary substantially among participants. A cohort's GCV describes the spread of the observations represented in that summary, but does not identify whether variation reflects differences in dosing, measurement, participant characteristics, or other causes. The registry record does not provide information that would separate those explanations.

How is AUC0-t obtained?

The endpoint describes AUC0-t as calculated using the linear up/log down method and measured concentration-time values above the limit of quantification. As a general explanation, this method approximates the area between measured time points using a linear approach when concentrations rise and a logarithmic approach when they fall. AUC0-t therefore depends on the observed concentration-time measurements and the last measured time point used for each participant. It is not the same as a concentration measured at a single scheduled time.

The registry states that measurements below the limit of quantification were not used in the AUC calculation. It does not report how many values fell below that limit, how they were handled for other pharmacokinetic outcomes, or whether the final measurement time differed among participants. Those details can affect interpretation of exposure summaries and cannot be inferred from the endpoint definition alone.

What can cohort summaries establish?

The Phase 1 results present a mean and GCV for each successive dose-escalation cohort. As a general statistical principle, descriptive summaries characterize the observed data, while inferential tests or confidence intervals address uncertainty about population quantities or differences. No inferential test or confidence interval for the primary cohort summaries is reported in the registry record. The estimates therefore do not establish that the observed cohort values differ beyond sampling variation.

The sequential cohort structure is also relevant. It is not the same as a concurrent randomized comparison across all Phase 1 cohorts. The record says that dose levels were varied across successive cohorts, but the complete dose assignments and details of cohort progression are not reported in the registry record. Consequently, comparisons of the cohort means cannot isolate the effect of a particular dose change using the information available.

In Phase 2, randomization was reported for treatment sequences in dose confirmation and fixed-dose combination stages. That does not make the Phase 1 primary endpoint a randomized two-arm comparison. A randomized estimate would require a defined contrast, the corresponding group summaries, and an analysis accounting for the trial structure. Those elements are not reported for the primary endpoint.

How should planning illustrations be distinguished from trial results?

As a general statistical concept, a sample-size calculation is a planning exercise based on assumptions about a target effect, variability, significance level, allocation, and analysis method. The planning illustration associated with this record uses a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; its target effect is expressed as a stated fraction of the observed effect. These assumptions describe the illustration, not the trial's design rationale.

Any participant counts generated by such an illustration would be hypothetical planning quantities, not observed participants and not observed power. The trial's own sample-size justification is not reported in the registry record. The observed Phase 1 cohort summaries do not establish that the trial was powered for a particular cohort contrast, and no such contrast is specified for the primary endpoint.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists 19 outcome measures, 14 posted secondary outcomes, and 4 analyses. The primary result is one of several outcomes in a study spanning pharmacokinetic, safety, and response-duration measures. When multiple outcomes or analyses are examined, the chance of finding an apparently notable result can increase unless the analysis plan addresses multiplicity. As a general statistical principle, an adjustment, prespecified hierarchy, or clearly defined primary analysis can help frame interpretation. The registry record does not report a multiplicity adjustment, testing hierarchy, or family-wise error strategy.

The primary endpoint population included participants who met dosing criteria for both ASTX727 and IV decitabine and had evaluable PK measurements. The criteria used to define successful dosing and evaluability are not reported in the registry record. The number of participants with missing or unusable PK measurements, reasons for exclusion, and handling of missing measurements are also not reported in the registry record.

The record does not report a missing-data method for the secondary outcomes or a complete analysis-population definition for each outcome. It also does not report whether all randomized participants were included in Phase 2 analyses, how withdrawals were handled, or whether analyses followed an intention-to-treat principle. These omissions limit assessment of possible selection effects, particularly when the primary endpoint is restricted to participants with evaluable pharmacokinetic measurements.

The registry does not report confidence intervals or p-values for the primary cohort estimates. Consequently, the posted endpoint summaries do not support a multiplicity-adjusted inferential conclusion. The sample-size planning illustration is not the trial's statistical analysis plan, and the registry record does not report the trial's prespecified sample-size rationale or interim-analysis procedures.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: febrile neutropenia (34.0%), pneumonia (33.3%), sepsis (33.3%), anemia (16.7%), abdominal pain (16.7%).

The safety record reports participants at risk and participants affected for serious adverse events and for other adverse events, separately by study group. For example, in Phase 1 Dose Escalation Cohort 1, 2 of 7 participants at risk were affected by a serious adverse event, while 6 of 7 were affected by other adverse events. These counts describe whether participants were affected; they are not counts of the total number of individual event episodes.

In Phase 2 Dose Confirmation, 39 of 50 participants at risk were affected by a serious adverse event and 48 of 50 by other adverse events. In Phase 2 Fixed-Dose Combination, the corresponding counts were 25 of 30 and 30 of 30. The record also reports deaths by group, including 29 in Phase 2 Dose Confirmation and 21 in Phase 2 Fixed-Dose Combination. Death counts are not, by themselves, evidence that treatment caused the deaths.

The registry lists febrile neutropenia at 34.0%, pneumonia and sepsis at 33.3% each, and anemia, abdominal pain, and gastrointestinal hemorrhage at 16.7% each among the top serious terms. The denominator and the method used to select these terms are not reported in the registry record. These percentages should therefore be read as registry-listed event summaries, not as comparative risks or causal estimates. The open-label design and the absence of a reported safety comparison analysis also limit causal interpretation.

12. What the Result Does, and Does Not, Mean

The main result is a set of Phase 1 cohort summaries for Day 5 decitabine exposure. The geometric mean AUC0-t ranged from 53.6 ng*h/mL in Cohort 1 to 221.0 ng*h/mL in Cohort 4 among the reported cohort estimates. Cohort 5 had a reported geometric mean of 146.0 ng*h/mL. The GCV values indicate the relative variability reported for each cohort, but they do not provide confidence intervals around the means.

These results describe pharmacokinetics in participants with evaluable measurements under the study's dosing conditions. They do not establish that one dose is better, that a particular regimen should be used, or that ASTX727 changes MDS outcomes. The complete dose assignments across the Phase 1 cohorts are not reported in the registry record, and the primary endpoint does not measure clinical response or survival.

The Phase 2 design included randomized treatment sequences, but the primary endpoint is not a Phase 2 randomized comparison. The registry entries available do not include results for the secondary outcomes, even though the registry lists pharmacokinetic outcomes, response duration, and other measures. No conclusion about those outcomes can be drawn from the primary AUC summaries.

As a general statistical point, a descriptive difference between observed estimates is not the same as a demonstrated difference in the populations from which participants were drawn. The registry record does not report confidence intervals or a formal test for the cohort estimates. It also does not report the full dose schedule, individual participant data, or the missing-measurement details needed for a more complete evaluation.

The safety counts show that adverse events were recorded in the study groups, but they do not establish causation. The listed deaths and serious adverse events should be understood as safety observations from the registry record, not as an estimate of treatment-attributable risk. A causal safety assessment would require additional design and analysis details not reported in the registry record.

13. Why This Trial Matters Statistically

This study illustrates how a clinical trial can address a pharmacokinetic question before, or alongside, questions about clinical outcomes. The primary endpoint is exposure to decitabine on Day 5, summarized across successive Phase 1 cohorts. Such a measure can characterize drug exposure under the recorded administration conditions, while remaining distinct from evidence about disease response or survival.

The endpoint's choice of geometric mean and GCV also highlights the importance of matching statistical summaries to the type of measurement. As a general statistical concept, pharmacokinetic observations may be interpreted on a relative scale, and geometric summaries can represent that scale. At the same time, the GCV is descriptive dispersion, not an interval for the estimated mean. Readers need to distinguish variability among observations from uncertainty about an estimate.

The record also shows why design labels need context. Although the study is recorded as randomized, the primary endpoint belongs to sequential Phase 1 dose-escalation cohorts. Phase 2 randomization concerns treatment sequences, not a randomized comparison across the Phase 1 cohort means. Recognizing the estimand and design for each outcome prevents an incorrect interpretation of descriptive cohort patterns as controlled treatment effects.

Finally, the registry record makes clear that outcome definitions and population restrictions matter. The primary analysis used participants meeting dosing criteria and with evaluable PK measurements, but the operational criteria and missing-data handling are not reported. Those details affect how broadly the cohort summaries can be interpreted. The study is therefore useful as an example of reading pharmacokinetic results with attention to the endpoint, analysis population, design stage, and limits of the reported uncertainty.

14. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The primary endpoint is confined to a pharmacokinetic summary in Phase 1 and does not report a clinical efficacy outcome. The registry record does not include confidence intervals, p-values, or a formal between-cohort analysis for the reported AUC0-t estimates. The GCV values describe relative variation but do not replace uncertainty intervals for the means.

The Phase 1 dose descriptions are incomplete. Although the record states that oral doses varied across successive cohorts, the full dose assignment for each cohort is not reported in the registry record. This prevents a direct mapping of cohort-level exposure estimates to specific dose changes and makes a dose-response interpretation especially uncertain.

The analysis population was limited to participants successfully dosed according to criteria for both ASTX727 and IV decitabine and with evaluable PK measurements. The criteria, the number excluded, and the reasons for missing or unevaluable measurements are not reported in the registry record. The complete handling of values below the limit of quantification beyond the stated AUC calculation rule is also not reported.

Phase 2 treatment descriptions are truncated, including details about later courses. The record does not provide Phase 2 efficacy results in the registry record for this analysis, nor a full analysis plan for the randomized sequences. The open-label design means masking did not protect assessments from knowledge of treatment assignment, although the primary endpoint is a measured pharmacokinetic outcome.

The registry record does not report the trial's sample-size justification, multiplicity approach, interim analyses, or detailed statistical analysis plan. Safety counts are descriptive and do not establish causation; denominators for the listed serious-event percentages are not reported in the registry record. These limitations constrain both statistical inference and interpretation beyond the posted cohort summaries.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Pharmacokinetic Guided Dose Escalation and Dose Confirmation With Oral Decitabine and Oral Cytidine Deaminase Inhibitor (CDAi) in Patients With Myelodysplastic Syndromes (MDS) — NCT02103478.
• Registry record last updated 2024-08-27; status last verified 2024-07.
• Results first posted 2020-10-19.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

NCT02103478 is a completed Phase 1–2 study of ASTX727 in patients with MDS. The record describes an open-label, first-in-human study with dose escalation, dose confirmation, and fixed-dose combination stages. Enrollment was 130. The primary endpoint was mean decitabine AUC0-t on Day 5 by Phase 1 cohort, reported as a geometric mean with geometric coefficient of variation.

The posted primary results are descriptive cohort estimates. Phase 2 included randomized treatment sequences, but the primary endpoint is not a randomized Phase 2 contrast. The registry record does not report inferential tests or confidence intervals for the primary estimates, complete cohort dose assignments, or the full missing-data and multiplicity procedures. Safety results are reported as group-level participant counts and listed serious-event terms; these observations do not establish treatment causation.