A Phase 1b/2 Study of Alvocidib Plus Decitabine or Azacitidine in Patients With MDS: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Phase 1b/2 Study of Alvocidib Plus Decitabine or Azacitidine in Patients With MDS (NCT03593915), a na phase 1, phase 2 study. The primary outcome is Number of Participants With Adverse Events and Serious Adverse Events.

2. Clinical Question

The study asks whether alvocidib, administered in sequence after decitabine or azacitidine, has preliminary safety and efficacy in patients with myelodysplastic syndromes (MDS). The registry record identifies safety—not a comparative treatment effect—as the primary outcome: the number of participants with adverse events and serious adverse events during the stated observation period.

3. Trial Design

This was a Phase 1b/2, open-label, single-group clinical study of alvocidib administered in sequence after decitabine or azacitidine in patients with MDS. The registry lists allocation as NA and masking as none. Although participants were assigned to treatment cohorts, the record does not describe a randomized allocation or a concurrent control arm. Cohort outcomes therefore do not provide a like-for-like treatment comparison.

The intervention description identifies alvocidib plus decitabine during dose escalation only, or alvocidib plus azacitidine. The safety results distinguish ALV-DEC: Cohorts 1 through 4, and ALV-AZA: Cohorts 5 and 6. The record does not explain the dose levels, rules for moving between cohorts, or how participants were assigned to a cohort. Those details are not reported in the registry record.

The planned enrollment is 20 participants. The study began on 2018-08-29, and the primary completion date is 2021-08-16. Its status is terminated. The reason for termination and whether it was related to safety, efficacy, recruitment, or another consideration are not reported in the registry record; termination alone does not establish why the study ended.

The arm description includes previously untreated patients with MDS and, during dose escalation only, patients who had received <6 cycles of hypomethylating agents. It also describes participants with de novo or secondary MDS who were not eligible for intensive induction chemotherapy or stem cell transplant. The description is incomplete, and the full eligibility criteria are not reported in the registry record.

The stated study purpose was preliminary assessment of safety and efficacy. The registry identifies adverse events and serious adverse events as the primary outcome and names complete response rate and improvement in transfusion dependence as secondary outcomes. The secondary-outcome results are not reported in the registry record.

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: In phase 1b, patients were enrolled in cohorts of 3-6 patients. Escalation of alvocidib (ALV) dose followed standard 3+3 dosing with sequential cohorts of 3 patients treated at incrementally higher doses of alvocidib administered in sequence after fixed doses of decitabine (DEC) or azacitadine (AZA) until MTD is reached.

Overall Study

Reasons for not completing this period:

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.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Adverse Events and Serious Adverse Events, measured over From the time of first dose to 30 days after the last dose, an average of 33.7 weeks..

The primary outcome is the number of participants with adverse events and serious adverse events. It is a participant-count outcome: it records whether participants experienced events, rather than expressing an event rate per unit of treatment exposure. The outcome description says safety was assessed by reporting adverse events and serious adverse events with alvocidib administered in combination with decitabine or azacitidine.

The observation period runs from the first dose to 30 days after the last dose, with an average duration of 33.7 weeks. That window defines which events the stated outcome is intended to capture. Because the average duration is reported, it should not be read as an identical follow-up period for every participant.

As a general statistical rationale, adverse-event outcomes are used to describe the safety experience during treatment and follow-up. Serious events are often reported separately because their clinical consequences can be important, while broader adverse-event reporting captures other harms. Counts of participants with events do not by themselves establish that treatment caused an event; attribution, severity, timing, and exposure context matter. Those details are not fully reported in the registry record.

The outcome is not a measure of antitumor efficacy. Complete response rate and improvement in transfusion dependence are listed as secondary outcomes, but results for them are not reported in the registry record. No combined primary endpoint estimate or inferential analysis is reported.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies a participant-count primary outcome: the number of participants with adverse events and serious adverse events. The posted cohort figures are counts of participants affected, alongside the numbers listed at risk. They are not event counts in the sense of every separate occurrence; a participant with repeated events may still contribute once to a participant-level count. The registry record does not provide enough detail to determine how repeated events were handled across all outcome reporting.

What does a participant count represent?

As a general statistical explanation, a participant count is a straightforward way to describe how many people experienced an outcome during a defined observation window. It differs from an event rate, which would account for time under observation, and from an event count, which could include repeated events in one person. The primary outcome is reported as participants with events; an exposure-adjusted rate is not reported in the registry record.

For an adverse-event outcome, the denominator and the follow-up window are important to interpretation. The registry gives cohort-specific counts and a timeframe from the first dose to 30 days after the last dose, with an average of 33.7 weeks. An average follow-up duration does not mean that each participant had the same duration of observation. The registry record does not report individual follow-up times, losses to follow-up, or the number of participants assessed at each time point.

Why separate serious from other adverse events?

As a general matter, separate reporting distinguishes events classified as serious from adverse events more broadly. This can make the safety profile easier to describe, but the counts remain descriptive unless the study also specifies event definitions, severity grading, attribution, and the analysis approach. The posted results do not provide a detailed grading system or a complete account of how seriousness and treatment relatedness were determined. Those details are not reported in the registry record.

Serious adverse events should not be interpreted as necessarily caused by the study treatment. A count indicates that events were recorded among participants during the stated observation period; it does not, by itself, establish a causal relationship. Likewise, a death count does not indicate cause or timing unless those details are reported. The registry gives death counts by cohort but does not report those additional details.

What can the cohort structure establish?

The study is described as single-group, with allocation listed as NA and masking as none. The posted safety results are separated into ALV-DEC and ALV-AZA cohorts, but this does not make the cohorts randomized comparison groups. As a general statistical point, nonrandomized cohort differences may reflect differences in participant characteristics, treatment stage, cohort size, follow-up, or other factors, as well as treatment. The registry does not report enough information to separate these possibilities.

The intervention description restricts decitabine to dose escalation only, while the listed cohorts include four ALV-DEC cohorts and two ALV-AZA cohorts. Details about dose levels, cohort assignment, escalation decisions, and protocol changes are not reported in the registry record. No adjusted analysis or formal comparison is reported.

How should uncertainty be understood?

As a general explanation, a confidence interval describes the range of values compatible with the observed data under the assumptions of the statistical method. Its width conveys precision: wider intervals indicate greater uncertainty. The registry record reports no confidence intervals for the primary outcome. The counts therefore do not provide a formal estimate of statistical uncertainty or a basis for judging how precisely a broader population rate has been estimated.

The record also reports no hypothesis tests or analyses. Statistical significance cannot be inferred from the descriptive counts, and absence of an analysis is not evidence of no effect. Because there is no randomized control group, the study cannot use the cohort counts alone to estimate a controlled treatment contrast.

What does the record say about planning?

The registry lists planned enrollment of 20 participants. A sample-size justification, target precision, power calculation, or statistical plan is not reported in the registry record. No sample-size illustration or observed-power interpretation should be treated as a result of the trial. The number enrolled is a design characteristic, not evidence by itself that a particular treatment effect was detected or ruled out.

The record lists a Phase 1b/2 design and describes preliminary safety and efficacy as the study purpose. It does not report whether interim analyses were planned or conducted, how decisions to terminate were made, or whether any stopping boundaries were used. Those matters are not reported in the registry record.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("ALV-DEC: Cohort 1", "ALV-DEC: Cohort 2", "ALV-DEC: Cohort 3", "ALV-DEC: Cohort 4", "ALV-AZA: Cohort 5", "ALV-AZA: Cohort 6")
n      <- c(3, 3, 3, 4, 3, 4)
events <- c(3, 3, 3, 4, 3, 4)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  ALV-DEC: Cohort 1  3  3  100.0  29.2  100.0  43.9  100.0  39.8  99.4
ARM  ALV-DEC: Cohort 2  3  3  100.0  29.2  100.0  43.9  100.0  39.8  99.4
ARM  ALV-DEC: Cohort 3  3  3  100.0  29.2  100.0  43.9  100.0  39.8  99.4
ARM  ALV-DEC: Cohort 4  4  4  100.0  39.8  100.0  51.0  100.0  47.8  99.5
ARM  ALV-AZA: Cohort 5  3  3  100.0  29.2  100.0  43.9  100.0  39.8  99.4
ARM  ALV-AZA: Cohort 6  4  4  100.0  39.8  100.0  51.0  100.0  47.8  99.5

11. Multiplicity, Missing Data and Analysis Populations

The registry names a primary safety outcome and two secondary outcomes: complete response rate and improvement in transfusion dependence. It does not report results for the secondary outcomes, nor does it describe how statistical testing across outcomes was handled. A multiplicity adjustment, testing hierarchy, or plan for controlling false-positive findings is not reported in the registry record. Without reported analyses, there are no inferential results from which to assess multiplicity in practice.

Missing-data handling is also not described. The record does not report whether all participants had complete follow-up, how participants who discontinued treatment were handled, or how outcome status was determined when information was unavailable. The average observation period of 33.7 weeks does not show whether follow-up was complete for each participant or whether missingness affected the event counts.

The analysis populations are not described. In particular, the registry record does not state whether outcomes were analyzed according to treatment received, enrollment cohort, or another defined population. It does not report a participant flow accounting for enrollment, treatment, follow-up, or inclusion in each outcome analysis. The planned enrollment is 20, but that alone does not establish the number assessed for every outcome.

These omissions limit assessment of how the reported safety counts were assembled and whether the same rules were applied across cohorts. They also prevent evaluation of the completeness of the secondary outcomes and of any statistical control for multiple comparisons.

12. 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: dyspnoea (33.3%), acute respiratory failure (33.3%), hypoxia (33.3%), pneumonia aspiration (33.3%), pulmonary embolism (33.3%).

The serious adverse-event counts are reported by cohort. The affected-participant counts are 2 of 3 in ALV-DEC: Cohort 1, 2 of 3 in Cohort 2, 1 of 3 in Cohort 3, 3 of 4 in Cohort 4, 3 of 3 in ALV-AZA: Cohort 5, and 1 of 4 in Cohort 6. These figures describe participants with serious adverse events in the registry’s cohort reporting; they are not counts of all separate serious-event episodes.

Other adverse-event counts are listed separately, as are death counts. The registry record does not give the timing or causes of deaths or establish a causal link between deaths and treatment. It also does not report event severity grades, duration, recurrence, or treatment attribution in sufficient detail to interpret each count clinically.

Each of the listed serious-event terms—dyspnoea, acute respiratory failure, hypoxia, aspiration pneumonia, pulmonary embolism, and lower gastrointestinal haemorrhage—is reported at 33.3%. The denominator for these percentages is not specified in the registry record, so they should not be converted into inferred participant counts or compared as rates.

Because the trial was open-label and single-group, these safety observations are descriptive. They do not provide a randomized estimate of excess risk compared with another treatment.

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

The results show that adverse events and serious adverse events were recorded among participants across the six treatment cohorts. The registry provides cohort-level participant counts and lists several serious-event terms at 33.3%. It also reports death counts by cohort. These are the safety observations entered in the registry; they should be understood in the context of the study’s single-group design and the limits of the accompanying detail.

The record does not report a formal analysis of the primary outcome, confidence intervals, or hypothesis tests. It therefore does not establish the precision of an overall safety estimate or support a statistical comparison between alvocidib with decitabine and alvocidib with azacitidine. Cohort counts are not randomized comparisons, and the cohorts should not be treated as equivalent control arms.

The posted results also do not establish that an adverse event or death was caused by study treatment. The registry does not provide the cause and timing of deaths or detailed event attribution. A safety count is an observation during the stated period, not by itself a causal conclusion.

The study’s stated purpose includes preliminary efficacy, but the listed secondary outcomes—complete response rate and improvement in transfusion dependence—have no reported results in the registry record. The safety findings therefore cannot answer whether either efficacy outcome occurred or how it compared with another treatment.

The registry status is terminated, but the reason for termination is not reported. That status should not be interpreted as evidence of a particular safety or efficacy finding. Overall, the record permits a descriptive account of posted safety counts while leaving key questions about uncertainty, causality, comparative effects, missing observations, and efficacy unresolved.

14. Why This Trial Matters Statistically

This study illustrates the distinction between describing events and estimating a comparative treatment effect. Its primary outcome is a count of participants with adverse events and serious adverse events, and its posted results separate those counts by cohort. Such data can document what was recorded during the study, but a single-group, open-label design does not supply a randomized control comparison.

The distinction matters because cohort-level counts can look directly comparable while reflecting differences beyond treatment. The record does not report how participants were assigned to cohorts, the cohort dose levels, or whether cohort characteristics were balanced. Without those details and a control group, the results cannot isolate the effect of choosing decitabine versus azacitidine in the listed combinations.

The study also highlights the importance of defining the outcome and observation window. The primary measure counts participants with events over a period from first dose to 30 days after the last dose, averaging 33.7 weeks. Participant counts are not the same as event rates adjusted for exposure time, and they do not describe repeated event burden or severity without additional reporting.

Finally, registry completeness shapes what can be concluded. The record lists secondary efficacy outcomes but does not report their results, and it provides no inferential analyses or confidence intervals for the primary outcome. The termination status is present, but the reason is not. These gaps show why statistical interpretation depends not only on the numbers recorded, but also on transparent methods, denominators, follow-up, and analysis populations.

15. 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 principal limitation is the single-group design. There is no randomized comparator, allocation is listed as NA, and masking is listed as none. The cohort results therefore cannot be read as a controlled comparison of alvocidib with decitabine versus alvocidib with azacitidine. Differences between cohorts may have explanations other than treatment, and cohort assignment details are not reported in the registry record.

The safety reporting is limited to participant counts by cohort and selected serious-event terms. The registry does not provide a full account of event severity, duration, recurrence, relatedness to treatment, or timing. It lists deaths by cohort but does not report causes or timing. The denominator for the serious-event term percentages is also not reported in the registry record.

The outcome window is described as extending from first dose to 30 days after the last dose, with an average duration of 33.7 weeks. The record does not report participant-level follow-up, missing observations, or how incomplete follow-up was handled. It also does not identify the analysis population or explain how participants were included in each outcome result.

No statistical analyses, confidence intervals, or hypothesis tests are reported. A sample-size justification, statistical analysis plan, interim-analysis details, and reason for termination are not reported in the registry record. Results for the secondary outcomes are absent. These limitations leave uncertainty about the precision of the safety observations and prevent conclusions about efficacy or comparative safety.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Phase 1b/2 Study of Alvocidib Plus Decitabine or Azacitidine in Patients With MDS — NCT03593915.
• Registry record last updated 2023-11-09; status last verified 2023-11.
• Results first posted 2022-10-21.
• 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.

19. Record Summary

The registry record describes NCT03593915, a Phase 1b/2, open-label, single-group study of alvocidib administered in sequence after decitabine or azacitidine in patients with MDS. Planned enrollment is 20. The study began on 2018-08-29, has a primary completion date of 2021-08-16, and is listed as terminated.

The primary outcome is the number of participants with adverse events and serious adverse events, measured from first dose to 30 days after last dose, an average of 33.7 weeks. Safety counts are reported across ALV-DEC: Cohorts 1 through 4 and ALV-AZA: Cohorts 5 and 6. The record also lists complete response rate and improvement in transfusion dependence as secondary outcomes.

No statistical analyses or secondary-outcome results are reported in the registry record. The reason for termination, full eligibility criteria, detailed analysis methods, and cause and timing of deaths are also not reported.