Pevonedistat, Azacitidine, Fludarabine Phosphate, and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pevonedistat, Azacitidine, Fludarabine Phosphate, and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome (NCT03813147), a na phase 1 study. The primary outcome is Number of Participants With Dose Limiting Toxicities of MLN4924 (Pevonedistat).

2. Clinical Question

This is a feasibility and safety question, not a comparison of the regimen with another treatment. In general, a dose-limiting toxicity outcome can help characterize tolerability during early evaluation of a regimen and inform decisions about dose escalation. The record’s description names the toxicity outcome and the cohort in which it is assessed, but does not provide the numerical primary outcome result or the toxicity criteria used to classify an event as dose limiting.

The broader study concerns patients whose AML or MDS had returned or had not responded to treatment. Its stated interest also includes antitumor activity, listed as a secondary outcome. However, the numerical result for that secondary outcome is not reported in the registry record. The available information therefore defines the clinical question and treatment context, but does not establish the frequency of dose-limiting toxicity or describe the observed antitumor activity.

3. Trial Design

This is a completed Phase I trial with a single-group model. The registry lists enrollment as 12 and allocation as NA; masking is listed as none. A single-group design means the trial record does not define a concurrent comparison group. The registry describes the primary dose-limiting toxicity outcome among participants in the dose-escalation cohort and by dose level.

The study’s official title describes a feasibility trial of MLN4924, also named as pevonedistat or TAK 924, in combination with azacitidine, fludarabine, and cytarabine in children, adolescents, and young adults with relapsed or refractory AML or MDS. The registry lists the National Cancer Institute as sponsor. The recorded start date is 2019-05-17, primary completion date is 2021-09-30, and status is completed.

The treatment description states that cytarabine is given intrathecally on day 0, at least 24 hours before each cycle. It then describes azacitidine on days 1-5, pevonedistat on days 1, 3, and 5, and fludarabine phosphate and cytarabine on days 1-5. The schedule description is truncated after the fludarabine and cytarabine administration details, so the full regimen instructions are not reported in the registry record.

Several design details needed to interpret a dose-escalation study are not reported in the registry record, including the dose levels, the rules for moving between levels, and the decision criteria for selecting a dose. The record also does not describe a statistical analysis plan. Because the design has no separate comparator, differences between treatment groups cannot be interpreted as treatment effects from this trial.

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: All patients were treated at the 20 mg/m2 dosing. An initial 6 patients were treated in this stratum to ensure this dose was feasible with the backbone therapy and then an additional 6 patients were treated in the PK stratum at this same dose to gain additional PK data.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All eligible patients

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.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Dose Limiting Toxicities of MLN4924 (Pevonedistat), measured over Up to 35 days.

The primary outcome is the number of participants with dose-limiting toxicities of pevonedistat. The registry describes the outcome as the frequency of patients with dose-limiting toxicity in the first cycle of pevonedistat added to azacitidine, fludarabine, and cytarabine re-induction. It specifies assessment within up to 35 days and describes results by dose level among participants in the dose-escalation cohort. The named population is all eligible patients.

This is a count outcome: it concerns participants who meet the dose-limiting toxicity definition, rather than the total number of adverse events. That distinction matters because a participant can experience more than one event, while the endpoint counts participants with the outcome. In general, a dose-limiting toxicity measure is used in early-phase evaluation to characterize tolerability over a defined treatment period and support dose-escalation decisions.

The registry record does not report the numerical count, the denominator used for each dose level, or the criteria defining a dose-limiting toxicity. Consequently, the outcome’s intended meaning can be described, but its observed frequency and precision cannot be assessed from the registry information.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a participant count, which is a binary outcome at the participant level: each eligible participant either meets the dose-limiting toxicity definition during the specified assessment period or does not. The reported count would describe how many participants met that definition. To understand the frequency, a reader also needs the relevant denominator, such as the number assessed at a dose level. Those numerical results are not reported in the registry record, so the endpoint cannot be reconstructed from the enrollment figure alone.

In general, binary outcomes may be presented as counts and proportions, sometimes accompanied by confidence intervals. A confidence interval expresses the statistical uncertainty around an estimate under the assumptions of the analysis. It is not a guarantee that the true value lies within the interval, nor does it account for every possible source of bias. The registry record does not report a confidence interval for the primary outcome, and the absent count and denominator prevent an independent estimate of one.

The registry describes the primary outcome by dose level and identifies a dose-escalation cohort. Dose-level descriptions are important because pooling participants across different levels could obscure how the outcome varies with dose. At the same time, small groups can yield imprecise estimates, and an observed count should be interpreted alongside its denominator and uncertainty. The dose levels, dose-level denominators, and analysis approach are not reported in the registry record. No dose-specific statistical result can therefore be evaluated.

The outcome timeframe is up to 35 days and the description focuses on the first cycle. A defined observation window helps specify which events can contribute to the endpoint. It also means the measure addresses the stated period rather than all possible later toxicities. The criteria for deciding whether an event qualifies as dose limiting, and the handling of participants with incomplete observation during that period, are not reported in the registry record.

For a single-group trial, the main descriptive question is the frequency of the outcome in the treated group or at each dose level. There is no concurrent control group against which to estimate a between-group treatment effect. General statistical concepts such as a treatment contrast, a randomized comparison, or adjustment for baseline imbalance do not create a comparison where none is specified. The registry lists allocation as NA and the model as single-group, so the record does not support a randomized comparative interpretation.

The record lists 9 outcome measures and 0 analyses. These entries do not provide a statistical analysis plan or numerical results for the primary outcome. The plan for defining analysis populations, handling repeated or multiple outcomes, calculating uncertainty, and presenting dose-level summaries is not reported in the registry record. It is therefore not possible to determine whether the registry’s intended outcome summaries were calculated using a particular statistical method.

Over-dispersion is a general concern when event counts vary more than a simple count model would expect; in such settings, a model that assumes less variation can understate uncertainty. This issue is not directly established by the primary endpoint description, which is a count of participants with an event rather than a reported repeated-event rate. The registry does not report a model for the endpoint, and no modeling assumptions should be inferred.

The sample-size assumptions described for the planning illustration are not the trial’s own design. The illustration is characterized as using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect set as a stated fraction of an observed effect. The record also warns that time-to-event illustrations use total events and other illustrations use participants per arm. These generic planning assumptions do not describe the actual single-group allocation of this trial. The record does not report the trial’s sample-size justification, and no calculated planning output can be inferred from the design details alone.

There are no recalculated primary outcome estimates available in the record information. In general, a recalculation from summary data would be an unadjusted calculation and could differ from a sponsor’s analysis if that analysis used a different population, definition, or method. No sponsor analysis of the primary endpoint is described, so there is no basis for substituting a recalculation for a reported result.

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("Stratum 1 With 20 mg/m^2", "PK With 20 mg/m^2")
n      <- c(6, 6)
events <- c(1, 2)
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  Stratum 1 With 20 mg/m^2  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  PK With 20 mg/m^2  6  2  33.3  4.3  77.7  9.7  70.0  9.9  71.0

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 9 outcome measures, including the primary dose-limiting toxicity outcome and a secondary outcome concerning antitumor activity. When a study assesses multiple outcomes, interpreting isolated findings can raise a multiplicity issue: the chance of observing an apparently notable result can depend on how many analyses or outcomes are considered. This is a general statistical concern, not evidence that a particular adjustment was or was not used in this trial.

The record lists 0 analyses, and a multiplicity strategy is not reported in the registry record. It is not reported whether outcomes were prioritized beyond the primary designation, whether any adjustment was planned, or how any secondary findings were intended to be interpreted. The numerical results for the primary endpoint and the listed secondary outcome are also not reported in the record information available.

Missing-data methods and analysis populations are not reported in the registry record. In particular, the record does not explain how participants with incomplete first-cycle observation, withdrawals, or unevaluable toxicity information would be handled. The primary description names all eligible patients, but does not give the number eligible or the endpoint denominator at each dose level. Enrollment alone cannot resolve those questions.

The record does not report interim analyses, rules for stopping enrollment, or a detailed statistical analysis plan. These omissions limit assessment of how outcome definitions and analyses were prespecified and applied. They do not establish that a method was absent; they mean that the method is not reported in the registry record.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: anemia (100.0%), lymphocyte count decreased (100.0%), neutrophil count decreased (100.0%), platelet count decreased (100.0%), white blood cell decreased (100.0%).

The serious adverse event summary lists “Stratum 1 With 20 mg/m^2” and “PK With 20 mg/m^2.” For each listed group, the record gives 6 participants at risk and 6 participants affected, and lists 0 deaths. It also lists anemia, decreased lymphocyte count, decreased neutrophil count, decreased platelet count, and decreased white blood cell count at 100.0%, and hypertension at 66.7%, among the top serious terms.

These figures should be read as the registry’s serious-event summary, not as the primary dose-limiting toxicity outcome. The endpoint definitions are different in the record: the primary measure is participants with dose-limiting toxicity during the first cycle, while the safety summary concerns serious adverse events and named terms. The record does not specify whether the serious-event groups correspond to the primary dose-escalation cohort or how the listed percentages were calculated for each term.

A reported percentage does not describe severity beyond the classification stated in the summary, duration, timing, or recurrence. Nor does 0 listed deaths establish that no other serious outcomes occurred outside the stated record or observation context. The safety figures provide descriptive information, but without fuller definitions and context they do not support comparisons between groups or a complete characterization of risk.

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

The registry record shows that this was a completed Phase I, single-group trial of pevonedistat with azacitidine, fludarabine, and cytarabine in children, adolescents, and young adults with relapsed or refractory AML or MDS. Its primary endpoint was the number of participants with dose-limiting toxicity during the first cycle, within up to 35 days, described by dose level among participants in the dose-escalation cohort.

The primary endpoint’s numerical result is not reported in the registry record. Accordingly, the record does not establish the observed frequency of dose-limiting toxicity, its precision, or how that frequency differed across dose levels. The listed serious adverse event percentages are separate safety summaries and cannot be used as substitutes for the primary endpoint result. Antitumor activity is listed as a secondary outcome, but its numerical result is not reported in the registry record.

Even with outcome results, a single-group design would answer a descriptive question about participants receiving the regimen, not a randomized question about how the regimen compares with another treatment. The record has no separate comparator group. It therefore cannot isolate a treatment effect from other explanations for an observed outcome.

In general, an early-phase feasibility study can provide information about treatment administration and observed safety in the studied setting. Such information is not equivalent to proof of efficacy or a definitive comparison. Here, the registry record provides the design and endpoint description, but the missing primary result and incomplete analysis details limit the conclusions that can be drawn from the posted information.

The listed enrollment of 12 and completed status are details about the study record, not evidence that a particular outcome occurred or that all enrolled participants contributed to every endpoint. Eligibility, evaluability, missing observations, dose-level denominators, and the analysis population are not reported in the registry record. Those details are essential for interpreting any count or percentage as an estimate of outcome frequency.

14. Why This Trial Matters Statistically

This trial raises a central statistical issue in early-phase research: the clinical question is tied to dose level and a defined period of observation, while the primary outcome is a count of participants with dose-limiting toxicity. To interpret such an outcome, readers need its definition, the number assessed at each dose level, the number meeting the definition, and an account of uncertainty. The registry record describes the intended measure but does not report those numerical results.

The single-group design also clarifies what the study can and cannot answer. Descriptive safety information can characterize events recorded among treated participants, but the absence of a comparator means the study does not estimate a randomized contrast. This distinction prevents descriptive findings from being mistaken for evidence about comparative benefit or harm.

The record’s serious-event summary illustrates why outcome definitions matter. Serious adverse events and dose-limiting toxicities are not interchangeable labels in the registry. A count or percentage in one summary cannot be assumed to answer the other endpoint’s question. Clear definitions, denominators, and observation windows are necessary for statistical interpretation.

Finally, a completed status and a listed enrollment figure do not replace outcome reporting. Without the primary result, dose-level denominators, and analysis details, readers cannot evaluate the endpoint’s frequency or precision. The record therefore offers useful design context while leaving the central statistical result unresolved.

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 main trial-specific limitation is that the registry record identifies the primary endpoint but does not report its numerical result. It also does not report dose-level denominators, the dose-limiting toxicity criteria, or the number of participants eligible and evaluable for that endpoint. These omissions prevent assessment of the observed frequency and its statistical precision.

The regimen description is truncated after the administration details for fludarabine phosphate and cytarabine. Although the record lists methotrexate and therapeutic hydrocortisone among interventions, it does not explain their roles in the regimen described. Dose levels and dose-escalation decision rules are not reported in the registry record.

The design is single-group, with allocation listed as NA and masking listed as none. No concurrent comparator is described, so the record cannot provide a randomized comparison. The listed serious-event groups do not have a reported relationship to the primary dose-escalation analysis, and the record does not supply enough detail to resolve that relationship.

Analysis populations, missing-data handling, statistical methods, interim analyses, and multiplicity procedures are not reported in the registry record. The numerical result for the secondary antitumor activity outcome is also not reported. These limitations concern what can be interpreted from the registry information and should not be taken to establish that unreported procedures or results did not exist.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Pevonedistat, Azacitidine, Fludarabine Phosphate, and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome — NCT03813147.
• Registry record last updated 2025-04-13; status last verified 2025-03.
• Results first posted 2023-03-03.
• 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

NCT03813147 is a completed Phase I, single-group feasibility trial sponsored by the National Cancer Institute. It enrolled 12 and studied pevonedistat with azacitidine, fludarabine, and cytarabine in children, adolescents, and young adults with relapsed or refractory AML or MDS. The primary outcome is the number of participants with dose-limiting toxicity during the first cycle, within up to 35 days, by dose level in the dose-escalation cohort.

The primary outcome’s numerical result, dose-level denominators, and detailed analysis methods are not reported in the registry record. The record lists serious-event summaries for two groups and identifies antitumor activity as a secondary outcome, but its numerical result is not reported in the registry record. The single-group design has no separate comparator and does not support a randomized treatment comparison.