A Study of Pevonedistat in People With Blood Cancers or Solid Tumors With Kidney or Liver Problems: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of Pevonedistat in People With Blood Cancers or Solid Tumors With Kidney or Liver Problems (NCT03814005), a non-randomized phase 1 study. The primary outcome is Part A, AUC∞: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity for Pevonedistat Following a Single Dose.

2. Clinical Question

The study asked how pevonedistat behaves in the blood of participants with specified cancers and severe renal impairment or mild to moderate hepatic impairment. Its primary outcome was pharmacokinetic: the area under the plasma concentration-time curve from time zero to infinity after a single dose in Part A. The study also assessed other pharmacokinetic measures for pevonedistat and azacitidine, and recorded adverse events.

3. Trial Design

The registry record identifies this as a phase 1 study with non-randomized allocation, no masking, and a sequential model. It lists enrollment of 17 and a completed status. The study description divides treatment and assessment into Parts A and B. Part A assessed pevonedistat exposure after a single intravenous infusion, with blood sampling from the pre-dose assessment through multiple time points up to 72 hours after dosing. The brief summary says participants were assigned to treatment groups according to the severity of their kidney and liver problems.

Part B was for participants who agreed to continue. The summary describes repeated pevonedistat infusions during cycles whose length depended on cancer type, along with standard-of-care medicines. Azacitidine is listed as an intervention. The arm descriptions name control, renal, and mild hepatic groups, but the descriptions in the registry record are incomplete. Details beyond the available descriptions, including the full set of treatment schedules and the number of participants who continued to Part B, are not reported in the registry record.

The term control in an arm label does not make this a randomized controlled comparison. Allocation was non-randomized, and the listed arms represent different clinical groups. Differences between them may reflect participant characteristics, impairment category, treatment, or other factors; the design does not isolate those influences. The registry record does not report a randomization procedure or masking. Its sequential design and pharmacokinetic focus are consistent with a study intended to characterize drug exposure and inform future dose selection, rather than to establish a comparative clinical treatment effect.

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: Participants with myelodysplastic syndromes (MDS), and acute myelogenous leukemia (AML) who also had severe renal impairment or mild hepatic impairment were enrolled in this study to receive single dose of pevonedistat in Part A followed by a wash out period and pevonedistat in combination with standard of care agent in Part B. No participants with chronic myelomonocytic leukemia (CMML) and solid tumors were enrolled in this study.

Part A: Day 1 to Day 4

Washout Period : Day 4 to Day 7

Part B: Day 8 to Day 343

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic (PK) population included all participants who had sufficient dosing in Part A and Part B Cycle 1, had sufficient concentration-time data to permit reliable estimation of PK parameters, and who had not received any excluded concomitant medications through the completion of Part A.

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: Safety population included all participants who received at least 1 dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as Part A, AUC∞: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity for Pevonedistat Following a Single Dose, measured over Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose.

The primary outcome is AUC∞ for pevonedistat following a single dose in Part A, expressed in hour*nanogram per milliliter(h*ng/mL). AUC∞ is the area under the plasma concentration-time curve from dosing through the extrapolated end of the concentration profile. In general, area under the curve represents overall systemic drug exposure over time; extending the measure to infinity incorporates the observed concentration-time data and an estimate of the remaining terminal portion of the profile.

Exposure is used in pharmacokinetic research to characterize how much drug reaches the circulation over time. This is particularly relevant to a study focused on participants with renal or hepatic impairment, because the study question concerns drug levels in those clinical groups. AUC∞ is not itself a measure of tumor response or clinical benefit. Interpreting it requires the estimated value and its uncertainty, as well as appropriate context about the population and sampling.

The registry record identifies the endpoint as a geometric mean with geometric coefficient of variation as its dispersion measure. It gives the sampling timeframe as Day 1 pre-dose and multiple time points up to 72 hours post-dose. The primary outcome result, including a geometric mean and its dispersion, is not reported in the registry record. The pharmacokinetic population required sufficient dosing in Part A and Part B Cycle 1, sufficient concentration-time data for reliable estimation, and no excluded concomitant medications through completion of Part A.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The statistical methods that can be described are limited to the endpoint definitions, analysis population, study structure, and posted outcome summaries. A detailed statistical analysis plan, including the exact estimation procedures and rules for handling incomplete pharmacokinetic profiles, is not reported in the registry record.

What does AUC∞ describe?

In general, pharmacokinetic sampling records drug concentrations at different times after dosing. A concentration-time curve represents how plasma concentration changes over time. The area under that curve summarizes exposure across the measured period. AUC∞ extends the exposure measure beyond the last observed sample by estimating the remaining area in the terminal part of the profile. Because that final portion is estimated rather than directly observed at every later time, its contribution and the rules used to estimate it can matter. The registry record gives the endpoint definition and sampling window, but does not report the estimation details or the observed endpoint value.

Why use a geometric mean?

The primary parameter is specified as a geometric mean, with geometric coefficient of variation as its dispersion measure. In general, pharmacokinetic measures such as exposure can be right-skewed: a smaller number of relatively high values can extend the upper tail. A geometric summary is based on multiplicative rather than additive variation and is commonly used when values are positive and their variation is naturally expressed proportionally. The geometric coefficient of variation describes relative spread on that scale. It is not the same as a standard deviation in the original measurement units. The registry record does not give the resulting geometric mean or geometric coefficient of variation.

Why can over-dispersion matter?

In general, over-dispersion means observed variability is greater than a statistical model would expect. When a model assumes less variation than the data contain, standard errors may be understated and confidence intervals may be too narrow. This concern is relevant in principle to small clinical groups and heterogeneous pharmacokinetic data, but the record does not report a model-based assessment of over-dispersion for the primary endpoint. The endpoint is presented as a geometric summary; details of any transformations, model checks, or adjustments are not reported in the registry record.

What is the role of the analysis population?

The primary outcome population is defined as participants who had sufficient dosing in Part A and Part B Cycle 1, enough concentration-time data for reliable pharmacokinetic estimation, and no excluded concomitant medications through completion of Part A. This is an analysis-population definition, not a statement that every enrolled participant contributed to the primary result. The registry record does not state how many participants met the definition, how many were excluded, or how incomplete profiles were handled. In general, population rules matter because exclusions can change which participants the estimate describes.

How should the study structure affect interpretation?

The study was non-randomized and sequential, with no masking. In general, random allocation helps balance known and unknown participant characteristics across treatment groups, while masking can reduce some sources of measurement or reporting bias. Neither feature is reported for this study: the registry record explicitly identifies non-randomized allocation and no masking. Its arms therefore should be read as descriptive clinical groups rather than randomized comparison groups. The study's primary pharmacokinetic aim is to characterize exposure, not to estimate a causal difference between assigned treatments.

The registry record also lists planning illustrations based on an observed effect, a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the effect to detect expressed as a fraction of the observed effect. Such calculations are planning illustrations, not observed power and not evidence that the original study was designed with those assumptions. The registry record does not report a sample-size justification for the trial itself. Any recalculated values based on posted summary statistics are unadjusted re-calculations; where a discrepancy is identified, the sponsor's own analysis takes precedence. No discrepancy is identified in the information.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists 22 outcome measures and zero analyses. It does not report a multiplicity strategy for interpreting results across the primary and secondary outcomes. In general, when many outcomes are tested, the chance of at least one apparently notable result can increase; procedures such as a prespecified hierarchy or adjustment can address that issue, but the registry record does not describe whether any such approach was planned or used. The number of outcomes alone does not establish that every outcome was formally tested.

Missing-data methods are also not reported in the registry record. The primary analysis population required sufficient dosing and concentration-time data for reliable estimation, and excluded participants with specified concomitant medication exposure through Part A. These criteria describe eligibility for the pharmacokinetic population, but do not explain how missing samples, incomplete concentration profiles, or exclusions were handled in the analysis. The number of participants meeting the criteria is not reported in the registry record.

The outcome population is not necessarily identical to all enrolled participants. The registry record does not report a participant flow by study part or provide the number contributing to each outcome. It also does not specify imputation, sensitivity analyses, or assumptions about data that were unavailable. In general, missing-data assumptions affect how an estimate should be interpreted, particularly when the reason data are missing may relate to participant condition, treatment, or measurement. Without the analysis details and outcome values, the extent and impact of missing data cannot be assessed.

The registry record identifies a primary endpoint, but the detailed statistical plan, including prespecified handling of multiple outcomes and missing observations, is not reported in the registry record. Therefore, the posted information does not support an assessment of whether the reported analyses followed a prespecified multiplicity or missing-data plan.

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: acute kidney injury (50.0%), pyrexia (33.3%), rectal haemorrhage (33.3%), febrile neutropenia (30.0%), acute myeloid leukaemia (25.0%).

The adverse-event summaries separate Part A from Part B and report participants at risk, participants affected by serious adverse events, participants affected by other adverse events, and deaths. In Part A, the control, renal, and mild hepatic arms report serious adverse events affecting 0 of 10, 0 of 4, and 0 of 3 participants, respectively. Other adverse events affected 2 of 10, 1 of 4, and 1 of 3, respectively; deaths were 0 in each of those Part A groups.

In Part B, serious adverse events affected 7 of 10 participants in the control arm, 3 of 4 in the renal arm, and 2 of 3 in the mild hepatic arm. Other adverse events affected 10 of 10, 4 of 4, and 3 of 3, respectively. The reported death counts were 2, 2, and 0, respectively. The serious adverse event terms with listed frequencies include Acute kidney injury at 50.0%, Pyrexia at 33.3%, Rectal haemorrhage at 33.3%, Febrile neutropenia at 30.0%, Acute myeloid leukaemia at 25.0%, and Chronic kidney disease at 25.0%.

These are descriptive counts, not randomized comparative estimates. The groups are small, and the registry record does not provide exposure-adjusted rates, event timing, or causal attribution for these summaries. They should not be interpreted as proving that a treatment caused or prevented an event. The record's serious event figures are also distinct from the primary pharmacokinetic outcome.

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

The registry record establishes that a completed phase 1 study evaluated pevonedistat pharmacokinetics in participants with specified cancers and renal or hepatic impairment. It identifies AUC∞ after a single dose as the primary outcome and gives the intended pharmacokinetic population and sampling timeframe. Those details clarify what the study was designed to measure. However, the primary outcome value and its dispersion are not reported in the registry record, so the actual exposure estimate and its precision cannot be interpreted.

The record also gives descriptive safety counts for Parts A and B and lists secondary pharmacokinetic outcomes. These details can describe the scope of measurement and the reported event counts, but do not establish comparative safety or treatment effects. The non-randomized, sequential design means that the named arms are not exchangeable groups created through random allocation. Any apparent differences across them could be related to clinical group characteristics or other factors, as well as treatment and study procedures.

In general, a pharmacokinetic study can inform understanding of drug exposure and support dose selection for further investigation. It does not, by itself, show whether a treatment improves cancer outcomes or has a favorable clinical benefit-risk balance. No clinical efficacy result or comparative treatment estimate is reported in the registry record. The listed adverse events likewise do not prove causation.

The absence of the primary numerical result does not imply that the result was zero or that the study failed to measure exposure. It means the posted record, as represented in the available information, does not contain the value needed to quantify the finding. Any conclusions should remain limited to the design, endpoint definitions, analysis-population criteria, and descriptive adverse-event information that are actually reported.

13. Why This Trial Matters Statistically

This study illustrates a statistical distinction between characterizing exposure and testing clinical effectiveness. A pharmacokinetic endpoint such as AUC∞ describes drug exposure over time. That can be relevant to dose selection and to understanding treatment in groups defined by organ impairment. It answers a different question from whether treatment changes a clinical outcome, and it cannot substitute for a clinical efficacy comparison.

The population is also central to interpretation. The registry record defines the primary pharmacokinetic population using dosing, availability of concentration-time data, and concomitant medication criteria. Those rules determine whose exposure contributes to the endpoint. Without the number meeting the criteria and the result itself, readers cannot assess how representative the estimate is of all enrolled participants or how precisely it is estimated.

The non-randomized design matters because the listed groups cannot serve as a straightforward randomized control comparison. This is especially important when groups are formed around different renal or hepatic impairment categories. Statistical adjustment, if any, would not automatically remove all differences between such groups; the registry record does not report a comparative analysis plan.

Finally, a completed registry status is not a substitute for posted outcome estimates. Clear endpoint definitions and safety counts are useful, but a result requires the numerical estimates and their uncertainty. The missing primary pharmacokinetic result limits what can be concluded about the study's central question from the registry record.

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 main limitation for interpretation is that the primary AUC∞ value and its dispersion are not reported in the registry record. The record therefore does not allow assessment of the magnitude or precision of the primary pharmacokinetic finding. It also does not report the number of participants who met the defined pharmacokinetic population criteria or contributed to each outcome.

Enrollment was 17, and the adverse-event summaries are divided among small groups. Counts from small groups can be unstable and should not be treated as precise comparative rates. The study was non-randomized, unmasked, and sequential, so its arms do not support like-for-like causal comparisons. The registry record does not describe adjustment for differences among participants or provide a detailed comparative analysis plan.

The arm descriptions are incomplete in the registry record. The brief summary describes treatment across Parts A and B, but does not provide complete treatment schedules, continuation counts, or the full detail needed to reconstruct exposure for each participant. The registry record also does not report the protocol's sample-size justification, interim analyses, detailed statistical plan, missing-data methods, or multiplicity approach. These omissions prevent assessment of whether all analyses and exclusions followed prespecified procedures.

Finally, the listed adverse events are descriptive, and the registry information available does not provide timing, exposure-adjusted rates, or causal attribution. The record does not report clinical efficacy results. These limitations mean the posted information supports a description of the study and its reported safety counts, but not a numerical conclusion about the primary exposure result or a causal treatment comparison.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study of Pevonedistat in People With Blood Cancers or Solid Tumors With Kidney or Liver Problems — NCT03814005.
• Registry record last updated 2024-09-05; status last verified 2024-08.
• Results first posted 2024-09-05.
• 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

NCT03814005 is a completed phase 1, non-randomized, unmasked, sequential study sponsored by Takeda. It enrolled 17 participants with blood cancers or solid tumors and specified renal or hepatic impairment. The primary outcome was pevonedistat AUC∞ after a single dose in Part A, assessed in a defined pharmacokinetic population. Azacitidine and pevonedistat are listed as interventions, and the study description includes treatment in Parts A and B.

The registry record lists 22 outcome measures and zero analyses. It includes adverse-event counts by study part and arm, but the primary outcome value and its dispersion are not reported in the registry record. The listed arms are not randomized comparison groups, so their outcomes should be interpreted descriptively rather than as causal contrasts.