Effects of Fluconazole and Itraconazole CYP3A-Mediated Inhibition on the Pharmacokinetics, Safety, and Tolerability of MLN4924 in Participants With Advanced Solid Tumors: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Effects of Fluconazole and Itraconazole CYP3A-Mediated Inhibition on the Pharmacokinetics, Safety, and Tolerability of MLN4924 in Participants With Advanced Solid Tumors (NCT02122770), a non-randomized phase 1 study. The primary outcome is Part A Cmax: Maximum Observed Plasma Concentration for MLN4924 and MLN4924 + Fluconazole.

2. Clinical Question

This is a drug-interaction question, rather than a randomized comparison of clinical outcomes. Fluconazole and itraconazole are studied as CYP3A-mediated inhibitors, and the stated purpose is to assess their effects on MLN4924 pharmacokinetics. The registry’s brief summary specifies multiple-dose inhibitor administration alongside single-dose intravenous MLN4924. Part A includes more than one itraconazole dose group, while Part B involves other drug combinations. Those additional study components broaden the record’s safety and tolerability context, but they do not change the primary Cmax comparison as it is named in the registry.

The question is clinically relevant to exposure assessment: Cmax describes the highest observed plasma concentration after a dose. A difference in this measure could be one part of understanding how coadministration relates to drug exposure. However, the registry record does not report the numerical Cmax values or their uncertainty, so it does not establish the direction or precision of any observed difference. It also does not report clinical outcome results that would support conclusions about treatment benefit.

3. Trial Design

NCT02122770 is recorded as a Phase 1 study with non-randomized allocation, no masking, and a parallel model. It enrolled 51 participants and is marked completed. The listed condition is advanced solid tumors. The recorded start date is 2014-04-01 and the primary completion date is 2017-06-05. The sponsor is Millennium Pharmaceuticals, Inc.

The study has distinct parts. In Part A, the main purpose is to evaluate the pharmacokinetics of single-dose intravenous MLN4924 in the presence of repeated fluconazole or itraconazole. The fluconazole arm description gives MLN4924 8 mg/m^2 intravenously on Days 1 and 8, with fluconazole 400 mg orally on Day 4 and 200 mg once daily on Days 5-10. The itraconazole description includes a Part A regimen with MLN4924 8 mg/m^2 and itraconazole 200 mg daily on Days 4-10, as well as a safety lead-in at 15 mg/m^2. The arm descriptions in the registry are incomplete, so all dosing details are not reported in the registry record.

Part B is described as involving MLN4924 combinations with docetaxel or carboplatin or paclitaxel. The posted descriptions indicate repeated treatment within a 21-day cycle for at least one regimen, but the full arm schedules are not reported in the registry record. The study is not a like-for-like controlled comparison: assignment was non-randomized, and arms differ in drug combinations, dose levels, and study parts. Comparisons across all arms therefore cannot be interpreted as if groups were exchangeable at baseline.

The registry lists 17 outcome measures and 12 analyses. Those counts describe the scope of recorded outcomes and analyses, but they do not reveal the analysis hierarchy or how hypotheses were prioritized. The sample-size justification and statistical analysis plan are not reported in the registry record. It is also not reported whether any interim analyses were planned or conducted. These omissions limit reconstruction of the design rationale and the intended inferential framework.

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 advanced solid tumors were enrolled in this study to receive MLN4924. This study included 2 parts: Part A (drug-drug interaction)- participants received MLN4924 with fluconazole or itraconazole and in Part B (standard of care)- participants received MLN4924 in combination with docetaxel or carboplatin and paclitaxel.

Part A: Drug-drug Interaction 2

Reasons for not completing this period:

Part B: Standard of Care

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The pharmacokinetic (PK) evaluable population included all enrolled participants who received all protocol-specified dose regimens within each period during Part A, did not received any excluded medications throughout the completion of PK sampling, and had sufficient MLN4924 plasma concentration-time data to estimate PK parameters.

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: The safety population for Part A included all enrolled participants who received at least 1 dose of MLN4924 during Part A.

6. Primary Endpoint

The registry lists the primary outcome as Part A Cmax: Maximum Observed Plasma Concentration for MLN4924 and MLN4924 + Fluconazole, measured over Day 1 (MLN4924) and Day 8 (MLN4924 + Fluconazole): pre-dose and at multiple time points (up to 72 hours) post-dose.

The primary endpoint is Part A Cmax, the maximum observed plasma concentration of MLN4924. It is recorded in nanogram per milliliter (ng/mL), with the reported summary measure specified as a geometric mean and dispersion specified as geometric coefficient of variation. Concentrations were scheduled from pre-dose through multiple post-dose time points up to 72 hours. The endpoint names MLN4924 on Day 1 and MLN4924 with fluconazole on Day 8.

General: Cmax captures the peak concentration observed during the sampling period. It is one pharmacokinetic measure of systemic exposure and can be useful when examining whether coadministration is associated with a change in peak concentration. It does not, by itself, describe the full concentration-time profile or the duration of exposure; other listed measures include clearance, time to Cmax, volume of distribution, terminal half-life, and the blood-to-plasma concentration ratio.

A geometric mean is commonly used for positive pharmacokinetic measurements that are analyzed on a multiplicative scale. The geometric coefficient of variation describes relative variability on that scale. General: a measure of spread is important because participants can have differing concentrations even under the same regimen. The actual Cmax values, geometric coefficient of variation values, number of evaluable participants, and any confidence interval or test result are not reported in the registry record. Consequently, the endpoint definition is available, but its estimated result and precision cannot be assessed from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The recorded primary measure is Cmax, the maximum observed plasma concentration of MLN4924. The registry specifies a geometric mean as the summary and geometric coefficient of variation as the measure of dispersion. The primary comparison is titled around MLN4924 on Day 1 and MLN4924 plus fluconazole on Day 8, with sampling from pre-dose through multiple times up to 72 hours after dosing. Numerical estimates and inferential results are not reported in the registry record.

Why use a geometric summary?

General: pharmacokinetic concentrations are positive measurements and may vary multiplicatively, with some observations substantially larger than others. A geometric mean summarizes values on a logarithmic scale and then expresses the summary on the original scale. A geometric coefficient of variation communicates relative dispersion rather than dispersion in the original units. This can make the summary more appropriate for skewed concentration data, but the choice of summary does not eliminate uncertainty or replace a description of the sample and analysis.

General: the estimate is only as informative as the measurements and analysis population behind it. The registry describes the pharmacokinetically evaluable population as participants who received all protocol-specified dose regimens within each period, did not receive excluded medications through completion of PK sampling, and had sufficient MLN4924 plasma concentration-time data. The number meeting those criteria is not reported in the registry record. The details of how insufficient or missing concentration observations were handled are also not reported.

What does a concentration-time endpoint represent?

General: Cmax is determined by the observed concentration measurements and their timing. It represents the highest measured concentration, not necessarily the exact biological peak between scheduled sample times. Sampling through up to 72 hours provides a defined observation window, while the density and timing of samples influence how well a peak can be characterized. The registry gives the broad sampling window but not the full sampling schedule or any result-level information about missing samples.

Other listed pharmacokinetic outcomes provide different views of disposition. Tmax records the time to reach Cmax. Clearance describes removal of drug from plasma relative to concentration; volume of distribution relates the amount of drug in the body to its plasma concentration; terminal half-life characterizes decline in the terminal phase; and the blood-to-plasma ratio compares measured concentrations in blood and plasma. General: these outcomes are related but not interchangeable, and a result for one cannot stand in for the others. Numerical findings for these outcomes are not reported in the registry record.

What can the design support?

The allocation is non-randomized, with no masking, and the model is parallel. The primary endpoint names two treatment periods, but the registry does not state that allocation to these periods was randomized. General: randomization can help balance measured and unmeasured baseline characteristics across comparison groups; without it, measured differences may be influenced by who entered each group or study part. A within-part pharmacokinetic assessment may be useful for a drug-interaction question, but the registry record does not provide enough participant-level or analysis detail to assess the exact comparison structure. No causal interpretation should be inferred solely from the arm labels.

The record contains several Part A regimens, including fluconazole and different itraconazole dose groups, and Part B combinations with other drugs. These are not all interchangeable comparison groups. In particular, differences between Part A and Part B can reflect different regimens and treatment contexts. The registry’s stated primary endpoint is specifically about MLN4924 and MLN4924 plus fluconazole; a broader pooled comparison is not described.

How should uncertainty be understood?

General: an estimate describes the result in the analyzed data, while a confidence interval gives information about its precision under a specified statistical model. A hypothesis test can quantify how compatible the data are with a null hypothesis, but it does not measure clinical importance. For a geometric mean comparison, an analysis may use a ratio-scale contrast, but the registry record does not report a comparison estimate, confidence interval, test, or model. No such quantity can be reconstructed from the endpoint title alone.

The sample-size justification is not reported in the registry record. The assumptions underlying any formal power calculation are also not reported. Any sample-size planning illustration based on an observed effect is a planning aid rather than observed power; it cannot substitute for the trial’s own design rationale or for a reported result. No power conclusion for the primary endpoint can be drawn from the available record.

Why can over-dispersion matter?

General: over-dispersion occurs when variability in observed data is greater than a chosen model expects. In count outcomes, it can make standard errors too small if ignored; in concentration data, substantial between-participant variability can likewise affect precision. The registry’s specification of geometric coefficient of variation acknowledges a relative-variability summary for Cmax, but numerical variability is not reported. The record does not describe a model addressing over-dispersion or any alternative analysis. It is therefore not possible to judge whether a particular variance model was appropriate.

Overall, the registry provides endpoint definitions, broad sampling timing, and the intended PK-evaluable population, but not enough detail to reproduce the statistical analysis. The model, handling of missing concentration data, multiplicity strategy, and analysis-specific sample sizes are not reported in the registry record. Interpretation must therefore remain at the level of the stated question and recorded design, rather than a quantitative conclusion about the drug interaction.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 17 outcome measures and 12 analyses, including several pharmacokinetic measures and safety outcomes. This indicates that the study recorded multiple questions, but the hierarchy among them is not reported in the registry record beyond the named primary Cmax outcome. The statistical plan for controlling multiplicity, if any, is not reported. When many outcomes or comparisons are considered, the chance of at least one apparently notable result can increase; general statistical practice may address this through prespecified prioritization or adjustment, but the registry does not describe such a method.

The primary endpoint is defined for the pharmacokinetically evaluable population. The criteria include receiving the specified regimens, avoiding excluded medications through PK sampling, and having sufficient plasma concentration-time data. The number analyzed is not reported in the registry record, nor is a participant flow showing how many enrolled participants met those criteria. The number excluded from the primary analysis and reasons for exclusion are not reported in the registry record.

Missing-data handling is also not reported in the registry record. It is not clear from the record whether incomplete concentration profiles were excluded, whether particular time points could be missing while retaining a participant, or how any other missing outcome data were handled. Those choices can affect the analyzed population and the precision or interpretation of estimates.

The sample-size justification, planned power, statistical model, and interim-analysis plan are not reported in the registry record. Without these details, it is not possible to assess whether the analyses followed a prespecified strategy or how the study was intended to handle multiple endpoints and incomplete data. These are reporting limitations, not evidence that a particular method was or was not used.

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 4% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: cholangiocarcinoma (16.7%), blood creatinine increased (16.7%), hyperkalaemia (16.7%), dyspnoea (16.7%), deep vein thrombosis (15.4%).

The registry reports serious adverse event counts by study group. In Part A, the listed counts are 3 of 13 for MLN4924 8 mg/m^2 with fluconazole, 3 of 13 for MLN4924 8 mg/m^2 with itraconazole, 2 of 6 for MLN4924 15 mg/m^2 with itraconazole, and 5 of 19 for MLN4924 20 mg/m^2 with itraconazole. In Part B, the listed counts are 14 of 23 for MLN4924 with docetaxel and 6 of 13 for MLN4924 with carboplatin or paclitaxel.

Other adverse events are listed for 13 of 13, 13 of 13, 6 of 6, and 18 of 19 in the four Part A groups, and 23 of 23 and 13 of 13 in the two Part B groups, respectively. Death counts are listed as 2, 3, 1, 2, 6, and 1 across those same groups. The registry lists serious-event terms including cholangiocarcinoma, blood creatinine increased, hyperkalaemia, dyspnoea, deep vein thrombosis, and nausea, with the posted percentages ranging from 15.4% to 16.7% for the listed terms.

These counts are descriptive. The groups differ in size and treatment regimen, and the registry summary does not give exposure-adjusted rates or enough detail to attribute events to a particular drug. Death counts do not establish cause. The event-term percentages should be read as the registry reports them; their precise denominators and any event-level context are not reported in the registry record.

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

This study addresses a pharmacokinetic interaction question: whether MLN4924 concentrations, particularly Cmax, differ when the drug is administered with fluconazole or itraconazole. The registry defines the primary endpoint and describes the relevant sampling window and analysis population. It does not report the numerical primary endpoint results, an estimated comparison, or uncertainty around an estimate. The record therefore does not establish whether Cmax was higher, lower, or similar under the named fluconazole regimen.

The trial is Phase 1 and includes safety and tolerability outcomes alongside pharmacokinetic outcomes. It also includes Part B combination regimens. These elements describe a broader early-phase study, but the registry record does not provide numerical results for the primary PK question or enough detail to interpret every secondary outcome. The listed safety counts provide a descriptive account by group and should not be treated as a controlled estimate of comparative risk.

General: a measured pharmacokinetic difference, if reported, would describe drug exposure under the studied regimen and conditions. It would not by itself establish a clinical benefit or harm, nor would it necessarily apply to other doses, populations, or treatment settings. Likewise, absence of a reported result in the registry is not evidence that no difference occurred; it means that the result cannot be evaluated from the registry record.

The non-randomized allocation and differing study parts further limit causal comparisons across arms. The record does not report baseline comparability, a detailed analysis model, or enough information to account for differences in time on treatment or participant characteristics. It is therefore inappropriate to treat the safety group counts as if they came from a randomized head-to-head trial.

The most defensible reading is that the registry documents the intended PK question, the main endpoint definition, broad study structure, and selected safety counts. It does not provide the numerical primary result or a complete statistical analysis plan. No conclusion about the size, direction, or precision of the fluconazole or itraconazole interaction can be drawn from the reported registry information alone.

13. Why This Trial Matters Statistically

This study illustrates a central statistical distinction in early-phase pharmacology: defining a question and endpoint is not the same as reporting an estimate. The registry specifies Cmax as the primary measure, identifies a geometric summary, and gives the sampling window and named Day 1 and Day 8 regimens. Those details clarify what the study set out to assess. Without the numerical estimate and its uncertainty, however, the central comparison cannot be quantified.

The record also illustrates why analysis populations matter in pharmacokinetic studies. The stated PK-evaluable population depends on receiving the specified regimens, avoiding excluded medications, and having sufficient concentration measurements. A result based on that population may answer a different question from one based on all enrolled participants. Since the analyzed number and exclusions are not reported in the registry record, readers cannot judge the impact of those eligibility criteria on the estimate.

Non-randomized, multi-part designs require careful interpretation. The study includes several inhibitor regimens, dose levels, and later combination treatments. Those groups serve different purposes and cannot automatically be treated as a common comparison set. The distinction between a planned drug-interaction comparison and cross-group safety descriptions is statistically important.

Finally, safety counts and pharmacokinetic endpoints convey different kinds of evidence. Counts provide descriptive information about events in each group, while Cmax is a continuous concentration measure intended to characterize drug exposure. Neither substitutes for the other. The record’s combination of endpoint definitions, sparse numerical outcome reporting, and group-level safety counts demonstrates why transparent reporting of estimates, precision, analysis populations, and missing-data methods is essential for evaluating an early-phase study.

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 central limitation for interpretation is that numerical results for the primary Cmax comparison are not reported in the registry record. The same is true for the listed secondary pharmacokinetic outcomes. Without estimates and uncertainty measures, the direction, size, and precision of the intended drug-interaction findings cannot be evaluated.

The registry describes a pharmacokinetically evaluable population but does not report how many participants were analyzed or how many failed to meet the criteria. Details of missing concentration data, exclusions, and the handling of incomplete profiles are not reported in the registry record. This prevents assessment of how the analysis population may differ from all enrolled participants.

The study is non-randomized and unmasked, with multiple parts and differing regimens. The record does not provide baseline characteristics or a detailed account of treatment assignment. Consequently, comparisons among groups, especially across study parts, may not be like-for-like. The registry also does not report exposure-adjusted safety analyses or enough event-level detail to interpret the listed deaths and adverse events as comparative risks.

The statistical analysis plan, sample-size justification, planned power, multiplicity approach, and interim-analysis plan are not reported in the registry record. The arm descriptions are partly truncated, so complete dosing schedules are unavailable. These gaps limit reproducibility and prevent a full assessment of whether the reported endpoint definitions correspond to prespecified analyses. They are limitations of the information available in the registry record and do not establish what methods were used in practice.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Effects of Fluconazole and Itraconazole CYP3A-Mediated Inhibition on the Pharmacokinetics, Safety, and Tolerability of MLN4924 in Participants With Advanced Solid Tumors — NCT02122770.
• Registry record last updated 2019-01-07; status last verified 2018-06.
• Results first posted 2019-01-07.
• 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

NCT02122770 is a completed Phase 1 study of MLN4924 pharmacokinetics, safety, and tolerability in participants with advanced solid tumors. The registry records non-randomized allocation, no masking, a parallel model, and enrollment of 51. Part A evaluates MLN4924 with fluconazole or itraconazole; Part B includes combinations with docetaxel or carboplatin or paclitaxel.

The primary endpoint is Part A Cmax for MLN4924 and MLN4924 with fluconazole, summarized as a geometric mean with geometric coefficient of variation. The registry describes a PK-evaluable population and sampling up to 72 hours, but does not report numerical primary results, analysis precision, or the number analyzed. It also does not report the statistical analysis plan, missing-data approach, multiplicity strategy, or sample-size justification. Safety counts are listed by group and are descriptive rather than randomized comparative estimates.