A Study of MLN8237, a Novel Aurora A Kinase Inhibitor, in Participants With Advanced Solid Tumors: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of MLN8237, a Novel Aurora A Kinase Inhibitor, in Participants With Advanced Solid Tumors (NCT00500903), a non-randomized phase 1 study. The primary outcome is Number of Participants With Dose-Limiting Toxicity (DLT).

2. Clinical Question

In general, early-phase dose-escalation research focuses on characterizing tolerability and selecting doses for further study. It is not designed like a randomized efficacy trial, and the cohort structure does not support a direct treatment-effect comparison. The registry record describes the study question and exposure schedules, while leaving the primary endpoint count and resulting dose decision unreported.

3. Trial Design

This was a phase 1, open-label, nonrandomized study with a parallel model. The registry lists enrollment of 87 and status as completed. The study start is recorded as 2007-05-15 and primary completion as 2010-08-01. The sponsor was Millennium Pharmaceuticals, Inc.

The dose-escalation arms differed in formulation and dosing schedule. In the PIC dose-escalation arm, alisertib doses of 5, 10, 20, 40, 80, 110 or 150 mg were taken orally once daily for 7 to 21 days, followed by a 14-day recovery period in each cycle. Treatment could continue until disease progression or unacceptable alisertib-related toxicity, up to 51 cycles. In the ECT dose-escalation arm, 10 or 20 mg was taken orally once daily for 7 days, followed by a 14-day recovery period, for up to 2 cycles.

The relative-bioavailability cohort used 40 mg ECT or PIC orally twice daily for 7 days, followed by a 14-day recovery period in cycle 1; the opposite formulation was then used in cycle 2. The registry description is truncated after that sequence, so any additional regimen details are not reported in the registry record.

Because treatment assignment was not randomized and the arms differed in dose, formulation, or schedule, their outcomes should not be read as a controlled comparison of equivalent groups. Open-label conduct means masking was absent. The registry record does not report a protocol rationale for the cohort sizes or a statistical sample-size justification. The design description supports interpretation as dose and formulation exploration, rather than a definitive comparative evaluation.

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 a diagnosis of advanced malignancies were enrolled in 1 of 3 treatment groups, alisertib 5 to 150 mg Powder-in-Capsule (PIC) dose escalation cohort, alisertib 10 or 20 mg Enteric-coated Tablet (ECT) dose escalation cohort, or alisertib 40 mg PIC/ECT in a crossover design followed by alisertib 50 mg relative bioavailability cohort.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: DLT-Evaluable Population included all participants who received at least 75% of their planned alisertib doses for their first cycle of treatment (unless interrupted by DLT) and had sufficient follow-up data to allow the investigators and sponsor to determine whether DLT occurred.

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 included all participants who received any amount of study drug.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Dose-Limiting Toxicity (DLT), measured over Cycle 1 Day 1 up to Day 35 (alisertib daily for 7 to 21 days followed by a 14-day recovery period).

The primary endpoint was the number of participants with dose-limiting toxicity (DLT). DLT was assessed from Cycle 1 Day 1 up to Day 35, during a regimen of daily alisertib for 7 to 21 days followed by a 14-day recovery period. The registry says toxicity was evaluated using National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.

The definition included specified severe blood-count abnormalities, gastrointestinal toxicities despite supportive treatment, other serious nonhematologic toxicities subject to stated exceptions, treatment delay due to inadequate recovery, and certain alisertib-related toxicities that led the investigator to require dose reduction or discontinuation. For example, the definition included Grade 4 neutropenia lasting at least 7 consecutive days, platelet count less than 25,000/mm^3, and treatment delay of more than 1 week due to failure of adequate recovery. These criteria make the endpoint a rule-based count rather than a continuous measurement.

In general, DLT is used in early dose-finding research to identify toxicities that constrain dose escalation and to inform selection of a dose for later evaluation. It is not by itself a measure of antitumor benefit or a complete account of longer-term safety. The registry record gives the endpoint definition and evaluation window, but the number of participants meeting the definition is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What kind of outcome is the primary endpoint?

The primary endpoint is a binary event summarized as a count: each participant either met the registry's DLT definition or did not. The corresponding group result is naturally expressed as the number meeting the definition among those evaluated. The registry records the outcome type as participants with an event, but no primary counts are reported. Without those counts and group denominators, an event proportion cannot be interpreted or recalculated.

In general, binary outcomes are often summarized using event counts and proportions, with uncertainty intervals that reflect the amount of information in the data. Those summaries are not present for the primary endpoint in the registry record. It would be inappropriate to infer them from enrollment or from the separate adverse-event figures, because those refer to different populations or outcome definitions.

Why does the DLT definition matter?

The endpoint is operationalized through criteria based on toxicity grade, duration, supportive treatment, treatment delay, and investigator judgment. This helps determine consistently which toxicities count toward the dose-limiting endpoint. The criteria include exceptions for specified symptoms and include certain alisertib-related toxicities at Grade 2 or greater when the investigator considered dose reduction or discontinuation necessary.

In general, a composite endpoint can combine events that differ in clinical nature or severity. Its overall count is therefore a summary of whether any qualifying criterion was met, not a measure of a single uniform toxicity. Here, the registry supplies the criteria but does not report the numbers meeting individual criteria or the overall DLT endpoint.

What does the population definition imply?

The DLT-evaluable population required receipt of at least 75% of planned alisertib doses for the first cycle, unless dosing was interrupted by DLT, together with sufficient follow-up to determine whether DLT occurred. This definition is relevant because participants who do not meet the exposure or follow-up requirements may not be included in that endpoint analysis. The number meeting the definition is not reported in the registry record.

In general, outcome estimates depend on the analysis population. A population restricted to participants with adequate exposure and follow-up may differ from all enrolled participants. Without the evaluated counts and reasons for exclusion, readers cannot assess how the selected population relates to the full enrollment.

How should the cohort structure be understood?

The trial was nonrandomized, open-label, and organized into dose-escalation and relative-bioavailability arms. The arms vary by dose, formulation, and schedule. In general, randomization helps balance measured and unmeasured factors between comparison groups, while masking can reduce some assessment and reporting influences. Neither feature was present. This is not inherently inconsistent with dose-finding research, but it limits interpretation of between-arm differences as treatment effects.

For these reasons, the cohort descriptions are best read as distinct exposure regimens, not as randomized treatment groups. The registry's stated warning that the arms are not a like-for-like control comparison is important. The record does not report a statistical plan for formal comparisons across cohorts.

What can be inferred about statistical precision?

No primary endpoint estimate, interval estimate, or p-value is reported in the registry record. In general, a confidence interval communicates statistical uncertainty around an estimate; narrower intervals indicate greater precision under the model and assumptions used. Statistical significance is a separate question from the size and precision of an effect. Neither precision nor significance can be assessed for the primary endpoint without posted results and an analysis.

The record includes a planning-illustration description based on an observed effect, two-sided significance level 0.05, equal allocation, and a normal approximation, with detectable effects defined as fractions of the observed effect. Such calculations are planning illustrations, not observed power and not evidence that the trial was designed around those assumptions. The specific planning outputs are not reported in the registry record. The registry record does not report its own sample-size justification.

In general, over-dispersion matters when count data vary more than a statistical model assumes: standard errors may otherwise be too small and intervals too narrow. That issue is relevant to some count outcomes, but the primary endpoint is a participant count with a binary event definition, and no model-based analysis is reported. No adjustment or model can be attributed to the registry without a stated analysis.

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("Alisertib 5 mg PIC QD 7D", "Alisertib 10 mg PIC QD 7D", "Alisertib 20 mg PIC QD 7D", "Alisertib 40 mg PIC QD 7D", "Alisertib 80 mg PIC QD 7D", "Alisertib 110 mg PIC QD 7D")
n      <- c(3, 3, 3, 3, 3, 6)
events <- c(0, 0, 0, 0, 0, 1)
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  Alisertib 5 mg PIC QD 7D  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Alisertib 10 mg PIC QD 7D  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Alisertib 20 mg PIC QD 7D  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Alisertib 40 mg PIC QD 7D  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Alisertib 80 mg PIC QD 7D  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Alisertib 110 mg PIC QD 7D  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 58 outcome measures, including the primary DLT outcome and pharmacokinetic measures. It reports no analysis records. A broad set of outcomes creates the general possibility that many separate statistical questions could be examined. In general, multiplicity procedures address the increased chance of false-positive findings when several hypotheses are tested. The registry record does not report whether multiplicity was addressed, which outcomes were included in any formal testing strategy, or whether a hierarchy of outcomes was specified.

Missing-data handling is also not reported in the registry record. The primary endpoint definition requires sufficient follow-up to determine whether DLT occurred, and the DLT-evaluable population has an exposure requirement with an exception for DLT-related interruption. These criteria define who could be evaluable, but they do not explain how incomplete assessments, withdrawal, or other missing outcome information were handled. The number of participants who were evaluable for DLT is not reported in the registry record.

In general, missingness can affect both the denominator and the interpretation of an observed event count. It is therefore useful to know how many participants had complete endpoint assessment and why others were not assessed. Those details are not reported in the registry record. Enrollment of 87 does not establish how many participants contributed to the primary endpoint analysis.

The registry record also does not report an interim-analysis plan, an analysis population beyond the stated DLT-evaluable definition, or a statistical analysis plan. These omissions limit assessment of prespecification and of how outcome data were handled. They should be treated as unreported information, not evidence that a particular method was or was not used.

12. Safety Results

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

Other (non-serious) adverse events

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

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: febrile neutropenia (7.7%), anaemia (6.2%), thrombocytopenia (6.2%), klebsiella bacteraemia (5.0%), enterococcal bacteraemia (5.0%).

The posted serious adverse-event figures are separated by cohort. In PIC Dose Escalation, serious adverse events affected 26 of 65 participants at risk. In ECT Dose Escalation, the recorded count was 0 of 2. In Relative Bioavailability, the count was 1 of 20. These are descriptive cohort counts; because treatment assignment was nonrandomized and the regimens differed, they do not establish a comparative safety effect.

The registry also lists serious adverse-event terms with percentages: febrile neutropenia, 7.7%; anaemia, 6.2%; thrombocytopenia, 6.2%; Klebsiella bacteraemia, 5.0%; enterococcal bacteraemia, 5.0%; and bile duct obstruction, 5.0%. The denominator and method used for these percentages are not reported in the registry record, so they should be read as registry-listed frequencies rather than recalculated rates.

In general, a serious adverse event is not synonymous with a DLT. DLT used its own criteria and evaluation period; the serious-event figures are a separate safety summary. Death counts are not reported in the registry record. The listed counts alone do not establish causation or provide a full account of event timing, duration, or severity beyond the registry's event classifications.

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

The registry record establishes that this was an open-label, nonrandomized phase 1 study of alisertib in participants with advanced solid tumors, with dose escalation across formulations and schedules. It defines DLT criteria and the population considered evaluable for that endpoint. Those design details clarify what the trial set out to assess.

The primary DLT result is not reported in the registry record. This means the posted information does not establish the number of participants who experienced DLT, the pattern by dose, or the maximum tolerated dose. It also does not permit estimation of the primary endpoint's precision. Missing results must not be interpreted as zero events or as proof that a dose was tolerable.

The serious adverse-event summaries report cohort counts and several event terms with percentages. They describe recorded safety events, but they do not replace the DLT endpoint, and they do not establish that alisertib caused each event. The nonrandomized design and differing regimens also preclude treating the cohorts as balanced comparative groups.

In general, phase 1 dose-escalation findings are used to characterize exposure and toxicity under study conditions. They do not by themselves demonstrate clinical benefit, establish how a regimen compares with another treatment, or predict outcomes in a different population. The registry lists pharmacokinetic outcomes, but their results are not reported in the registry record.

The record therefore supports a description of study design, endpoint definitions, and selected serious adverse-event counts. It does not support a numerical conclusion about the primary toxicity endpoint or a claim of efficacy. A fuller assessment would require the unreported endpoint results, analysis populations, and statistical methods.

14. Why This Trial Matters Statistically

This trial illustrates why early-phase studies need to be interpreted according to their design question. Dose escalation is structured around tolerability across exposure regimens, whereas a randomized comparative trial addresses a different question. The nonrandomized, open-label design and the differing PIC, ECT, and relative-bioavailability regimens mean that cohort contrasts cannot be read as controlled treatment effects.

The DLT endpoint also shows the importance of operational definitions. The registry defines qualifying toxicity using grading, duration, treatment support, recovery delay, and investigator judgment. That specificity makes clear what counts as an event, while also reminding readers that the resulting count is a composite of different kinds of toxicity. The endpoint cannot be reconstructed from general adverse-event counts.

Statistically, a clearly defined outcome is only part of the evidence. Interpretation also requires the analyzed population, event counts, denominators, uncertainty estimates, and a description of the analysis. The registry record provides the DLT-evaluable population criteria but does not report the number evaluated or the primary result. As a result, readers cannot assess the frequency or precision of DLT from the primary outcome.

The record further lists many outcome measures and some serious adverse-event summaries. This demonstrates why outcome scope and multiplicity procedures matter in general: numerous measures can raise questions about which findings were prespecified and how they were interpreted. The registry record does not report such procedures. Overall, this study is a useful example of distinguishing a trial's design and endpoint definition from the quantitative evidence needed to answer its primary statistical question.

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.

A central limitation of the registry record is that the primary DLT result is not reported. The record gives the endpoint definition and evaluation window, but not the count of participants with DLT, the dose-specific results, or the maximum tolerated dose. It also does not report the number meeting the DLT-evaluable population criteria, so the primary endpoint denominator cannot be established.

The cohort structure limits comparative interpretation. Allocation was nonrandomized, masking was absent, and the cohorts differed in dose, formulation, or schedule. The registry explicitly cautions that the arms are not a like-for-like control comparison. The listed serious adverse-event counts should therefore be read descriptively, not as estimates of relative treatment effect.

The registry record does not report a statistical analysis plan, sample-size justification, interim-analysis plan, missing-data approach, or multiplicity procedure. The record lists 58 outcome measures but no analysis records. This leaves uncertainty about how the outcomes were analyzed and whether any formal comparisons or adjustments were planned. The pharmacokinetic outcome names are listed, but their results are not reported in the registry record.

Safety summaries are also limited in scope. Serious-event counts and selected term percentages are posted, but the denominator for the term percentages is not reported, and death counts are not reported in the registry record. These summaries do not supply event timing or the full context needed to link individual events to treatment. The relative-bioavailability arm description is truncated, so its complete regimen details are not available in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study of MLN8237, a Novel Aurora A Kinase Inhibitor, in Participants With Advanced Solid Tumors — NCT00500903.
• Registry record last updated 2019-03-14; status last verified 2018-11.
• Results first posted 2019-03-14.
• 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 describes a completed, open-label, nonrandomized phase 1 study of alisertib in participants with advanced solid tumors. Enrollment was 87. Dose-escalation cohorts used PIC or ECT formulations, and a relative-bioavailability cohort was also listed. The primary outcome was the number of participants with DLT, assessed during the initial treatment period using defined toxicity criteria.

The DLT-evaluable population required sufficient first-cycle exposure and follow-up, but its size and the primary outcome result are not reported in the registry record. Serious adverse-event counts are posted by cohort, along with selected event terms and percentages. The registry lists 58 outcome measures and no analysis records. Its design and outcome definitions are described, but the missing primary result and statistical details prevent quantitative assessment of the primary DLT question.