Alisertib (MLN8237) in Participants With Ovarian, Fallopian Tube or Peritoneal Cancer Preceded by Phase 1 Study of MLN8237 Plus Paclitaxel Treatment of Ovary or Breast Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Alisertib (MLN8237) in Participants With Ovarian, Fallopian Tube or Peritoneal Cancer Preceded by Phase 1 Study of MLN8237 Plus Paclitaxel Treatment of Ovary or Breast Cancer (NCT01091428), a randomized phase 2 study. The primary outcome is Phase 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs).

2. Clinical Question

The clinical question therefore has two distinct parts in the study description. Phase 1 included ovarian and breast cancer participants and evaluated alisertib alongside paclitaxel at several alisertib dose levels. Phase 2 randomized participants with recurrent ovarian, fallopian tube, or primary peritoneal cancer to the specified alisertib-plus-paclitaxel regimen or paclitaxel alone. The Phase 1 safety outcome does not, by itself, answer whether the Phase 2 regimens differed in efficacy or safety.

The record lists 191 participants enrolled overall. It does not report how that total was divided between study portions in the summary information, nor does the primary outcome define a single comparison between the randomized Phase 2 arms. Consequently, interpretation of the reported event counts should remain tied to the named Phase 1 and Phase 2 groups rather than treating them as one pooled treatment comparison.

3. Trial Design

The registry describes a Phase 2 randomized, parallel-group study, preceded by a nonrandomized Phase 1 portion. Phase 1 enrolled participants with ovarian or breast cancer, while the Phase 2 population was recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. The overall enrollment was 191, and the study status is completed. The record lists a start date of 2010-04-16 and primary completion on 2014-08-12.

During Phase 1, ovarian and breast cancer groups received alisertib at 10, 20, 30 or 40 mg, twice daily on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel at 60 or 80 mg/m^2 on Days 1, 8 and 15 in 28-day cycles. The registry describes the Phase 1 regimens as continuing for up to 37 cycles. Phase 2 tested the specified alisertib 40 mg plus paclitaxel 60 mg/m^2 regimen against paclitaxel 80 mg/m^2 alone, with both regimens scheduled weekly on Days 1, 8 and 15 in 28-day cycles and allowed for up to 28 cycles.

The record classifies allocation as randomized and the model as parallel. It also labels masking as quadruple, while the brief description calls the study open-label and specifically describes the Phase 2 portion as open-label. The registry does not explain this discrepancy, so the masking conditions cannot be resolved from the record alone. The allocation ratio and details of the randomization procedure are not reported in the registry record.

Although the study includes a randomized Phase 2 comparison, the posted primary outcome is explicitly a Phase 1 measure: counts of participants with adverse events and serious adverse events. The record lists 27 outcome measures and includes pharmacokinetic measures and a Phase 1 combined best overall response rate among the secondary outcomes. It does not present a Phase 2 efficacy outcome as the primary endpoint in the information summarized for this analysis.

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 ovarian cancer or breast cancer were enrolled equally in a dose escalation study to determine the recommended Phase 2 dose. In Phase 2 participants were randomized equally to receive alisertib 40 mg BID + paclitaxel 60 mg/m\^2 or single agent paclitaxel 80 mg/m\^2.

Phase 1

Reasons for not completing this period:

Phase 2

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: DLT-Evaluable Population was defined as all participants in the phase 1 who either experienced DLT during Cycle 1 or completed treatment with at least 15 of the planned 18 doses of alisertib and 2 of the planned 3 doses of paclitaxel in Cycle 1 and had sufficient follow-up data.

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 was defined as all participants who received at least 1 dose of any study drug.

6. Primary Endpoint

The registry lists the primary outcome as Phase 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs), measured over First dose to 30 days past last dose (Up to 36 Months).

The primary outcome is the number of Phase 1 participants with adverse events and serious adverse events. The registry defines an adverse event as an untoward medical occurrence in a participant administered a drug; it need not be causally related to treatment. A serious adverse event is an experience indicating significant hazard, contraindication, side effect, or precaution, including death, a life-threatening event, inpatient hospitalization or prolonged hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or another medically significant event.

The timeframe runs from first dose to 30 days after the last dose, with the listed duration stated as up to 36 months. The safety population includes all participants who received at least one dose of any study drug. This definition matters because the endpoint concerns observed events among treated participants, not only events judged to have been caused by a study drug.

Counting participants with events is a descriptive way to summarize how many people experienced an event during the specified observation period. It can communicate the observed burden of events within each listed group, but the count alone does not establish causality, event severity beyond the serious-event classification, or a comparative treatment effect. The registry record does not report a single inferential primary comparison for this outcome. Its primary endpoint is also specific to Phase 1, so it should not be interpreted as the main result of the randomized Phase 2 comparison.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count measure?

General statistical explanation: A count records how many people in a defined group experienced an event. It is straightforward to interpret, but it does not account for how long each person was observed or how many times an event occurred in one person. A count also does not automatically distinguish events caused by treatment from events that happened during treatment. The registry’s adverse-event definition expressly does not require a causal relationship.

In this record, the primary outcome is the number of Phase 1 participants with adverse events and serious adverse events. The posted safety populations are described as people who received at least one dose of any study drug. The event counts are therefore understood within those group denominators and the recorded safety follow-up period. They should not be read as counts from an untreated comparison group.

Why distinguish Phase 1 from Phase 2?

General statistical explanation: Random allocation can help make groups comparable on average, while a nonrandomized set of groups may differ for reasons other than the regimen being evaluated. This is why design information is essential before comparing observed counts. In this study, Phase 1 was nonrandomized and included ovarian and breast cancer groups. Phase 2 was randomized and concerned recurrent ovarian, fallopian tube, or primary peritoneal cancer. Pooling the portions or treating the Phase 1 groups as comparators would disregard those design and population differences.

The registry describes a parallel Phase 2 comparison of alisertib plus weekly paclitaxel against weekly paclitaxel alone. However, the primary outcome is a Phase 1 safety outcome. A randomized design does not itself turn every posted outcome into a randomized comparison: the outcome definition, analysis population, and actual analysis also matter. The record does not post a formal primary-outcome comparison between the Phase 2 arms.

What would a confidence interval add?

General statistical explanation: A confidence interval is an estimate range that expresses statistical uncertainty around a quantity, such as a group difference or event rate. A narrow interval indicates greater precision under the analysis assumptions; a wide interval indicates less precision. The interval does not make a result clinically important or establish causality by itself. No confidence intervals are reported for the primary outcome in the registry record, so the precision of a between-group contrast cannot be assessed from the posted counts alone.

Likewise, a p-value would address compatibility between observed data and a specified statistical null hypothesis under a particular model. It would not measure the probability that a treatment works, and it would not communicate the size or practical importance of an effect. The registry record contains no posted analysis records for these outcomes, and no p-value for the primary safety outcome is reported.

How do endpoint definitions affect interpretation?

General statistical explanation: An endpoint’s definition determines which observations qualify as events, which participants are included, and the period over which events are counted. Here, adverse events can be unrelated to the study drugs, while serious adverse events are classified by serious consequences or medical significance under the registry definition. These categories should not be conflated. The primary outcome lists both adverse events and serious adverse events, and the safety counts distinguish serious events from other recorded events.

The safety population includes participants who received at least one dose. This is a treatment-exposed population definition, not a statement that every randomized participant was included in every analysis. Whether there were randomized participants who did not receive treatment, and how such cases were handled, are not reported in the registry record. Nor does the record state whether the primary count includes all events, only the first event per person, or a specific event-coding convention beyond the participant-count description.

Why might event rates need exposure adjustment?

General statistical explanation: If participants have different lengths of observation, raw participant counts can be harder to compare because there is more opportunity to detect an event among people observed for longer. Analyses can sometimes account for time at risk, but the suitable method depends on the endpoint and data structure. The registry specifies a follow-up period from first dose to 30 days after last dose and a stated duration up to 36 months. It does not report group-level exposure time or an exposure-adjusted analysis, so no such adjustment should be assumed.

Similarly, the record does not report whether repeated occurrences were analyzed separately, whether event onset dates were considered, or how participants with incomplete follow-up were handled. Those details can change the interpretation of an event summary, especially when a count is presented without a model or interval estimate.

What do the planning assumptions mean?

General statistical explanation: Sample-size planning uses assumptions about the outcome, target effect, significance level, allocation, and analysis method to illustrate how much information a future study might need. Such calculations are planning exercises, not observed study results and not a measure of the probability that a completed trial detected an effect. The record describes a planning illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. It also states that the effect to detect is a stated fraction of the observed effect.

Those planning assumptions are not described as the trial’s original design justification. The sample-size justification used when this study was planned is not reported in the registry record. Nor does the record report an interim-analysis plan, a prespecified statistical analysis plan, or the inferential model for the primary outcome. No calculated planning sample-size values are stated in the record summarized for this analysis, so none can be interpreted as a trial target or observed power.

Finally, the registry identifies 27 outcome measures but reports no analysis records. A list of outcomes does not establish which analyses were conducted, which outcomes were prioritized after data collection, or how multiplicity was handled. Those aspects require a statistical plan or analysis results, neither of which is reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 27 outcome measures, including the Phase 1 primary safety outcome, a Phase 1 combined best overall response rate, and several pharmacokinetic measures for alisertib and paclitaxel. When a study assesses multiple outcomes, the chance of at least one apparently notable result can increase if many statistical tests are conducted. General statistical explanation: Multiplicity procedures can control or otherwise address that concern, but the appropriate method depends on the outcome hierarchy and analysis plan.

No multiplicity adjustment or hierarchy for testing is reported in the registry record. The record also contains no analysis records, so it does not show which comparisons were tested or whether any adjustment was applied. The number of listed outcomes alone does not establish that all were formally tested or that multiplicity affected a particular result.

Missing-data handling is also not reported in the registry record. There is no account of missing outcome observations, loss to follow-up, withdrawal, or the methods used to include participants with incomplete data. The safety population is defined as participants who received at least one dose, but that definition does not explain how missing safety information was handled.

The registry does not state whether the randomized Phase 2 population was analyzed according to assignment, treatment received, or another analysis population. The primary endpoint’s safety population definition applies to participants who received study drug and is specific to the Phase 1 safety outcome. It should not be assumed to define the analysis population for every secondary or Phase 2 outcome. The analysis populations for those outcomes are not reported in the registry record.

11. 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 (15.8%), cellulitis (9.1%), sepsis (9.1%), pyrexia (9.1%), fatigue (9.1%).

The serious adverse event counts are 13 of 38 participants in the Phase 1 ovarian group, 2 of 11 in the Phase 1 breast group, 30 of 73 in the Phase 2 alisertib-plus-paclitaxel group, and 19 of 69 in the Phase 2 paclitaxel group. These are counts within the named groups and should be read alongside the study portions and populations to which they refer. The Phase 1 ovarian and breast groups were nonrandomized; the Phase 2 groups belonged to the randomized portion.

The registry also reports other adverse-event counts of 38 of 38, 11 of 11, 73 of 73, and 64 of 69, in the same group order. The outcome definition says an adverse event need not be caused by treatment. Thus, occurrence during the study is not the same as a finding that a regimen caused the event. The record does not give a causal attribution breakdown in the information.

The listed serious adverse event terms include febrile neutropenia at 15.8%, and cellulitis, sepsis, pyrexia, fatigue, and pulmonary embolism at 9.1% each. No arm-specific percentages for these terms are reported in the record summary. These figures should not be combined or interpreted as group comparisons, and a term’s presence does not establish its cause. The registry does not report confidence intervals or inferential tests for these safety counts.

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

The posted results establish that adverse events and serious adverse events were recorded in each of the named study groups, with the participant counts stated for each group. They also identify several serious adverse event terms and their listed percentages. These are descriptive safety observations from the registry, not a formal estimate of the comparative effect of alisertib plus paclitaxel versus paclitaxel alone.

The randomized Phase 2 design is relevant to a comparative question, but the registry’s primary endpoint is a Phase 1 count. The Phase 1 ovarian and breast groups were nonrandomized, and they differ from the Phase 2 population described in the record. Therefore, the four group counts should not be read as if they arose from one randomized comparison. Even the Phase 2 counts cannot establish a difference without an analysis that specifies the comparison and quantifies uncertainty.

The posted counts do not show whether events were judged related to treatment, how many events occurred per participant, or how event timing and exposure duration varied. They also do not provide an inferential estimate, confidence interval, or hypothesis test. Accordingly, they do not establish that either regimen caused more or fewer events, and they do not establish a treatment benefit or lack of benefit.

The record lists a Phase 1 combined best overall response rate as a secondary outcome, but no result for that outcome is included in the information. It likewise does not provide a Phase 2 efficacy comparison in the primary outcome information. The safety data therefore cannot answer the efficacy question on their own. They should be understood as registry-reported event counts and terms, with the limits created by the endpoint, design, and absence of posted statistical analyses.

13. Why This Trial Matters Statistically

This trial is statistically notable because its overall description combines two distinct study phases, populations, and design approaches. The nonrandomized Phase 1 portion explored alisertib with weekly paclitaxel in ovarian and breast cancer groups. The randomized Phase 2 portion compared a specified alisertib-plus-paclitaxel regimen with paclitaxel alone in recurrent ovarian, fallopian tube, or primary peritoneal cancer. Keeping those components separate is necessary for interpreting any group-level safety count.

A second important point is the alignment between the study design and the posted primary outcome. The study description emphasizes the randomized Phase 2 comparison, yet the stated primary outcome is Phase 1 safety. This is not necessarily contradictory, but it means the primary endpoint does not directly summarize the randomized treatment contrast. Readers need to distinguish a trial’s overall clinical question from the endpoint and analysis actually reported in the registry.

The registry also illustrates why descriptive counts and inferential comparisons are different. Counts make the observed number of participants with events clear, but without comparative estimates and uncertainty measures they do not establish a statistical difference. This is particularly relevant when groups include distinct disease populations, treatment regimens, and study phases.

Finally, the record lists multiple outcomes but no analysis records. That absence limits assessment of the analysis plan, multiplicity, missing data, and precision. The study can therefore be described accurately at the level of its design and recorded safety counts, while statistical conclusions about comparative effects remain unsupported by the posted analysis information.

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.

Several limitations are specific to the information in this registry record. First, the primary endpoint is a Phase 1 safety count, whereas the study also includes a randomized Phase 2 comparison. The primary outcome therefore does not directly provide a Phase 2 treatment contrast. The record does not report an inferential analysis of the Phase 2 safety counts.

Second, Phase 1 was nonrandomized and included both ovarian and breast cancer groups. These groups should not be used as though they were randomized comparators. The Phase 2 population is described separately as recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. The record does not provide baseline characteristics that would help assess group comparability.

Third, the registry labels masking as quadruple but describes the study as open-label in its brief summary, including the Phase 2 portion. It does not explain the discrepancy. The allocation ratio, randomization details, and practical masking procedures are not reported in the registry record.

Fourth, the posted safety summaries do not include confidence intervals, hypothesis tests, event timing, exposure-adjusted rates, or a detailed accounting of repeated events. The record does not explain causal attribution beyond defining adverse events as not necessarily related to treatment. Missing-data methods, analysis populations beyond the Phase 1 safety definition, and multiplicity procedures are also not reported.

Finally, although secondary outcomes include Phase 1 response and pharmacokinetic measures, results for these outcomes are not included in the information summarized for this analysis. The registry’s listed outcome set and completed status alone do not supply those results or a statistical analysis plan.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Alisertib (MLN8237) in Participants With Ovarian, Fallopian Tube or Peritoneal Cancer Preceded by Phase 1 Study of MLN8237 Plus Paclitaxel Treatment of Ovary or Breast Cancer — NCT01091428.
• Registry record last updated 2018-06-04; status last verified 2018-05.
• Results first posted 2018-06-04.
• 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

The record describes a completed randomized Phase 2 study preceded by a nonrandomized Phase 1 portion. Overall enrollment was 191. Phase 1 included ovarian and breast cancer groups receiving alisertib with weekly paclitaxel at several dose levels. Phase 2 compared alisertib 40 mg with paclitaxel 60 mg/m^2 against paclitaxel 80 mg/m^2 alone in recurrent ovarian, fallopian tube, or primary peritoneal cancer.

The primary outcome is the number of Phase 1 participants with adverse events and serious adverse events, with follow-up from first dose to 30 days after the last dose. The record reports group-level participant counts and a list of serious adverse event terms. It does not report a primary Phase 2 efficacy analysis, inferential results for the safety counts, multiplicity procedures, or missing-data methods. The registry also contains an unexplained difference between its quadruple-masking classification and its open-label study description.