Eribulin Mesylate and Everolimus in Treating Patients With Triple-Negative Metastatic Breast Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Eribulin Mesylate and Everolimus in Treating Patients With Triple-Negative Metastatic Breast Cancer (NCT02120469), a na phase 1 study. The primary outcome is Number of Participants Experiencing a Dose Limiting Toxicity (DLT) (Phase I) and the Recommended Phase IB Dose (RP2D).

2. Clinical Question

3. Trial Design

This was a Phase I/IB trial sponsored by City of Hope Medical Center. The registry record lists an enrollment of 27 and a completed status. The recorded start date is 2014-11-17, and the primary completion date is 2019-03-20. The study was single-group, with no masking and no randomized allocation. These features mean that the record does not describe a randomized comparison of the combination against another treatment or a control condition.

The treatment combined everolimus with eribulin mesylate. Everolimus was given orally once daily on days 1–21, and eribulin mesylate was given intravenously on days 1 and 8. Courses were to repeat every 21 days if disease had not progressed and toxicity remained acceptable. The registry also lists pharmacological study and laboratory biomarker analysis as interventions; it does not provide further details about their role in this account.

The primary outcome is framed around dose-limiting toxicity in Phase I and the recommended Phase IB dose. The registry describes dose-limiting toxicity as an adverse event or abnormal laboratory value considered at least possibly related to study medication and meeting criteria under NCI CTCAE v4.0. The available record does not state the full criteria used to select the recommended dose or report the selected dose.

Secondary outcomes listed for Phase IB include participants with Grade 3 or higher toxicities, best response using RECIST, median overall survival, and median progression-free survival. The registry record lists six outcome measures overall, but the measure-specific results are not included in the registry entries. The dose-level safety counts describe participants within dose-level groups; they do not establish a controlled 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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Number analyzed for DLT only include participants that are evaluable. A1: 1 participant was not evaluable due to progression prior to completion of first two cycles and 1 participant was not evaluable due to toxicity attributed to diabetes. A2: 1 participant was not evaluable due to HER2+ repeat biopsy. B1: 1 participant was not evaluable due to HER2+ repeat biopsy.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants Experiencing a Dose Limiting Toxicity (DLT) (Phase I) and the Recommended Phase IB Dose (RP2D), measured over First cycle on treatment, up to 21 days.

The primary endpoint asks how many participants experienced a dose-limiting toxicity during the first cycle of treatment, with the timeframe specified as up to 21 days. The registry definition includes an adverse event or abnormal laboratory value judged at least possibly related to study medication and meeting criteria under NCI CTCAE v4.0. This is a participant count: it concerns how many evaluable participants met the toxicity definition, rather than the number of separate symptoms or laboratory abnormalities.

Dose-limiting toxicity is used in early-phase studies to characterize important treatment-related toxicity while doses are being assessed. In this trial, the primary outcome also names the recommended Phase IB dose, linking the toxicity assessment to dose selection. The registry record does not provide the detailed decision rule used to select that dose, so the relationship between the observed count and the eventual dose recommendation cannot be reconstructed from the available record.

The population description says that only participants evaluable for dose-limiting toxicity were included in that analysis. It notes some participants who were not evaluable, but the actual evaluable denominator and dose-limiting toxicity count are not reported in the registry record. As a result, the primary endpoint cannot be interpreted as a rate or compared across dose levels using the information available.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Some statistical context is useful for reading the outcomes. The primary endpoint is a count of participants who meet a defined toxicity criterion. A count has to be interpreted alongside its analysis population: the number of participants who could be evaluated for the endpoint. If participants are excluded from an evaluable analysis, the count does not describe all enrolled participants unless the analysis explicitly says so. The registry record notes that the primary analysis included participants evaluable for dose-limiting toxicity, but does not report the final evaluable denominator or the endpoint count.

What does a dose-limiting toxicity count measure?

A dose-limiting toxicity is an operational endpoint: an event must meet the study’s severity and attribution rules to count. The registry defines the event broadly as an adverse event or abnormal laboratory value at least possibly related to study medication and meeting criteria under NCI CTCAE v4.0. The count is therefore not interchangeable with the number of all adverse events. One participant may experience more than one event, while the primary count is described in terms of participants. The precise criteria and dose-selection algorithm are not reported in the registry record.

For a count to convey the frequency of toxicity, readers also need a denominator and a clearly defined observation period. The stated observation window is the first cycle on treatment, up to 21 days. This aligns the primary safety assessment to a specified early treatment period, but the posted material does not give the count or denominator needed to describe the observed frequency. It would be inappropriate to infer either from enrollment or from the separate safety summaries.

How should uncertainty be understood?

In general, a confidence interval expresses the range of values reasonably compatible with an estimate under a statistical model. For a participant count or an event proportion, uncertainty depends in part on how many participants contributed information and how many met the endpoint definition. A small or incomplete evaluable population can leave substantial uncertainty even when the observed count is available. No confidence interval for the primary endpoint is reported in the registry record, so its precision cannot be assessed from the available information.

A hypothesis test answers a different question from a confidence interval: it assesses compatibility with a specified null model, under the assumptions of the test. The available record does not provide a primary-endpoint hypothesis test, a null hypothesis, or a test result. More importantly, the trial is single-group, so the primary toxicity count is not itself a comparison against a control group. A statistical test cannot substitute for a comparator that the design does not include.

Why does the design matter?

In general, random allocation can help balance measured and unmeasured prognostic characteristics between comparison groups. This study is recorded as single-group, with allocation not applicable and masking none. The dose-level groups in the safety summary do not change that overall design description. Their sizes differ, and the registry record does not establish that assignment to dose level was randomized. Comparisons between their counts therefore should be read descriptively, not as unbiased estimates of dose effects.

Masking can reduce some forms of assessment or reporting bias, depending on the outcome and how it is measured. With masking listed as none, the registry indicates an open-label design. This fact does not show that any particular outcome was biased, but it is relevant when considering outcomes involving clinical assessment, such as best response. The record does not describe independent or blinded response review.

What do the planning assumptions mean?

General sample-size planning uses assumptions about the effect to detect, the significance level, allocation, and the statistical approximation. The stated planning illustration uses a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It describes detecting a stated fraction of an observed effect. Such a calculation is a planning illustration, not a result from this trial and not observed power. The registry record does not report the trial’s own sample-size justification, and the available information does not give planning values to interpret.

For time-to-event outcomes, the stated planning convention expresses sample size as a total number of events; for other outcomes it expresses participants per arm. These are general planning conventions and should not be confused with the trial’s enrollment of 27 or the counts in the dose-level safety summaries. Since the study is single-group, the equal-allocation planning assumption does not describe its recorded design.

Why can event data be harder to compare?

General statistical methods may need to account for over-dispersion when observed variation exceeds what a simple model expects. Over-dispersion can make model-based uncertainty too small if it is ignored. The registry record does not report a model for the primary count, an over-dispersion assessment, or an adjustment for clustering or repeated events. This matters because the endpoint is a participant count, while safety summaries can also include multiple event terms and events per participant. Those are different statistical units and cannot be combined without a stated method.

Overall, the available record supports a description of the design, treatment schedule, endpoint definition, and selected safety counts. It does not support reconstruction of an adjusted analysis, a confidence interval, a treatment comparison, or the dose-selection calculation. Those methods and results are not reported in the registry record.

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("Dose Level B1", "Dose Level A1", "Dose Level A2")
n      <- c(12, 8, 3)
events <- c(4, 4, 2)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Dose Level B1  12  4  33.3  9.9  65.1  13.8  60.9  13.9  61.4
ARM  Dose Level A1  8  4  50.0  15.7  84.3  21.5  78.5  21.2  78.8
ARM  Dose Level A2  3  2  66.7  9.4  99.2  20.8  93.9  19.4  93.2

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists six outcome measures and one analysis. The listed Phase IB secondary outcomes include participants with Grade 3 or higher toxicities, best response using RECIST, median overall survival, and median progression-free survival. The primary outcome combines the dose-limiting toxicity count with the recommended Phase IB dose. No hierarchy among outcomes, multiplicity adjustment, or prespecified strategy for interpreting multiple endpoints is reported in the registry record.

Multiplicity matters when several outcomes or statistical tests are considered, because the chance of a misleading finding can increase as the number of inferences grows. General approaches include prespecifying a hierarchy or adjusting inference across tests, but the record does not say whether either approach was used. The presence of several outcomes does not by itself establish that each was tested or that any particular correction was appropriate.

The primary endpoint population is described as participants evaluable for dose-limiting toxicity, not all enrolled participants. For Dose Level A1, the record says one participant was not evaluable because of progression before completing the first two cycles, and one was not evaluable because of toxicity attributed to diabetes. For Dose Level A2, one participant was not evaluable for a reason described as HER2+ repeat bi; that description is incomplete in the registry record. The final analysis denominators and the handling of missing outcome data are not reported.

The record does not specify whether missing data were imputed, whether participants were analyzed according to an intention-to-treat principle, or how incomplete follow-up was handled for response and survival outcomes. Those choices can affect interpretation, particularly when analysis populations differ by outcome. They should not be inferred from the enrollment count or the statement that the primary endpoint included evaluable participants.

12. Safety Results

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

Deaths

Other (non-serious) adverse events

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

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: abdominal pain (25.0%), mucositis oral (25.0%), infections and infestations - other (25.0%), generalized muscle weakness (25.0%), dyspnea (20.0%).

The safety summary is organized by Dose Level B1, Dose Level A1, and Dose Level A2. For Dose Level B1, it reports 13 participants at risk for serious events and 1 affected; for other events it reports 13 at risk and 13 affected, with 6 deaths recorded. Dose Level A1 lists 10 at risk for serious events and 3 affected; for other events it lists 10 at risk and 10 affected, with 10 deaths recorded. Dose Level A2 lists 4 at risk for serious events and 1 affected; for other events it lists 4 at risk and 4 affected, with 3 deaths recorded.

These are descriptive counts, not comparisons against a control group. The record does not specify the timing or cause of the reported deaths in this summary, and the counts alone do not establish a relationship to treatment. The listed serious-event terms include abdominal pain, mucositis oral, infections and infestations - other, generalized muscle weakness, dyspnea, and febrile neutropenia. Their posted percentages are 25.0%, 25.0%, 25.0%, 25.0%, 20.0%, and 10.0%, respectively. The denominator for these term percentages is not reported in the registry record; terms may also occur in the same participant, so the percentages should not be added or read as mutually exclusive categories.

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

The record establishes that a Phase I/IB study of everolimus with eribulin mesylate was conducted in patients with triple-negative metastatic breast cancer, with a primary focus on dose-limiting toxicity and recommended Phase IB dose. It documents the treatment schedule, the endpoint definition, and selected safety counts by dose level. It also lists response and survival outcomes planned or recorded for Phase IB.

The available information does not report the primary dose-limiting toxicity result or the recommended Phase IB dose. It therefore cannot show the observed frequency of the primary event, the precision of that estimate, or the basis for the dose recommendation. The named secondary outcomes likewise lack their numerical results in the registry record. Their names should not be mistaken for evidence that a particular response, survival duration, or toxicity level was observed.

Because the study is single-group, the results cannot provide a randomized estimate of how the combination compares with another treatment. The dose-level safety counts do not constitute a controlled comparison, and the available information does not establish randomized assignment between those levels. The record also does not provide enough detail to assess whether differences in patient characteristics, exposure, follow-up, or evaluability affected the group counts.

In general, early-phase toxicity and dose-selection findings address a different question from comparative effectiveness. They can characterize tolerability under the study conditions and inform a dose choice, while a controlled comparison is needed to estimate differences in outcomes between treatments. Here, even the primary toxicity result and selected dose are not reported in the available record. No conclusion about treatment benefit, lack of benefit, or comparative safety follows from the information summarized in the registry record.

14. Why This Trial Matters Statistically

This trial is statistically notable for the way its primary question is framed: it combines a count of participants with dose-limiting toxicity and identification of a recommended Phase IB dose. That pairing reflects an early-phase focus on dose assessment rather than a controlled estimate of treatment effect. Understanding that distinction prevents a toxicity count from being misread as evidence of comparative efficacy.

The record also illustrates why an endpoint definition and an analysis population need to be read together. Dose-limiting toxicity is defined by event attribution and clinical criteria, and only participants described as evaluable were included in the primary assessment. The reasons for some exclusions are recorded, but the final denominator and outcome count are absent. Without those elements, neither frequency nor precision can be assessed.

The single-group design is another central statistical feature. Dose-level summaries may look like separate groups, but the record does not identify them as randomized controls. Differences in their counts are descriptive and cannot isolate a dose effect. This is especially important when group sizes differ and the record does not provide adjusted analyses or sufficient context about assignment.

Finally, the registry names several secondary outcomes while the available record does not include their numerical results or explain how multiple outcomes were handled. This distinction between outcome registration and outcome reporting is important: a listed endpoint communicates what was of interest, but does not itself supply evidence about what occurred. The record’s limits leave key statistical questions unresolved, including the observed DLT count, the dose selected, and uncertainty around the safety findings.

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.

Several trial-specific limitations constrain interpretation. The study is recorded as single-group, with no masking and allocation listed as not applicable. There is no randomized control condition for estimating differences from another treatment. Dose-level safety summaries do not remove this limitation, because the registry record does not describe those levels as randomized comparison groups or provide an analysis that adjusts for differences among them.

The primary result is not reported in the available registry record. Although the endpoint definition and first-cycle timeframe are given, the DLT count, evaluable denominator, and recommended Phase IB dose are absent. The record also does not report confidence intervals or other measures of uncertainty for this endpoint. Consequently, the magnitude and precision of the primary safety finding cannot be evaluated.

The analysis population is described as evaluable, with non-evaluability noted for participants in Dose Level A1 and Dose Level A2. The A2 reason is incomplete in the registry record. The record does not explain how missing outcomes were handled, whether follow-up differed across participants, or whether separate analysis populations were used for secondary outcomes. The dose-level group sizes reported in safety information are also unequal.

Finally, the secondary outcomes are named without numerical results in the available record, and the statistical plan is not detailed. Multiplicity handling, response-assessment procedures, survival-analysis methods, and the dose-selection algorithm are not reported. These omissions prevent a fuller assessment of endpoint-specific bias, statistical uncertainty, and how safety findings informed dose selection.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Eribulin Mesylate and Everolimus in Treating Patients With Triple-Negative Metastatic Breast Cancer — NCT02120469.
• Registry record last updated 2026-10-28; status last verified 2026-10.
• Results first posted 2022-04-25.
• 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

NCT02120469 is a completed Phase I/IB, single-group study sponsored by City of Hope Medical Center. It enrolled 27 participants with triple-negative metastatic breast cancer and evaluated everolimus with eribulin mesylate. Everolimus was given orally once daily on days 1–21 and eribulin mesylate intravenously on days 1 and 8, with courses repeating every 21 days in the absence of progression or unacceptable toxicity.

The primary outcome concerns dose-limiting toxicity during the first cycle, up to 21 days, and the recommended Phase IB dose. The registry describes the toxicity definition and notes that only evaluable participants were included, but the primary result and selected dose are not reported in the available record. Phase IB secondary outcomes include toxicity, response, and survival measures. The study has no randomized comparator, and the posted dose-level safety counts should be interpreted descriptively.