A Dose-Escalation Study Evaluating the Combination of Trastuzumab Emtansine (T-DM1) With Neratinib in Women With Metastatic HER2-Positive Breast Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Dose-Escalation Study Evaluating the Combination of Trastuzumab Emtansine (T-DM1) With Neratinib in Women With Metastatic HER2-Positive Breast Cancer (NCT02236000), a na phase 1, phase 2 study. The primary outcome is Number of Evaluable Patients With Dose Limiting Toxicity Events in Phase 1.

2. Clinical Question

3. Trial Design

This completed study combined Phase I dose escalation and Phase II evaluation in one open-label, single-group trial. The registry reports enrollment of 49 and lists the sponsor as NSABP Foundation Inc. The study started in 2014-08 and reached primary completion in 2020-12. No masking was used, and allocation is listed as NA.

In Phase I, the study evaluated neratinib in combination with T-DM1 to determine the highest neratinib dose that could be given safely with T-DM1. The listed Phase I dose groups paired neratinib at 120mg, 160mg, 200mg, or 240mg with T-DM1 at 3.6mg/kg. The registry describes a rule for dose escalation based on the number of dose-limiting toxicities observed in a cohort. Patients with a dose-limiting toxicity, or those who completed the first cycle, were eligible for the endpoint population as described in the record.

The Phase II portion was intended to assess whether the neratinib dose selected in Phase I, combined with T-DM1, would keep breast cancer from worsening for a period of time. Progression-free survival and clinical benefit rate are listed among secondary outcomes. The record also lists adverse events as a secondary outcome and describes research blood and tumor samples, including optional biopsies.

Because the study has no control group, the design does not support a randomized comparison of the combination against another treatment. The registry record does not report the detailed statistical analysis plan, a sample-size justification, or the results for the primary endpoint.

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: Endpoint information is not available for 1 patient.

Overall Study

Analysis population for the primary outcome, as defined in the registry: ITT patients who are evaluable for toxicity during the 1st cycle (patients who completed Cycle 1 or had a DLT) of the Phase 1 portion of the study.

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 Evaluable Patients With Dose Limiting Toxicity Events in Phase 1, measured over Day 1, 8, and 15 of cycle 1..

The primary endpoint is the number of evaluable patients in the Phase I portion who experience dose-limiting toxicity. The registry defines the evaluable population as intention-to-treat patients who were evaluable for toxicity during the first cycle: patients who completed Cycle 1 or had a dose-limiting toxicity. The stated assessment period is Day 1, 8, and 15 of cycle 1.

This endpoint is used in a dose-escalation study because early-cycle toxicities can inform whether a dose level is tolerable enough for further evaluation. The registry’s decision rule specifies how the number of observed dose-limiting toxicities in a cohort affects whether the next dose level is considered or the combination is considered too toxic. That is a rule for dose progression, not evidence by itself about later clinical benefit.

The endpoint is a count of participants with dose-limiting toxicity, rather than a measure of tumor response or time until disease progression. The registry record does not report the observed primary endpoint count, a rate, or an uncertainty interval. It also does not provide the operational definition of dose-limiting toxicity beyond the stated cohort rule. As a result, the endpoint’s intended role is clear, but the posted record does not allow readers to assess the Phase I endpoint result or its precision.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a Phase I dose-escalation component and a Phase II component in a single-group, open-label study. These design features determine what the statistical results could describe. A single-group study can report outcomes observed among enrolled participants, but it does not provide a randomized control group for estimating how outcomes differ under another treatment. Open-label means masking was not used; the registry does not describe additional protections against assessment bias.

What a dose-escalation rule does

In a dose-escalation study, an observed toxicity count can guide decisions about whether to continue at a dose, enroll more participants at that dose, move to a higher dose, or stop escalation. The registry specifies a rule for this study: if 1 of 3 patients in a cohort experiences a dose-limiting toxicity, 3 more patients are added at the same dose. If 0 of 3 initial patients or 1 of 6 patients in an expanded cohort experiences a dose-limiting toxicity, the next cohort escalates to dose level 2; otherwise, the combination is considered too toxic. This describes a decision rule; it does not reveal which branch was followed or what dose was ultimately selected.

The registered primary endpoint is a count of evaluable patients experiencing dose-limiting toxicity in Phase I. Counts are straightforward descriptions of how many participants met an outcome definition. Their interpretation depends on the definition of the event and on who is included in the denominator. Here, the record defines the endpoint population as intention-to-treat patients evaluable for toxicity during the first cycle, including patients who completed Cycle 1 or had a dose-limiting toxicity. The observed endpoint count and denominator are not reported in the registry record.

How to interpret uncertainty

General statistical explanation: a confidence interval describes a range of values compatible with the observed data under a specified statistical method. It helps distinguish a precise estimate from one that is uncertain. For a small cohort, a count may be highly sensitive to the experience of a few participants, so an interval estimate can be informative alongside the count. The registry record does not report a confidence interval for the primary endpoint or the safety counts, so the precision of those estimates cannot be assessed from the posted results.

General statistical explanation: a p-value evaluates how unusual data would be under a stated statistical model and null hypothesis. It is not a measure of clinical importance, and it does not by itself establish causation. No analysis results or p-values are reported in the registry record. There is therefore no posted inferential test to interpret for the primary endpoint or for comparisons between groups.

Why the dose groups are not controls

The listed dose groups reflect dose escalation, not randomized assignment. Participants in different cohorts may differ for reasons other than dose, and later cohorts are not a concurrent control for earlier ones. A numerical contrast between such groups would be descriptive, not a randomized estimate of a dose effect. The record explicitly identifies the study as single group and does not report allocation to a control arm.

General statistical explanation: when events are uncommon or the number of participants is limited, estimates can have substantial sampling uncertainty. A larger count of participants with an event does not automatically indicate greater risk if the group sizes differ. Rates and uncertainty intervals can help contextualize counts, but the registry record does not provide adjusted estimates, inferential comparisons, or a complete analysis for the outcomes listed.

What the analysis plan does not tell readers

The registry record does not report the statistical analysis plan, a sample-size justification, an interim-analysis plan, or methods for handling missing outcome data. It does not report whether outcome assessors used prespecified criteria beyond the endpoint description, or whether analyses accounted for multiple outcomes. These details should not be inferred from the fact that the study had Phase I and Phase II components or from the listed dose-escalation rule.

General statistical explanation: sample-size planning asks how many participants would be needed to estimate an effect or detect a specified difference under stated assumptions. Such planning is distinct from observed power, which should not be treated as a post hoc explanation of a result. Any planning illustration is not the trial’s actual design justification unless the registry says it was. The registry record does not report its own sample-size justification. Without outcome estimates and a prespecified analysis description, the posted record cannot support a detailed assessment of the study’s statistical power or the robustness of its results.

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("Phase 1 Neratinib 120mg; T-DM1 3.6mg/kg", "Phase 1 Neratinib 160mg; T-DM1 3.6mg/kg", "Phase 1 Neratinib 200mg; T-DM1 3.6mg/kg", "Phase 1 Neratinib 240mg; T-DM1 3.6mg/kg", "Neratinib and T-DM1")
n      <- c(6, 9, 8, 3, 26)
events <- c(1, 0, 4, 2, 7)
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  Phase 1 Neratinib 120mg; T-DM1 3.6mg/kg  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  Phase 1 Neratinib 160mg; T-DM1 3.6mg/kg  9  0  0.0  0.0  33.6  -0.0  29.9  0.3  30.8
ARM  Phase 1 Neratinib 200mg; T-DM1 3.6mg/kg  8  4  50.0  15.7  84.3  21.5  78.5  21.2  78.8
ARM  Phase 1 Neratinib 240mg; T-DM1 3.6mg/kg  3  2  66.7  9.4  99.2  20.8  93.9  19.4  93.2
ARM  Neratinib and T-DM1  26  7  26.9  11.6  47.8  13.7  46.1  13.8  46.3

11. Multiplicity, Missing Data and Analysis Populations

The registry lists several outcomes: the Phase I primary endpoint of patients with dose-limiting toxicity, progression-free survival, adverse events, and clinical benefit rate in Phase II. It does not report how these outcomes were ordered for confirmatory testing, whether any outcome was designated as a key secondary endpoint, or whether the analysis plan adjusted for multiple comparisons. Without that information, the possibility of multiplicity and its handling cannot be evaluated from the registry record.

Missing-data handling is also not reported in the registry record. The primary endpoint population is described as patients evaluable for toxicity during the first cycle, including those who completed Cycle 1 or had a dose-limiting toxicity. The record does not explain how patients without sufficient toxicity information were treated, whether missing assessments were imputed, or how missing follow-up was addressed for progression-free survival or clinical benefit rate.

The record does not report the analysis populations used for outcomes beyond the primary endpoint’s stated population. It does not specify whether the Phase II analyses used all enrolled participants, a subset, or another defined population. Nor does it report the number of participants included in each outcome analysis or the reasons for any exclusions. These gaps limit interpretation of the safety counts and prevent assessment of whether outcome denominators align with the enrolled population.

These are reporting gaps, not evidence that particular statistical procedures were or were not used. The record does not report the analysis plan, missing-data methods, or multiplicity procedures.

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: dehydration (25.0%), diarrhoea (18.2%), hypertension (16.7%), hypokalaemia (12.5%), blood creatinine increased (12.5%).

The registry reports serious adverse event counts by listed group. The Phase I dose groups are 1 of 6 at neratinib 120mg with T-DM1 3.6mg/kg, 3 of 10 at 160mg, 3 of 8 at 200mg, and 0 of 3 at 240mg. The broader Phase I entry reports 7 of 27, while the Phase II entry reports 10 of 22. These are participant counts, not randomized comparisons. The broader Phase I entry summarizes the Phase I portion and should not be treated as an additional independent dose cohort.

The record also lists participants with other adverse events in each group, and those counts include all participants at risk in the listed groups. The listed deaths are 0, 1, 0, and 0 in the individual Phase I dose groups, 1 in the Phase I aggregate, and 1 in Phase II. The registry does not report whether the deaths were considered related to study treatment, so the counts should not be interpreted as evidence of causation.

Several serious adverse event terms are listed with percentages, including dehydration, diarrhoea, and hypertension. The registry record does not specify the denominator for each percentage or provide enough detail to interpret them as comparative risks. Counts and percentages are descriptive; without a control group, a complete event definition, and an analysis plan, they do not establish a treatment effect or comparative safety profile.

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

The study addresses an important statistical problem in early-phase development: how to evaluate tolerability while escalating dose, then proceed to a later-phase assessment. The Phase I endpoint and cohort rule show that dose-limiting toxicity was intended to guide escalation. The design also included a Phase II question about progression-free survival and collected safety information.

What the record does not establish is whether the combination improved outcomes, how progression-free survival compared with another treatment, or whether the observed safety profile was better or worse than a control. No control group was included, and no Phase II outcome analysis is reported in the registry record. The record also does not report the primary endpoint result needed to evaluate the dose-escalation question.

Descriptive adverse event counts can tell readers how many participants in the listed groups were recorded as having events. They cannot, on their own, tell whether an event was caused by treatment, whether differences between groups arose from dose, or how outcomes would have differed under another treatment. The cohorts were not randomized controls, and the record does not report adjusted comparisons or uncertainty intervals.

The listed aims and outcomes should therefore be distinguished from findings. A stated purpose to assess progression-free survival is not a reported result. Likewise, a completed study status and an enrollment count do not show that a particular endpoint was met. Because the registry record contains no analysis results for the primary endpoint or listed efficacy outcomes, conclusions about those outcomes are not available from this record.

The information is most useful as a description of the study design, the intended role of the Phase I toxicity endpoint, and the safety counts posted for the listed groups. Further interpretation would require outcome results and their denominators, definitions, analysis methods, and uncertainty estimates. Those details are not reported in the registry record.

14. Why This Trial Matters Statistically

This trial illustrates how early-phase dose escalation uses toxicity observations to guide the next study step. The registry’s rule makes the decision structure explicit: cohort-level dose-limiting toxicity counts inform whether additional patients are enrolled at a dose, whether escalation proceeds, or whether the combination is considered too toxic. That is a distinct statistical purpose from testing whether a treatment improves an efficacy outcome.

The study also demonstrates why design labels matter when interpreting numbers. Although several dose groups are listed, the trial is single group and allocation is NA. The cohorts are not randomized controls. Their adverse event counts can be described, but comparisons between them cannot be treated as causal estimates of dose effects. A registered Phase II progression-free survival question likewise needs an outcome estimate and an appropriate interpretive framework; the registry record does not report those results.

Finally, the record highlights the importance of complete outcome reporting. It describes the primary endpoint, population, and escalation rule, but does not report the primary endpoint result, an analysis plan, or outcome uncertainty. Without those elements, readers can understand the intended statistical approach but cannot judge the precision of the primary finding or evaluate the Phase II outcome question from the registry record. Clear reporting of counts, denominators, definitions, analysis populations, and uncertainty is central to assessing early-phase clinical evidence.

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.

The registry record provides limited information for evaluating outcomes. It reports enrollment of 49 and lists safety counts, but does not report the primary endpoint result or analyses. The dose-limiting toxicity definition is not detailed beyond the cohort decision rule, and the number of evaluable patients for the primary endpoint is not stated. The record also does not provide confidence intervals or other uncertainty measures for the endpoint and safety counts.

The single-group, open-label design limits what can be inferred from group differences. There is no randomized control group, and the dose cohorts are part of escalation rather than like-for-like comparisons. The record does not report an adjusted analysis that could address differences between cohorts. Safety counts also lack detail about event timing, duration, severity beyond the serious-event designation, or attribution to treatment.

For the Phase II outcomes, progression-free survival and clinical benefit rate are listed, but their results and analysis populations are not reported in the registry record. The record does not state how missing data were handled, how outcomes were assessed, whether multiplicity was addressed, or what sample-size justification was used. These limitations mean the record is informative about study structure and selected safety counts, but insufficient for judging efficacy, precision, or comparative treatment effects.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Dose-Escalation Study Evaluating the Combination of Trastuzumab Emtansine (T-DM1) With Neratinib in Women With Metastatic HER2-Positive Breast Cancer — NCT02236000.
• Registry record last updated 2023-01-26; status last verified 2023-01.
• Results first posted 2023-01-26.
• 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

NCT02236000 is a completed Phase Ib/II, open-label, single-group study of neratinib with T-DM1 in women with metastatic HER2-positive breast cancer. Enrollment was 49. The listed sponsor is NSABP Foundation Inc; the study started in 2014-08 and reached primary completion in 2020-12.

The Phase I primary endpoint was the number of evaluable patients with dose-limiting toxicity during the first cycle, with assessments on Day 1, 8, and 15. The registry describes a cohort-based dose-escalation rule. Progression-free survival, adverse events, and Phase II clinical benefit rate are listed as secondary outcomes. The record includes serious adverse event counts by group but does not report the primary endpoint result, efficacy analyses, or a statistical analysis plan.