Combination of Letrozole, Everolimus and TRC105 in Postmenopausal Women With Hormone-Receptor Positive and Her2 Negative Breast Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Combination of Letrozole, Everolimus and TRC105 in Postmenopausal Women With Hormone-Receptor Positive and Her2 Negative Breast Cancer (NCT02520063), a non-randomized phase 1, phase 2 study. The primary outcome is Number of Participants Who Experienced Dose-limiting Toxicities.

2. Clinical Question

3. Trial Design

This was a completed Phase I/II study sponsored by the University of Alabama at Birmingham. The registry lists an enrollment of 15, a start date of 2015-02-01, and a primary completion date of 2022-12-01. The design was non-randomized, unmasked, and single-group. It therefore does not provide a randomized comparison against another treatment or a control group.

The Phase I component described three dose cohorts. Cohort 1 received letrozole 2.5 mg PO daily until surgery, everolimus 5 mg PO daily for 24 weeks, and TRC105 15 mg/kg IV every 2 weeks for 24 weeks. Cohort 2 used everolimus 10 mg PO daily with the same stated letrozole and TRC105 regimen. Cohort -1 used everolimus 5 mg PO daily and TRC105 10 mg/kg IV every 2 weeks, with letrozole again continued until surgery. The registry states that no patients were enrolled in cohort -1 because of the lack of toxicities in Phase I cohorts 1 and 2.

The Phase II regimen was to use everolimus 5 or 10 mg PO daily and TRC105 15 or 10 mg/kg IV every 2 weeks, with the dose and regimen determined from Phase I data. The registry does not identify the final Phase II dose selection or report a separate Phase II efficacy estimate. Treatment was preoperative, and the study description frames the combination as an investigation of safety and efficacy in breast cancer.

The registry record does not report a randomization procedure, masking, or a concurrent comparator, consistent with its listed design. A detailed statistical analysis plan and the rationale for the enrollment target are not reported in the registry record. The cohort descriptions indicate dose exploration, but the record does not provide enough detail to reconstruct the dose-selection process beyond its stated dependence on Phase I data.

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

Analysis population for the primary outcome, as defined in the registry: There were no patients enrolled in the phase 1 cohort -1 portion of the protocol due to lack of toxicities in phase 1 cohort 1 and 2.

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: Phase 1 Cohort -1 had no patients enrolled. as there was not enough toxicities to warrant a dose reduction.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants Who Experienced Dose-limiting Toxicities, measured over 4 weeks.

The primary endpoint counts participants who experienced a dose-limiting toxicity (DLT). The registry defines the assessment timeframe as 4 weeks. A DLT was defined by specified serious toxicity criteria: grade 3 or 4 non-hematologic toxicity, with listed exceptions; failure to recover to baseline after delaying the next dose by more than 14 days, except for alopecia; specified grade 3 or 4 neutropenia; or specified grade 3 or 4 thrombocytopenia.

In general, a DLT endpoint is used in early-phase dose evaluation to identify treatment-related toxicity that is severe enough to affect dose selection. The registry states that the maximum tolerated dose is the highest dose at which 0 out of the first 3 or 1 out of a total of 6 patients experience a DLT during the first cycle. It also states that this dose would be the recommended Phase II dose. These are protocol definitions, not a reported result: the number of participants meeting the primary endpoint in each Phase I cohort is not reported in the registry record.

The endpoint is a count of participants with an event, rather than a measure of tumor response or change in tumor size. The registry lists other outcomes, including pathologic complete remission, tumor proliferation changes, and letrozole and everolimus pharmacokinetic measures. Those outcomes do not substitute for the primary safety endpoint, and their numerical results are not reported in the registry record summarized for this analysis.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is a binary event at the participant level: a participant either met the registry’s DLT definition during the specified assessment period or did not. The endpoint is then reported as a count of participants experiencing DLT. In general, binary outcomes differ from continuous measures such as a laboratory value: they record whether a defined event occurred rather than the magnitude of a measurement.

What does the DLT definition contribute?

A clear event definition determines which clinical experiences qualify for the endpoint. The registry specifies grade thresholds and exceptions for non-hematologic toxicities, a recovery rule after delaying a dose by more than 14 days, and criteria involving neutropenia and thrombocytopenia. These rules make the endpoint more specific than a general count of any adverse event. They also mean that the primary DLT count should not be treated as interchangeable with the broader serious adverse-event listing.

The DLT timeframe is stated as 4 weeks. The dose-selection description refers to DLTs during the first cycle of therapy. A time window matters because an event outside the defined window may not count toward the primary endpoint even if it is clinically important. The registry does not report how the DLT window was applied for each participant, whether any assessment was incomplete, or whether adjudication procedures were used.

How does the dose rule work?

In general, an early-phase dose rule uses observed toxicity counts at dose levels to guide whether a dose is retained or selected for further study. The registry defines the maximum tolerated dose as the highest dose at which 0 out of the first 3 or 1 out of a total of 6 patients experience DLT during the first cycle. It states that this dose would be the recommended Phase II dose. This is a protocol decision rule; it is not itself evidence that a particular dose met the rule. The numerical cohort-specific DLT counts and the final recommended dose are not reported in the registry record.

The three Phase I cohort descriptions differ in the doses of everolimus or TRC105, while letrozole is specified at 2.5 mg PO daily until surgery. The Phase II description allows more than one dose for everolimus and TRC105 and says the final dose and regimen would be determined from Phase I data. The record does not explain the exact selection algorithm or report the resulting dose choice. No additional dose-escalation method should be assumed from the cohort labels alone.

What can counts tell readers?

In general, event counts and the number of participants at risk provide a descriptive account of observed events in each group. A count of zero does not establish that the underlying risk is zero; it means that no affected participants were recorded in that group for the listed event category. Counts are more informative when accompanied by clearly defined populations, time windows, and uncertainty intervals. The registry lists group-level counts for serious adverse events but does not report confidence intervals for these figures.

A confidence interval, in general, is a range of values that reflects statistical uncertainty around an estimate under a stated method. It does not correct for non-randomized design, incomplete reporting, or differences between cohorts. No confidence interval for the primary DLT result is available in the registry record, and the numerical DLT result itself is not reported. It would therefore be inappropriate to construct or imply a precision estimate for that endpoint from the available description.

Why is over-dispersion not central to this endpoint?

In general, over-dispersion describes count data that vary more than a model’s assumed distribution would predict. It can matter when analyzing repeated counts or event rates across units, particularly when a simple model understates variability. The primary outcome is described as the number of participants with a binary DLT event, and the registry does not report a model-based count analysis or an over-dispersion assessment. The available record therefore does not establish that an over-dispersion adjustment was used or needed.

The registry also lists a sample-size planning illustration based on an observed effect, but no effect estimate or planning output is included in the registry record for this analysis. In general, a planning calculation is a design illustration under stated assumptions; it is not observed power and does not describe what the completed trial demonstrated. The registry’s detailed statistical plan, including any planned tests, models, or interim analyses, is 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("Phase I Cohort 2", "Phase I Cohort 1")
n      <- c(4, 6)
events <- c(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  Phase I Cohort 2  4  0  0.0  0.0  60.2  0.0  49.0  0.5  52.2
ARM  Phase I Cohort 1  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 lists 11 outcome measures and 1 analysis. The listed outcomes include pathologic complete remission, tumor proliferation changes, and pharmacokinetic measures for letrozole and everolimus, alongside the primary DLT outcome. Multiple outcomes can create multiplicity: when many hypotheses are examined, the chance of at least one apparently notable result can increase. In general, multiplicity may be addressed through a prespecified hierarchy, adjustment, or a clearly exploratory interpretation. The registry record does not report a multiplicity strategy, so it is not possible to determine whether any adjustment was planned or used.

Missing-data handling and analysis populations are not reported in the registry record. The record does not state how participants with incomplete endpoint assessments, early surgery, treatment interruption, or withdrawal were handled in the primary analysis. It also does not identify whether the primary endpoint used an intention-to-treat, safety, or evaluable population. These details matter because the denominator and inclusion rules affect interpretation of an event count.

The record gives an enrollment of 15 and separate at-risk counts in the adverse-event listing, but does not provide an account of participants’ completeness for each outcome. It does not report participant flow by phase, outcome-specific missingness, or imputation methods. No assumption about missing outcomes should be made. Since the numerical primary DLT counts are absent, neither a missing-data adjustment nor a complete-case estimate can be reconstructed.

In general, a registry’s lack of a reported method does not establish that no method was used; it means that the method cannot be evaluated from that record. The statistical analysis plan, rules for multiplicity, treatment of missing data, and definitions of analysis populations are not reported in the registry record.

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: headache (16.7%).

The serious adverse-event listing gives the number at risk and the number affected in each group. Phase I cohort 1 lists 1 participant affected among 6 at risk; Phase I cohort 2 lists 0 among 4. Phase I cohort -1 lists 0 at risk and 0 affected, and the registry separately states that no patients were enrolled in that cohort. Phase II lists 0 affected among 5 at risk. The listing reports 0 deaths in each group.

The registry also identifies headache at 16.7% among the leading serious adverse-event terms. The denominator and scope used for that term are not reported in the registry record, so it should not be assumed to represent a particular cohort or the full study population. A serious adverse event is not automatically a dose-limiting toxicity: the primary endpoint uses its own stated criteria and timeframe. The numerical DLT counts are not reported in the registry record.

These are descriptive safety figures from a non-randomized study, not a controlled comparison. A zero in a group means no affected participants were listed for that category; it does not establish absence of risk. The registry does not report confidence intervals for these counts.

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

The record describes a preoperative study that examined a combination of letrozole, everolimus, and TRC105 in postmenopausal women with hormone-receptor positive and HER2-negative breast cancer. Its Phase I component explored dose cohorts, and the Phase II regimen was intended to depend on Phase I data. The primary outcome focused on dose-limiting toxicity, which is relevant to early-phase dose selection. The registry provides the DLT criteria and a rule for defining the maximum tolerated dose.

What the registry does not provide is the observed primary endpoint count for the Phase I cohorts or the final Phase II dose choice. It also does not report numerical results for pathologic complete remission, tumor proliferation changes, or the listed pharmacokinetic outcomes. Those gaps prevent a quantitative assessment of either the primary safety endpoint or the secondary efficacy outcomes from this record.

The serious adverse-event fields report a small number of affected participants in the listed groups and no deaths in those fields. These descriptive counts should be interpreted with the group sizes and the non-randomized design in mind. They do not establish that the combination is safer or less safe than another treatment, since no randomized comparator is listed. Nor do they provide a causal comparison among dose cohorts.

In general, a completed registry record can document study design and selected results while still leaving important analysis details unavailable. Here, missing numerical DLT results, unspecified analysis populations and missing-data methods, and the absence of a reported multiplicity strategy restrict how much can be concluded statistically. The record supports a description of the study and its posted safety counts; it does not support a comparative treatment-effect conclusion.

14. Why This Trial Matters Statistically

This trial raises a central statistical issue in early-phase research: the primary question is not a randomized comparison, but whether toxicity observations can guide selection of a dose for later study. The registry’s rule links observed DLT counts to the maximum tolerated dose and the recommended Phase II dose. Such rules depend on explicit event definitions, an assessment window, and complete reporting of the counts used to apply them.

The registry offers those definitions and cohort dose descriptions, but does not report the cohort-specific primary DLT results or the final selected dose. That gap is important because readers cannot verify from the registry record how the stated rule was applied. A statement that cohort -1 was not enrolled because of the lack of toxicities in cohorts 1 and 2 explains a design decision, but does not replace numerical DLT results.

The study also illustrates why descriptive safety reporting should be separated from comparative inference. The adverse-event listing provides counts within dose groups, but non-randomized cohorts are not like-for-like controls. Any apparent difference between groups could reflect dose, cohort composition, or other unreported factors. Without a randomized comparator and appropriate analysis details, these counts remain descriptive.

Finally, the registry lists multiple secondary outcomes alongside the primary safety question. In general, interpretation of multiple outcomes depends on knowing which analyses were prespecified and how multiplicity was handled. Those methods are not reported in the registry record. The result is a useful record of the study’s intended questions and reported safety fields, but an incomplete basis for evaluating the statistical evidence across its outcomes.

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 key limitation is that the registry record does not report the numerical result for the primary DLT endpoint. It gives the endpoint definition, timeframe, and dose-selection rule, but not the number of participants meeting the DLT criteria in each Phase I cohort. The record also does not identify the final Phase II regimen or recommended Phase II dose.

The study was non-randomized and single-group, with no concurrent control group listed. The Phase I cohorts differed in dose, so their outcomes cannot be treated as randomized comparisons. The registry’s adverse-event counts are descriptive and do not establish comparative safety. The Phase I cohort -1 group had no enrolled patients, as stated in the record.

The registry lists an enrollment of 15 but does not report detailed participant flow by cohort and outcome. Analysis populations, missing-data handling, confidence intervals, and the statistical analysis plan are not reported in the registry record. The record also does not report numerical results for the listed secondary outcomes, including pathologic complete remission. The sponsor’s rationale for enrollment and any interim analysis procedures are not reported in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Combination of Letrozole, Everolimus and TRC105 in Postmenopausal Women With Hormone-Receptor Positive and Her2 Negative Breast Cancer — NCT02520063.
• Registry record last updated 2026-02-06; status last verified 2026-02.
• Results first posted 2023-08-21.
• 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

NCT02520063 is a completed Phase I/II, non-randomized, unmasked, single-group study sponsored by the University of Alabama at Birmingham. The registry lists an enrollment of 15 and describes preoperative letrozole, everolimus, and TRC105 for postmenopausal women with newly diagnosed hormone-receptor positive, HER2-negative breast cancer. Phase I used dose cohorts; the Phase II dose was to be determined using Phase I data.

The primary endpoint was the number of participants experiencing DLT during the stated 4 weeks. The record defines DLT criteria and a dose-selection rule, but the numerical primary endpoint result and final selected dose are not reported in the registry record. Serious adverse-event fields list 1 affected participant in Phase I cohort 1, none in Phase I cohort 2 or Phase II, and no patients in Phase I cohort -1. The record lists 0 deaths in each group. Numerical efficacy outcomes and detailed statistical analysis methods are not reported in the registry record.