Panobinostat and Letrozole in Treating Patients With Metastatic Breast Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Panobinostat and Letrozole in Treating Patients With Metastatic Breast Cancer (NCT01105312), a na phase 1, phase 2 study. The primary outcome is Maximum-tolerated Dose (Phase I).

2. Clinical Question

3. Trial Design

This completed study is registered as Phase I/II and uses a single-group model. The registry lists enrollment of 28. It does not describe random allocation, masking, or a concurrent comparison group: allocation is NA and masking is none. Consequently, the Phase I dose levels and Phase II cohort should not be read as treatment and control arms in a randomized comparison.

The Phase I component focused on dose finding. The primary endpoint is maximum-tolerated dose, with a stated timeframe of up to 2.5 months. The record says all 12 Phase I patients were eligible and analyzed for this endpoint. Its definition uses dose-limiting toxicity to identify a dose threshold, with cohort expansion or movement to a lower dose described in the endpoint text. The actual maximum-tolerated dose and dose-limiting toxicity counts are not reported in the registry record.

The Phase II component is associated with outcomes including survival time, time-to-disease progression, progression-free survival, duration of response, clinical benefit rate, and time to treatment failure. Confirmed response rate is listed for Phase I. The registry record does not give results for these outcomes in the registry entries, nor does it report their analysis methods.

The record describes a regimen combining panobinostat and letrozole. Panobinostat is listed as oral dosing 3 days per week for a total of 4 weeks, while letrozole is listed as 2.5 mg orally on Days 1-28 every 4 weeks. The panobinostat dose itself is not reported in the available arm description. RNA analysis, microarray analysis, reverse transcriptase-polymerase chain reaction, enzyme-linked immunosorbent assay, immunohistochemistry staining, and laboratory biomarker analysis are also listed as interventions or assessments.

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: All 12 phase I patients were eligible and analyzed for MTD.

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: All phase I and phase II patients were used for baseline analysis

6. Primary Endpoint

The registry lists the primary outcome as Maximum-tolerated Dose (Phase I), measured over Up to 2.5 months.

The primary endpoint is maximum-tolerated dose in Phase I, measured in participants, over a timeframe of up to 2.5 months. It is a dose-finding endpoint rather than a direct measure of tumor response or survival. The registry definition links the dose decision to dose-limiting toxicity: the maximum-tolerated dose is defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least one-third of patients, with at least 2 of a maximum of 6 new patients specified in the description.

The endpoint is used to characterize tolerability while selecting a dose for further study. The record describes rules for treating additional patients at a dose level or moving to a lower dose level according to observed dose-limiting toxicities. Such rules explain how the endpoint is intended to be determined; they do not reveal the dose selected or the number of toxicities observed.

All 12 Phase I patients are reported as eligible and analyzed for maximum-tolerated dose. The endpoint result itself, including the maximum-tolerated dose and the dose-limiting toxicity counts, is not reported in the registry record. The listed Phase II outcomes address disease course and response, but they are not the primary endpoint described for this study, and their results are also not reported in the available record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical methods must be interpreted in light of the study question and design. This study has a single-group model, with no randomized comparison group reported. The Phase I dose levels are used within a dose-finding process. They should not be treated as if participants had been randomly allocated between a treatment and a control. Differences in outcomes across dose levels, even if reported, would be descriptive unless the record specified an appropriate comparative analysis and its assumptions.

What does maximum-tolerated dose measure?

The primary endpoint is maximum-tolerated dose, a dose-selection outcome based on dose-limiting toxicity. The registry description defines the dose threshold and gives rules for enrolling additional patients at a dose level or moving to a lower dose level. This is a decision process, not an estimate of treatment benefit. In general, dose-finding designs use observed toxicity patterns to guide which dose is evaluated next. The actual dose levels, toxicity counts, and selected maximum-tolerated dose are not reported in the registry record, so the rule cannot be applied independently from the information available.

The endpoint is recorded as a count of participants, while the definition also refers to toxicity occurring at a dose level. For interpretation, it matters whether a count refers to participants experiencing at least one event, the number of events, or another endpoint-specific summary. The record says the number of dose-limiting toxicities will be reported, but those results are not reported in the registry entries. The distinction between an event count and a participant count is generally important because a participant can experience more than one event.

What can a confidence interval tell a reader?

As general statistical context, a confidence interval describes uncertainty around an estimated quantity under a specified statistical procedure. It is not a guarantee that the true value lies within the interval, nor does it show that an effect is clinically important. For a small group or a sparse binary outcome, the interval can be wide, reflecting limited precision. The registry entries do not report confidence intervals for the primary endpoint or the listed efficacy outcomes, so there is no interval-based precision assessment to interpret for those results.

For binary outcomes, a count of participants with an event is often interpreted alongside the number at risk. The serious adverse event summaries provide both figures for the listed groups. General statistical practice would report an estimate of the event frequency together with uncertainty, while making clear the period and event definition. Here, the record includes group counts and a list of serious adverse event terms with percentages, but does not provide all the supporting details needed to reconstruct comparable estimates or their uncertainty.

Why does over-dispersion matter?

As general statistical context, over-dispersion occurs when outcome variability is greater than assumed by a statistical model. If ignored, standard errors can be underestimated and intervals or tests can appear more certain than warranted. This issue can arise in count data when event rates vary across participants or groups. The primary endpoint is a dose-finding measure, and the adverse-event summaries include counts, but no statistical model for these outcomes is reported in the registry record. It would therefore be inappropriate to claim that an over-dispersion adjustment was used or needed in the sponsor's analysis.

For time-to-event outcomes, methods commonly account for follow-up time and censoring, which occurs when the event status is not observed through the relevant endpoint time. General interpretation depends on the event definition, time origin, follow-up, and censoring rules. The record lists survival time, time-to-disease progression, and progression-free survival for Phase II, but does not report their estimates, analysis methods, event definitions, or handling of censoring. Without these details, the listed outcomes cannot be independently interpreted as time-to-event analyses.

What does a planning calculation represent?

As general context, a sample-size calculation estimates the number of participants needed under specified assumptions about an effect, variability, significance level, allocation, and analysis method. It is a planning exercise, not a measure of the probability that a completed study has detected an effect. The registry's stated planning assumptions use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the calculation is described as an illustration based on the observed effect. The study itself is single-group, so those planning assumptions do not describe the trial's allocation or create a randomized comparator. Any planning figures should not be called observed power.

The statistical analysis plan, interim analyses, and sample-size justification for the original trial are not reported in the registry record. The number of analyses is recorded as zero. That registry entry does not establish whether analyses took place outside the record; it means no analysis results are available there to evaluate. In particular, no p-values, adjusted estimates, or uncertainty intervals are reported for the primary endpoint or Phase II outcomes. The sponsor's own analysis takes precedence if a recalculated result differs from the sponsor's result; no recalculated efficacy result is included in the registry entries.

These distinctions matter because design, endpoint definition, estimation, and inference are separate parts of a statistical analysis. The registry offers a dose-finding rule and some descriptive safety counts, but lacks the results and analysis details needed to assess efficacy estimates, precision, model assumptions, or robustness.

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: Dose Level One", "Phase I: Dose Level Two")
n      <- c(6, 6)
events <- c(1, 3)
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: Dose Level One  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  Phase I: Dose Level Two  6  3  50.0  11.8  88.2  18.8  81.2  18.4  81.6

11. Multiplicity, Missing Data and Analysis Populations

The registry lists multiple outcomes: maximum-tolerated dose is the primary endpoint, while secondary outcomes include survival time, time-to-disease progression, progression-free survival, duration of response, clinical benefit rate, time to treatment failure, and confirmed response rate. When several outcomes are examined, the chance of at least one apparently notable result can increase. As general statistical context, multiplicity procedures may be used to control error rates or to distinguish confirmatory outcomes from exploratory ones. The registry record does not report a multiplicity strategy, hierarchy of testing, or adjustment method. It also does not report statistical analyses or results for the listed outcomes.

Missing-data methods and the extent of missingness are not reported in the registry record. The registry entries do not describe how incomplete follow-up, unavailable outcome assessments, or withdrawals were handled. Without those details, it is not possible to assess whether missing observations could have affected outcome estimates or to determine which assumptions were used.

For the primary endpoint, the record states that all 12 Phase I patients were eligible and analyzed for maximum-tolerated dose. This identifies the stated analysis population for that endpoint, but does not provide the corresponding endpoint results. The record does not describe the Phase II efficacy analysis population or provide participant flow by outcome. Safety summaries identify participants at risk and affected for the listed groups, but do not supply a broader missing-data account. The registry therefore supports only a limited description of analysis populations and does not document how the full set of outcomes was analyzed.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: platelet count decreased (18.8%), bladder infection (16.7%), hypokalemia (16.7%), hyponatremia (16.7%), lung infection (6.2%).

The registry records serious adverse event summaries separately for Phase II and two Phase I dose levels. In Phase II, 4 of 16 participants at risk are recorded as affected. At Phase I Dose Level One, 1 of 6 are recorded as affected; at Dose Level Two, 2 of 6 are recorded as affected. These figures describe participants with serious adverse events in the listed groups. They are not randomized comparisons, and they do not by themselves establish differences in risk between dose levels.

The serious adverse event terms listed with percentages include platelet count decreased (18.8%), bladder infection (16.7%), hypokalemia (16.7%), hyponatremia (16.7%), lung infection (6.2%), and fracture (6.2%). Those percentages are presented as registry values. The registry entries do not specify the denominator or provide event-specific group breakdowns for these terms, so they should not be converted into comparisons across groups or interpreted as incidence rates over a defined follow-up period.

Adverse event counts are descriptive and depend on how events and affected participants are defined and collected. They do not establish causation. Death counts are not reported in the registry record. The listed safety information therefore gives a partial account of recorded events, not a complete characterization of the combination's safety.

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

The record establishes that a completed Phase I/II, single-group study evaluated panobinostat with letrozole in metastatic breast cancer. It gives the primary Phase I endpoint definition, states that all 12 Phase I patients were eligible and analyzed for maximum-tolerated dose, and reports selected serious adverse event counts. It also lists disease-course and response outcomes intended for Phase II.

It does not report the maximum-tolerated dose, the dose-limiting toxicity counts, or results for the listed response and time-to-event outcomes. Accordingly, the available record does not permit a statistical estimate of efficacy, a statement about the precision of an efficacy estimate, or an assessment of whether a result differs from a reference value. The endpoint names and study purpose are not substitutes for observed outcome data.

Because there is no reported control group, the design cannot provide a randomized comparison of the combination with another treatment or with no treatment. Even complete outcome estimates from a single-group study would need cautious interpretation: observed outcomes alone do not show what would have occurred to comparable participants under a different intervention. The Phase I dose levels also should not be treated as equivalent to randomized treatment arms.

The safety counts describe affected participants within the recorded groups, but they do not establish that an event was caused by the study drugs or that the groups differ in safety. The registry entries do not provide a complete adverse-event profile, event timing, or death counts. The statistical meaning is therefore bounded: the record documents the design and selected descriptive safety information, while leaving the primary dose-finding result and the Phase II outcome results unreported.

14. Why This Trial Matters Statistically

This study illustrates why a trial's question and design must be read together. The Phase I primary endpoint is maximum-tolerated dose, which addresses dose selection using dose-limiting toxicity. It is different from the Phase II outcomes addressing response and disease course. A study can list both dose-finding and efficacy objectives, but each requires its own reported endpoint results and analysis to support an interpretation.

The single-group structure is also central. The registry does not describe random allocation or a control group. That makes it especially important to distinguish within-group observations from comparative evidence. The Phase I dose levels are part of the dose-finding process; they do not supply the counterfactual comparison that a randomized control group is designed to provide.

The record further demonstrates the difference between a protocol-style endpoint definition and a completed result. The dose-limiting toxicity rule is described, and the population analyzed for the primary endpoint is identified, yet the selected dose and toxicity counts are absent. Similarly, the Phase II outcome list names measures of response and disease course but does not report their estimates. Statistical interpretation requires results, not merely a list of intended measures.

Finally, safety counts and event-term percentages can be informative as descriptive summaries, but their interpretation depends on group definitions, denominators, event definitions, and follow-up. The available record provides only part of that context. Recognizing what is documented—and what is not—prevents descriptive counts from being overstated as comparative or causal 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.

A major limitation of the available record is that it does not report the primary endpoint result. Although maximum-tolerated dose is defined and all 12 Phase I patients are stated to have been eligible and analyzed, the selected dose and observed dose-limiting toxicity counts are not reported. The listed Phase II efficacy outcomes also lack results, estimates, and uncertainty intervals.

The design is single-group, with no randomized comparator described. This limits the ability to make causal comparisons, even if outcome results were available. The registry also does not report the statistical analysis plan, interim analyses, sample-size justification, missing-data methods, multiplicity strategy, or the analysis populations for Phase II efficacy outcomes. These omissions restrict assessment of how results were intended to be analyzed and how robust any findings would be.

The available arm description is incomplete: it reports the letrozole dose and schedule and the panobinostat schedule, but does not report the panobinostat dose. The registry's safety information is also partial. Serious adverse event counts are listed for the groups, along with selected event terms and percentages, but event-specific group breakdowns, timing, follow-up, and death counts are not reported in the registry record.

These limitations concern the information available in the registry record; they do not establish that additional data or analyses do not exist elsewhere. They do mean that efficacy, precision, dose selection, and full safety cannot be assessed from the registry entries alone.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Panobinostat and Letrozole in Treating Patients With Metastatic Breast Cancer — NCT01105312.
• Registry record last updated 2017-06-27; status last verified 2017-05.
• Results first posted 2017-06-27.
• 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

NCT01105312 is a completed Phase I/II single-group study of panobinostat (LBH589) and letrozole in metastatic breast cancer. The official title specifies triple negative metastatic breast cancer. Enrollment is recorded as 28, and the sponsor is the Alliance for Clinical Trials in Oncology. The primary endpoint is Phase I maximum-tolerated dose, with a timeframe of up to 2.5 months; all 12 Phase I patients are stated to have been eligible and analyzed for that endpoint.

The record lists Phase II outcomes for survival, progression, response, and treatment failure, but does not report their results or the maximum-tolerated dose result. It reports serious adverse event counts for Phase II and two Phase I dose levels, and lists selected serious event terms with percentages. The study has no reported randomized comparator, and its statistical analysis plan and missing-data methods are not reported in the registry record.