Study of LDE225 (Sonidegib) in Combination With Docetaxel in Triple Negative (TN) Advanced Breast Cancer (ABC) Patients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of LDE225 (Sonidegib) in Combination With Docetaxel in Triple Negative (TN) Advanced Breast Cancer (ABC) Patients (NCT02027376), a na phase 1 study. The primary outcome is Incidence Rate of DLT Within the First Two Cycles of LDE225 (Sonidegib) in Combination With Docetaxel.

2. Clinical Question

The study was designed to examine the safety and tolerability of combining sonidegib with docetaxel while escalating the sonidegib dose. It also listed secondary outcomes covering adverse events, electrocardiogram changes, time to progression, drug concentrations and clearance, and objective response rate. These additional measures could describe different aspects of safety, drug exposure, and disease response, but their results are not reported in the registry record.

The clinical question is therefore primarily about early dose-finding, not about whether the combination is better than another treatment. Without a concurrent comparator and a reported primary endpoint result, the record cannot establish a comparative benefit or quantify the frequency of dose-limiting toxicity during the specified period.

3. Trial Design

This was a phase Ib, open-label, multicenter, single-group study of sonidegib with docetaxel in triple-negative advanced breast cancer. The registry lists enrollment as 12 and the study status as completed. The recorded start is 2014-05, and primary completion is recorded as 2016-04. Allocation is listed as not applicable, consistent with the absence of a randomized control group.

The dose-escalation plan included oral sonidegib dose levels of 400, 600, and 800mg once daily, with a lower dose level included if de-escalation was needed. Docetaxel was administered intravenously in cycles every three weeks; the arm description specifies 75mg/m2. The combination was intended to continue on day 1 of a 21-day cycle until radiographic or symptomatic progression, unacceptable toxicity, or withdrawal of informed consent. The registry record does not report which participants received each dose level or how dose escalation decisions were made.

Open-label means that treatment assignment was not masked. In a dose-finding study, the absence of masking can matter when clinical judgments or event attribution are involved. The registry describes dose-limiting toxicity as events assessed as possibly, probably, or definitively related to study drugs, using NCI-CTCAE version 4.0 grading. It does not report independent or blinded event review.

The primary outcome was the incidence rate of dose-limiting toxicity within the first two cycles, expressed as a count of participants. Other registered outcomes include adverse events, QT/QTc changes, time to progression, pharmacokinetic measures for both drugs, and objective response rate. The registry lists nine outcome measures but no analyses. Results for the primary endpoint and the listed secondary outcomes are not reported in the registry record.

Because the trial is single-group and dose-escalating, its dose cohorts are not randomized comparison arms. Their sizes and treatment experiences may differ, and the record does not describe a method for adjusting comparisons across dose levels. The design is suited to early safety and dose exploration, but by itself does not provide a controlled estimate of efficacy.

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: Two patients at DL 1 and one patient at DL 2 were replaced due to early progressive disease before completing the first 2 cycles.

Overall Study

Reasons for not completing this period:

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 Incidence Rate of DLT Within the First Two Cycles of LDE225 (Sonidegib) in Combination With Docetaxel, measured over Up to cycle 2.

The primary endpoint is the incidence rate of dose-limiting toxicity during the first two cycles of sonidegib plus docetaxel. It is measured as a count of participants experiencing at least one qualifying dose-limiting event, rather than as a continuous measurement. The registry record defines the assessment period as up to cycle 2.

The listed definition includes specified blood-count abnormalities, febrile neutropenia, elevated creatinine phosphokinase, severe non-hematologic toxicity, prolonged gastrointestinal toxicity, inability to resume dosing because of treatment-related toxicity, and dose reductions in the first two cycles. Events were to be graded using NCI-CTCAE version 4.0 and assessed as possibly, probably, or definitively related to study drugs. The detailed definition distinguishes particular grades and durations, so the outcome is not simply a count of all adverse events.

In a dose-escalation study, this endpoint is used to characterize early toxicity at the studied dose levels. That information can contribute to decisions about a maximum tolerated dose and a recommended phase II dose, the stated aims of the study. General statistical context: counting participants with an event is useful for a clearly defined safety outcome, but the count alone does not convey uncertainty or account for differences in how long participants were observed.

The registry record does not report the observed dose-limiting-toxicity count, the number assessed for this endpoint at each dose, or an interval estimate. Consequently, the primary endpoint’s result and its precision cannot be described from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The design and outcomes determine what statistical conclusions are possible. The central feature is a single-group dose-escalation study: participants received the combination, with sonidegib administered at different dose levels. There was no randomized control group. The registry record reports no analyses, and it does not report the primary endpoint result. Accordingly, interpretation must remain descriptive rather than treating dose groups as controlled comparisons.

What does a count of participants with toxicity represent?

The primary endpoint is a count of participants who experienced a qualifying dose-limiting toxicity within the first two cycles. This differs from counting every event: one participant may have more than one event, while the endpoint is defined around participants meeting the toxicity criteria. The record specifies event types, severity grades, duration criteria for some events, and relationship to study drugs. Applying those criteria consistently is important because a small change in classification can change a count.

General statistical explanation: a count is easiest to interpret when its denominator—the number of participants who could be assessed during the stated period—is also available. The denominator gives context for the count. Here, the registered primary result and dose-specific numbers assessed for that endpoint are not reported in the registry record. No event proportion should be reconstructed from the separate adverse-event figures, because those are not identified as the primary endpoint result.

Why are dose groups not control groups?

The study is listed as single-group, with allocation not applicable. Dose levels in an escalation study are selected as part of the study’s dose-finding process, not assigned as randomized alternatives. A simple contrast between the groups could reflect differences in who was treated at each dose, how dose escalation proceeded, or how much treatment participants received. The registry record does not report a statistical method to account for such factors. Therefore, differences in group counts should not be presented as causal dose effects.

General statistical explanation: randomization helps balance participant characteristics on average between comparison groups. In its absence, an observed difference may have multiple explanations. Even in a randomized study, small groups can have considerable uncertainty; in a dose-escalation study, the lack of random allocation adds further limits to direct comparisons.

What does precision mean for a safety estimate?

General statistical explanation: an estimate describes the observed data, while a confidence interval expresses uncertainty around that estimate under a statistical model. The interval depends on the number of observations and the analysis assumptions. For a binary safety outcome, limited observations can leave considerable uncertainty even when a count is reported. Since the primary endpoint estimate and its denominator are not reported, its precision cannot be evaluated from the registry record.

Over-dispersion is a general concern when count data vary more than a simple model expects. It can make model-based uncertainty too small if the model assumes less variability than the data contain. This concept does not establish that over-dispersion occurred in this study; the registry record does not report a count model or an analysis of over-dispersion. More generally, no inferential model for the primary endpoint is reported.

How should the safety counts be read?

The serious adverse-event figures give counts of participants affected within each listed dose group, alongside the numbers at risk. These are descriptive summaries. They do not show event timing, duration, recurrence, severity beyond the serious classification, or a causal relationship to study treatment. Other adverse-event counts are also reported, but the record does not provide a complete account of event-level data or the methods used to summarize them.

General statistical explanation: safety summaries can use participant counts, event counts, or rates over time. Those measures answer different questions. Participant counts describe how many people had one or more events; event counts include repeated events; rates account for time at risk. The registry figures should not be reinterpreted as a rate over time because the record does not report person-time or a rate calculation.

What can planning calculations establish?

The posted planning illustration is described as based on the observed effect, with two-sided significance level 0.05, equal allocation between two arms, and a normal approximation. It describes planning under assumed fractions of an observed effect; it is not an observed trial result or observed power. The record characterizes the illustration as a planning exercise, not the trial’s own design. Because this trial had no randomized two-arm comparison and the primary endpoint result is not reported, the illustration should not be treated as evidence about the study’s actual power or as a prospective sample-size justification. The registry record does not report a sample-size justification for this trial.

Overall, the statistical methods that were actually used for endpoint analysis are not reported in the registry record. The registry lists no analyses. The design and descriptive safety counts can be explained, but they do not reveal an unreported analysis plan or substitute for the missing primary endpoint result.

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("LDE225 (Sonidegib) 400mg in Combination With Docet", "LDE225 (Sonidegib) 600mg in Combination With Docet", "LDE225 (Sonidegib) 800mg in Combination With Docet")
n      <- c(5, 4, 3)
events <- c(0, 0, 0)
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  LDE225 (Sonidegib) 400mg in Combination With Docet  5  0  0.0  0.0  52.2  0.0  43.4  0.4  45.9
ARM  LDE225 (Sonidegib) 600mg in Combination With Docet  4  0  0.0  0.0  60.2  0.0  49.0  0.5  52.2
ARM  LDE225 (Sonidegib) 800mg in Combination With Docet  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists a primary toxicity endpoint and several secondary outcomes, including adverse events, QT/QTc changes, time to progression, pharmacokinetic measures, and objective response rate. It does not report how many statistical tests were planned, whether any adjustment for multiple testing was intended, or which outcome analyses were performed. The registry lists no analyses. Therefore, a multiplicity strategy cannot be described.

General statistical explanation: when many outcomes or comparisons are tested, the chance of at least one apparently notable result can increase. Methods that account for multiple testing may be used to control that risk, but the appropriate approach depends on the analysis plan and the purpose of each outcome. No such plan is reported in the registry record, so no claim about adjustment or unadjusted interpretation is warranted.

The registry record also does not report missing-data methods, the amount of missing outcome data, or how participants who stopped treatment or were not evaluable were handled. It does not describe analysis populations, such as whether analyses included all enrolled participants, only treated participants, or only those with an evaluable assessment. The primary endpoint’s result and denominator are not reported, so the completeness of its assessment cannot be judged.

These omissions matter because endpoint counts depend on who was assessed and how missing observations were handled. They also limit interpretation of secondary outcomes, whose results are not reported. No assumptions about imputation, exclusion, censoring, or analysis population should be made from 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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: overdose (25.0%).

The registry reports serious and other adverse-event counts separately for the three sonidegib dose groups. For the 400mg group, the serious-event count is 0 among 5 participants at risk, and the other-event count is 5 among 5; 1 death is recorded. For the 600mg group, the corresponding counts are 1 among 4 for serious events and 4 among 4 for other events; no deaths are recorded. For the 800mg group, the counts are 0 among 3 for serious events and 3 among 3 for other events; no deaths are recorded.

These figures are descriptive and should be read within each dose group. The groups were not randomized control arms, and the counts do not support a causal comparison between doses. The registry does not report event timing, repeated-event counts, details about the death, or whether each event was considered related to treatment. It lists Overdose at 25.0% as the leading serious adverse-event term, but does not report the denominator or additional context for that percentage.

General statistical explanation: a participant count is not the same as an event rate over time. A rate requires information about time at risk, which is not reported. The primary dose-limiting-toxicity outcome is separately defined and its result is not reported in the registry record; these broader adverse-event counts should not be substituted for it.

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

The record establishes that a phase Ib, open-label, multicenter, single-group dose-escalation study of sonidegib with docetaxel was completed, with enrollment of 12. It describes a primary safety objective focused on dose-limiting toxicity during the first two cycles, and it lists dose levels and additional safety, pharmacokinetic, progression, and response outcomes.

The posted adverse-event counts provide a limited descriptive account of serious and other adverse events in the listed dose groups. They do not give the full event histories, establish causation, or permit a controlled comparison. The registry’s reported death count likewise does not establish the cause of death or its relationship to treatment. The serious-event term listed as Overdose at 25.0% lacks denominator context in the record.

Most importantly, the primary endpoint result is not reported. The record therefore does not show the observed count of participants with dose-limiting toxicity, and it does not provide an estimate of the maximum tolerated dose or the recommended phase II dose. Although defining those doses was a study aim, the available record does not document the conclusion reached.

The record also does not report results for the listed secondary outcomes. It cannot support conclusions about objective response, time to progression, electrocardiogram changes, or drug concentrations and clearance. The single-group design provides no randomized comparator against which to assess relative efficacy or safety.

General statistical context: a study can be informative about feasibility and early safety while still leaving substantial uncertainty about treatment effects. That distinction is especially important when outcome results, denominators, and uncertainty estimates are unavailable. The findings described in the registry should not be expanded into claims about benefit, lack of benefit, or comparative safety.

14. Why This Trial Matters Statistically

This study raises familiar statistical issues in early-phase combination research. Dose escalation is intended to gather safety information across dose levels and support later dose selection. The primary endpoint’s focus on defined dose-limiting toxicities in the first two cycles makes the assessment period explicit, while the event criteria specify which toxicities count toward that endpoint.

At the same time, a single-group escalation design is not a randomized comparison. The dose groups are part of the dose-finding process, and their observed counts cannot be interpreted as if participants had been randomly allocated to alternative doses. This distinction matters when readers encounter safety figures organized by dose: descriptive differences do not, on their own, isolate a dose effect.

The registry record illustrates the importance of separating an outcome’s definition from its result. It supplies a detailed primary endpoint definition and lists several secondary outcomes, but does not report the primary result or results for those secondary measures. Without the endpoint count, denominator, and an uncertainty estimate, readers cannot assess the magnitude or precision of the primary safety finding.

General statistical context: transparent reporting of analysis populations, missing data, methods, and uncertainty helps readers understand how a result was produced and how robust it may be. Those details are not reported in the registry record. The descriptive adverse-event counts remain useful as limited safety information, but their scope should not be overstated.

The statistical lesson is not that the design can answer every clinical question. Rather, it is that early-phase dose-finding and controlled evaluation serve different purposes. A dose-escalation study can be designed to investigate tolerability, while claims about comparative efficacy require evidence that this record does not report.

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 primary limitation for interpreting this trial is that the registry record does not report the primary dose-limiting-toxicity result. It also does not give the number assessed for that endpoint at each dose level, so the primary outcome’s frequency and precision cannot be evaluated. The study aim of determining a maximum tolerated dose and recommended phase II dose is stated, but the dose-selection conclusions are not reported.

The study had a single-group, open-label dose-escalation design with no randomized control group. Its dose groups are not like-for-like controls, which limits dose-to-dose interpretation and prevents comparative treatment-effect conclusions. The record does not describe how decisions to escalate or de-escalate were made, how participants were assigned to dose levels, or how differences between groups were handled in analysis.

The listed safety data are limited to participant counts by dose group and a leading serious-event term. The record does not report event-level details, timing, duration, recurrence, treatment relatedness for the summarized events, or context for the death. It also does not explain the denominator for the Overdose percentage. The primary toxicity endpoint has its own specific definition and should not be inferred from these broader safety counts.

Methods for missing data and analysis populations are not reported. Neither the statistical analysis methods nor any multiplicity approach is described, and the registry lists no analyses. Results for the secondary outcomes are also not reported. These gaps prevent a fuller assessment of the study’s findings, uncertainty, and completeness of outcome ascertainment.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study of LDE225 (Sonidegib) in Combination With Docetaxel in Triple Negative (TN) Advanced Breast Cancer (ABC) Patients — NCT02027376.
• Registry record last updated 2023-04-03; status last verified 2023-03.
• Results first posted 2018-12-04.
• 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.

19. Record Summary

This completed phase Ib study evaluated sonidegib with docetaxel in triple-negative advanced breast cancer. It was open-label, multicenter, and single-group, with enrollment of 12. The registry describes oral sonidegib dose levels of 400, 600, and 800mg alongside intravenous docetaxel, and identifies dose-limiting toxicity during the first two cycles as the primary outcome.

The registry reports descriptive serious and other adverse-event counts by dose group and lists Overdose at 25.0% as the leading serious-event term. It records 1 death in the 400mg group and no deaths in the other listed groups. These figures are not randomized comparisons. The primary endpoint result, secondary outcome results, analysis methods, missing-data handling, and analysis populations are not reported in the registry record. Consequently, the record does not establish the observed dose-limiting-toxicity result or the dose-selection conclusions.