Dose Escalation, Combination Chemotherapy Safety Study of Birinapant (TL32711), in Subjects With Advanced or Metastatic Solid Tumors: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Dose Escalation, Combination Chemotherapy Safety Study of Birinapant (TL32711), in Subjects With Advanced or Metastatic Solid Tumors (NCT01188499), a non-randomized phase 1, phase 2 study. The primary outcome is Number of Subjects With Adverse Events as a Measure of Safety and Tolerability.

2. Clinical Question

3. Trial Design

The study is listed as a Phase 1B/2A, open-label, non-randomized, multi-arm study of TL32711, or birinapant, combined with chemotherapy in people with advanced or metastatic solid tumors. Its recorded phase categories are Phase 1 and Phase 2. The registry status is completed, with enrollment of 176. The recorded start is 2010-10 and primary completion is 2013-10.

Five combinations are listed: carboplatin and paclitaxel with birinapant; irinotecan with birinapant; docetaxel with birinapant; gemcitabine with birinapant; and liposomal doxorubicin with birinapant. The schedules differ across regimens. For the carboplatin and paclitaxel, irinotecan, and docetaxel arms, chemotherapy is scheduled once every 3 weeks, while birinapant is scheduled weekly for 2 consecutive weeks followed by a week off. Gemcitabine is scheduled weekly for 3 consecutive weeks followed by a week off, and the birinapant schedule has 2 consecutive treatment weeks followed by 2 weeks off. Liposomal doxorubicin is scheduled every 4 weeks, with birinapant scheduled for 2 consecutive weeks followed by 2 weeks off.

The record describes dose escalation and safety evaluation, but it does not report the dose-escalation rules, dose levels, stopping criteria, or the rationale for choosing the listed schedules. It also does not describe how participants entered each arm or whether treatment decisions followed a particular allocation procedure beyond identifying the study as non-randomized. Because the study was open-label and non-randomized, the arms are not randomized comparisons. The registry record does not report a protocol-level sample-size justification or a detailed statistical analysis plan.

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

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 Subjects With Adverse Events as a Measure of Safety and Tolerability, measured over 1 Cycle (3-4 weeks).

The primary outcome is the number of participants with adverse events as a measure of safety and tolerability during one cycle, defined as 3-4 weeks. The outcome description includes changes in vital signs, electrocardiograms, safety measures, and laboratory parameters. The outcome is a count of participants with an event rather than a continuous measurement or a time-to-event quantity.

In general, recording whether participants experience adverse events is a way to describe the safety experience during treatment. Counts can indicate how many participants in an arm were recorded as affected, but they do not by themselves describe event severity, duration, recurrence, or the time each participant was observed. Those details matter for understanding the clinical context of an event. The registry’s stated outcome timeframe is one cycle, while the arm-level adverse-event figures also distinguish serious events and other events. The record does not explain how those reported figures map to every component in the primary outcome description.

In general, safety and tolerability outcomes are important in early-phase combination studies because each drug regimen may have its own adverse-event profile. These counts are descriptive. They do not establish that birinapant caused an event, distinguish the contribution of birinapant from chemotherapy, or make the regimens directly comparable. The registry record does not report a definition of the analysis population for this outcome or details about how missing safety observations were handled.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What kind of outcome is reported?

The primary outcome is a binary participant-level event summarized as a count: participants are classified according to whether an adverse event was recorded. The registry describes the primary measure as the number of subjects with adverse events and gives a timeframe of one cycle, or 3-4 weeks. The posted safety results separately give counts of participants with serious adverse events and other adverse events. These summaries are not event rates over person-time and are not counts of every event episode.

In general, a participant count is easiest to interpret when its denominator, observation window, event definition, and analysis population are clear. The arm-level safety results include at-risk counts, which give context for the affected counts. But the registry record does not report detailed event definitions, observation duration for each participant, or the analysis-population rules. It also does not clarify how the arm-level serious and other event summaries relate to every component of the stated primary outcome.

What do the arm counts establish?

The reported counts describe what was recorded in each arm. They do not isolate the effect of birinapant because every listed arm combines birinapant with a chemotherapy regimen, and there is no birinapant-free randomized control group described. They also do not support direct causal comparisons between the chemotherapy combinations. In general, randomization can help balance participant characteristics across comparison groups; a non-randomized design does not provide that protection. Differences in arm-level counts may therefore reflect participant mix, treatment selection, observation, or other differences as well as treatment-related effects.

In general, an uncertainty interval around an estimate describes the range of values compatible with the data under the specified statistical method. The registry record does not report confidence intervals for these adverse-event counts or comparative estimates. Without such estimates and their uncertainty, the counts should be treated as descriptive rather than as precise measures of differences between regimens.

How should the planning illustration be understood?

The planning illustration is described as using the observed effect, a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; its effect to detect is a stated fraction of the observed effect. The stated assumptions distinguish participants per arm for non-time-to-event outcomes from total events for time-to-event outcomes. The primary safety outcome is a participant event count, not a time-to-event outcome.

The illustration is not the trial’s design justification and is not observed power. In general, a sample-size calculation estimates the amount of information that might be needed to detect an assumed effect under specified assumptions. Its result depends on the assumed effect and statistical model. The registry record does not report the numerical effect value or the resulting planning counts in the registry record described for this study. It also does not report that the trial was designed using this illustration. The illustration should therefore be understood as a hypothetical planning exercise, not as evidence that the completed study had a particular probability of detecting a treatment effect.

What can be inferred from the listed percentages?

The serious adverse-event terms are accompanied by percentages, but the record does not specify the denominator for those percentages or a method for their calculation. They can be quoted as listed, but interpreting them as arm-specific risks, participant percentages, or event frequencies would require information not reported in the registry record. In general, percentages require an explicit denominator and a defined observation period to support clear interpretation.

What statistical analysis is described?

The registry record does not report an inferential analysis of the safety counts, a model for comparing arms, adjustment variables, or a method for handling repeated events. It does not report interim analyses, prespecified decision thresholds, or a detailed statistical analysis plan. No inferential result should be inferred from the descriptive counts. The study’s non-randomized, multi-arm structure also means that a simple comparison of the arm counts would not by itself establish a treatment effect.

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("Arm 1: Carboplatin/Paclitaxel + TL32711", "Arm 2: Irinotecan + TL32711", "Arm 3: Docetaxel + TL32711", "Arm 4: Gemcitabine + TL32711", "Arm 5: Liposomal Doxorubicin")
n      <- c(24, 83, 33, 18, 18)
events <- c(24, 83, 33, 18, 18)
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  Arm 1: Carboplatin/Paclitaxel + TL32711  24  24  100.0  85.8  100.0  86.2  100.0  86.3  99.9
ARM  Arm 2: Irinotecan + TL32711  83  83  100.0  95.7  100.0  95.6  100.0  95.7  100.0
ARM  Arm 3: Docetaxel + TL32711  33  33  100.0  89.4  100.0  89.6  100.0  89.7  99.9
ARM  Arm 4: Gemcitabine + TL32711  18  18  100.0  81.5  100.0  82.4  100.0  82.4  99.9
ARM  Arm 5: Liposomal Doxorubicin  18  18  100.0  81.5  100.0  82.4  100.0  82.4  99.9

11. Multiplicity, Missing Data and Analysis Populations

The study includes five treatment arms and lists multiple outcome areas: safety and tolerability as the primary outcome, with anti-tumor efficacy and pharmacokinetics and translational biomarkers as secondary outcomes. In general, evaluating multiple arms or outcomes can create multiplicity: the more comparisons or tests considered, the greater the chance that an apparently notable result arises by chance. Statistical plans sometimes address this through prespecified testing order, adjustment procedures, or a clear distinction between confirmatory and exploratory analyses.

The registry record does not report a multiplicity strategy, a hierarchy among secondary outcomes, or which comparisons were prespecified. It also does not report inferential tests for the posted safety counts. Consequently, the listed figures should be treated as descriptive rather than as results from a declared set of comparative hypotheses.

The record does not describe missing-data rules, the number of participants with incomplete safety information, or whether all enrolled participants contributed to every outcome. The arm-level at-risk counts are reported, but the registry does not define a separate analysis population or explain how participants with limited follow-up were handled. In general, missing observations can affect an outcome summary if the people without recorded information differ from those with complete information; without the missingness details, that possibility cannot be assessed for this record.

The registry record also does not report the statistical analysis plan, interim analyses, or a sample-size justification for the trial. The planning illustration is not identified as the trial’s design method. These omissions limit assessment of how the analyses were planned and how completely the posted outcomes reflect the intended analysis.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pyrexia (16.7%), pleural effusion (16.7%), disease progression (15.2%), pneumonia (15.2%), abdominal pain (11.1%).

The serious adverse-event figures are participant counts accompanied by at-risk counts. The carboplatin/paclitaxel plus birinapant arm reports 9 affected among 24 at risk; irinotecan plus birinapant reports 41 among 83; docetaxel plus birinapant reports 16 among 33; gemcitabine plus birinapant reports 13 among 18; and liposomal doxorubicin plus birinapant reports 9 among 18. These figures describe the arms as reported and are not randomized comparisons.

For other adverse events, the reported affected counts match the at-risk counts: 24 in the carboplatin/paclitaxel arm, 83 in the irinotecan arm, 33 in the docetaxel arm, 18 in the gemcitabine arm, and 18 in the liposomal doxorubicin arm. The registry record does not give additional breakdowns of these other events in the reported figures. The serious-event terms are listed with percentages, but the denominator for those percentages is not reported in the registry record.

In general, an adverse-event count does not establish that a treatment caused the event. These summaries also do not show event duration, recurrence, time at risk, or the number of event episodes. They should be read as descriptive safety information, not as a ranking of the regimens or a basis for estimating comparative risk.

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

The results document safety-event counts across five birinapant and chemotherapy combinations in a completed, open-label, non-randomized study of advanced or metastatic solid tumors. The record reports serious adverse events and other adverse events by arm, along with a list of serious adverse-event terms and associated percentages. These data give a descriptive account of the recorded events in the study arms.

They do not establish that birinapant caused a particular event, because every listed regimen includes chemotherapy and the record does not provide a randomized birinapant-free control. Nor do they establish that one combination is safer than another. The arms are non-randomized, use different chemotherapy agents, and may differ in participant characteristics or observation. The arm counts alone cannot separate those influences.

The primary outcome is a safety and tolerability measure over one cycle, defined as 3-4 weeks. The posted figures do not provide a complete account of event timing, duration, severity beyond the serious-event distinction, recurrence, or person-time at risk. The term percentages lack a reported denominator in the registry record, so their precise interpretation is limited.

The study lists anti-tumor efficacy and pharmacokinetics and translational biomarkers as secondary outcome areas, but results for those outcomes are not reported in the registry record. The safety results therefore do not answer whether the combinations reduced tumor burden, altered survival, or produced particular pharmacokinetic or biomarker findings. They also do not provide a basis for medical decisions. Their meaning is limited to the descriptive safety information recorded for this early-phase, multi-arm study.

14. Why This Trial Matters Statistically

This study is statistically informative as an example of the challenges of interpreting safety results from an early-phase, multi-arm combination study. A central task is to distinguish a descriptive account of events from a comparison that can support causal conclusions. The registry reports event counts separately for five regimens, but the non-randomized allocation and differing chemotherapy combinations mean that those counts are not controlled estimates of comparative effects.

The denominators matter. The serious-event counts are presented alongside the number at risk in each arm, while the other-event counts list all participants at risk as affected. Keeping the numerator and denominator in view makes the reported summaries easier to interpret without turning them into an unsupported ranking. The listed serious-event terms add detail, but their percentages cannot be fully interpreted without the denominator and calculation details.

The study also illustrates why an endpoint’s definition and observation window matter. The primary outcome is framed as participants with adverse events during one cycle, while the registry’s arm-level figures distinguish serious events from other events. The record does not explain all details of the analysis population, missing observations, or how those summaries connect to every element of the primary outcome description.

Finally, a planning illustration should not be confused with the design or the evidence collected. Its assumptions are described, but the registry does not report that it determined the trial’s enrollment or provide a sample-size justification. Treating planning calculations, observed safety counts, and comparative efficacy evidence as distinct statistical objects is essential to interpreting this record accurately.

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 has several limitations specific to interpreting this study. It identifies the design as open-label and non-randomized, and the five arms combine birinapant with different chemotherapy regimens. There is no randomized control group described, so the arm-level event counts cannot isolate the contribution of birinapant or support like-for-like comparisons between combinations.

The outcome description refers to adverse events during one cycle, but the record does not provide detailed event definitions, assessment procedures, or an explanation of how the primary outcome relates to the separate serious-event and other-event counts. The record also does not report the analysis population, missing safety observations, participant-level follow-up, event duration, recurrence, or person-time at risk. Those omissions constrain interpretation of the counts and listed percentages.

The serious-event terms have percentages, but their denominators and calculation details are not reported in the registry record. Comparative estimates, confidence intervals, inferential tests, adjustment methods, multiplicity procedures, and a detailed statistical analysis plan are also not reported. The record does not describe interim analyses or the rules used for dose escalation. It does not report a protocol-level sample-size justification.

Although anti-tumor efficacy and pharmacokinetics and translational biomarkers are listed as secondary outcome areas, their results are not reported in the registry record. The available safety summaries therefore cannot be extended to claims about efficacy, drug exposure, or biomarker effects.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Dose Escalation, Combination Chemotherapy Safety Study of Birinapant (TL32711), in Subjects With Advanced or Metastatic Solid Tumors — NCT01188499.
• Registry record last updated 2016-05-30; status last verified 2016-04.
• Results first posted 2016-05-30.
• 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

NCT01188499 is a completed Phase 1B/2A, open-label, non-randomized, multi-arm study of birinapant with chemotherapy in advanced or metastatic solid tumors. The registry records enrollment of 176, a start of 2010-10, and primary completion in 2013-10. The five chemotherapy combinations were carboplatin and paclitaxel, irinotecan, docetaxel, gemcitabine, and liposomal doxorubicin, each combined with birinapant.

The primary outcome was the number of participants with adverse events as a measure of safety and tolerability during one cycle, defined as 3-4 weeks. The posted safety figures report serious and other adverse-event counts by arm, plus serious-event terms with percentages. Because the study was non-randomized and the arms used different chemotherapy regimens, the counts are descriptive rather than direct comparative estimates. The registry record does not report results for the listed secondary outcome areas of anti-tumor efficacy or pharmacokinetics and translational biomarkers.