Trial Exploring Afatinib (BIBW 2992) + Paclitaxel (Part A), Afatinib + Paclitaxel + Bevacizumab (Part B), Afatinib + Carboplatin (Part C) and Afatinib+ Paclitaxel +Carboplatin(Part D) in Patients With Advanced Solid Tumours: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Trial Exploring Afatinib (BIBW 2992) + Paclitaxel (Part A), Afatinib + Paclitaxel + Bevacizumab (Part B), Afatinib + Carboplatin (Part C) and Afatinib+ Paclitaxel +Carboplatin(Part D) in Patients With Advanced Solid Tumours (NCT00809133), a non-randomized phase 1 study. The primary outcome is Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD).

2. Clinical Question

3. Trial Design

NCT00809133 is recorded as a Phase I, open-label, non-randomized trial. It was sponsored by Boehringer Ingelheim and is listed as completed. The registry gives the study start as 2007-05 and primary completion as 2015-02, with enrollment of 83. These are study-level record details; they do not specify how many participants were treated in each dose group or included in each outcome analysis.

The study had four parts. Part A assessed afatinib with paclitaxel; Part B added bevacizumab to that combination; Part C paired afatinib with carboplatin; and Part D combined afatinib, paclitaxel and carboplatin. The registry lists multiple labeled groups within these parts. The group labels identify the registry's dose-group categories, but the record does not give a complete dose-escalation procedure or explain how dose decisions were made.

The primary outcome concerned dose-limiting toxicities in the first treatment cycle. The registry defines the cycle timeframe as 21 days for Parts C and D and 28 days for Parts A and B. The described primary population is the treated set, defined as patients who received at least one dose of study treatment.

Because allocation was non-randomized and masking was absent, this design was not set up as a blinded randomized comparison. The registry record does not report a comparator arm, the allocation procedure, eligibility criteria in detail, or the statistical analysis plan. It describes the study's purpose as assessing optimum doses and the effects of the combinations; it does not establish from the posted information how those assessments were performed.

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: This was a dose-escalation trial, using a 3+3 rule based design. Patients were eligible for repeated treatment courses in the absence of clinical disease progression or undue toxicity.

Only the first 6 of 14 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Treated Set: Patients who received at least 1 dose of study treatment were included in the treated set.

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: Treated Set: Patients who received at least 1 dose of study treatment were included in the treated set.

Only the first 6 of 15 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD), measured over Cycle 1: 21 days (part C and D) or 28 days (part A and B).

The primary endpoint is the number of participants with dose-limiting toxicities during the first treatment cycle. The registry defines a dose-limiting toxicity as an adverse event or laboratory abnormality considered related to study treatment. It specifies the treated set as the endpoint population: patients who received at least one dose.

In general, dose-limiting toxicity counts are used in early-phase research to describe treatment-related tolerability during a specified observation period and to inform dose selection. A count is an event measure, not a complete description of how severe, prolonged or manageable each event was. Interpretation also depends on the number of participants assessed in each group, the definition and attribution rules, and whether the observation period was completed. Those details matter especially when groups are small.

The registry record gives the endpoint definition and cycle timeframes, but it does not report the primary endpoint counts, group denominators for that endpoint, or an estimated maximum tolerated dose. The separate serious adverse event figures should not be treated as the primary endpoint: the endpoint is specifically about dose-limiting toxicities judged related to treatment in the first cycle, while the serious adverse event listings are a separate safety summary. The posted record does not establish that these categories coincide.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies a count endpoint: the number of participants with a dose-limiting toxicity in the first cycle. It does not report an analysis of this endpoint. The statistical concepts below are general explanations of how such outcomes and early-phase dose-finding questions are usually interpreted; they do not describe methods confirmed for this trial.

What does a participant count represent?

A count records how many participants meet a defined event criterion. For interpretation, it should be considered alongside the number of participants assessed and the rules used to classify an event. A count without its denominator cannot show the proportion affected. Even when a denominator is available, a proportion is an estimate with uncertainty, not a guarantee that the same frequency would occur in another group or study.

Here, the primary endpoint definition includes a judgment that an adverse event or laboratory abnormality was related to study treatment. Such attribution requires a stated assessment process to support consistent classification. The registry defines the endpoint but does not report the attribution procedures, adjudication process or outcome counts. It also does not describe how participants with incomplete first-cycle observation would be handled.

Why is a first-cycle endpoint used in dose finding?

In general, early-phase dose-finding studies examine toxicities during a defined initial exposure period because these events can inform whether a dose is tolerable enough to investigate further. The maximum tolerated dose is a dose-selection concept tied to specified toxicity criteria and a decision procedure. A toxicity count alone does not determine that dose: the dose levels tested, rules for escalation or de-escalation, observation requirements and target toxicity criteria all matter. The registry record does not report those procedural details or the resulting dose decision.

The first-cycle window differs by study part: 21 days for Parts C and D, and 28 days for Parts A and B. That distinction should be kept in mind when considering the endpoint across parts. A participant observed over a different timeframe has a different opportunity for an event to be recorded. The registry does not explain how these part-specific timeframes were incorporated into a common dose-selection analysis.

What can group-to-group differences establish?

In general, randomized allocation helps balance participant characteristics across groups, supporting causal comparisons when other design and analysis conditions are appropriate. This trial is recorded as non-randomized. Therefore, the dose groups may differ in ways that influence observed outcomes, and a difference in counts cannot be attributed to the drug combination or dose alone. Open-label conduct can also affect reporting, assessment or attribution, although the registry does not report whether such effects occurred in this trial.

The groups represent different regimens and labeled dose categories, not a single randomized contrast. Parts differ in their accompanying drugs, and the first-cycle length also differs between parts. Pooling groups or comparing them without a prespecified rationale could obscure these differences. The record does not report an analysis that accounts for them.

How should uncertainty be understood?

In general, a confidence interval expresses the range of estimates compatible with the observed data under a stated statistical model and its assumptions. It helps distinguish a relatively precise estimate from one that remains uncertain. Small groups commonly produce wide uncertainty, even when the observed count appears clear. The registry record does not report confidence intervals for the primary endpoint or for the serious adverse event summaries.

Statistical tests, if used, would also require a defined hypothesis, analysis population, handling of multiple outcomes and a stated significance threshold. These are not reported for the primary endpoint. The number of listed outcome measures is 24, while the record lists zero analyses. The registry therefore does not permit a reader to reconstruct inferential results from the outcome descriptions alone.

Are the serious adverse event summaries the primary analysis?

No such equivalence is reported. The primary endpoint is defined around treatment-related dose-limiting toxicities during the first cycle. The separate adverse event summary gives serious adverse event counts and other adverse event counts by listed group. Seriousness, treatment relatedness and dose-limiting status are distinct classifications; an event may satisfy one definition without satisfying another. The registry does not report participant-level cross-classification that would show how the categories overlap.

General principles for reading the posted summaries are therefore straightforward: retain the group label, count and denominator; avoid treating descriptive differences as causal effects; and do not infer the primary endpoint from a different safety category. For this trial, the registry record does not provide the endpoint analysis, uncertainty estimates, or sufficient methodological detail to support a more formal comparison.

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("Part A: A20P80 (Afatinib + Paclitaxel)", "Part A: A40P80 (Afatinib + Paclitaxel)", "Part A: A50P80 (Afatinib + Paclitaxel)", "Part B: A20P80B5 (Afatinib + Paclitaxel + Bevacizu", "Part B: A30P80B5 (Afatinib + Paclitaxel + Bevacizu", "Part B: A40P80B5 (Afatinib + Paclitaxel + Bevacizu")
n      <- c(3, 6, 6, 3, 5, 6)
events <- c(0, 0, 2, 0, 2, 2)
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  Part A: A20P80 (Afatinib + Paclitaxel)  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Part A: A40P80 (Afatinib + Paclitaxel)  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Part A: A50P80 (Afatinib + Paclitaxel)  6  2  33.3  4.3  77.7  9.7  70.0  9.9  71.0
ARM  Part B: A20P80B5 (Afatinib + Paclitaxel + Bevacizu  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Part B: A30P80B5 (Afatinib + Paclitaxel + Bevacizu  5  2  40.0  5.3  85.3  11.8  76.9  11.8  77.7
ARM  Part B: A40P80B5 (Afatinib + Paclitaxel + Bevacizu  6  2  33.3  4.3  77.7  9.7  70.0  9.9  71.0

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 24 outcome measures and zero analyses. It includes the primary dose-limiting toxicity outcome and secondary outcomes covering adverse events and pharmacokinetic measures. The record does not report a multiplicity strategy, such as a hierarchy of hypotheses, adjustment for multiple testing, or a distinction between confirmatory and exploratory analyses. Consequently, no interpretation of statistical significance across outcomes can be reconstructed from the record.

Missing-data procedures are not reported in the registry record. The primary population is defined as the treated set, meaning patients who received at least one dose, but the record does not explain how missing toxicity assessments, early discontinuations, incomplete first-cycle observation or unavailable pharmacokinetic samples were handled. It also does not state whether all treated participants contributed to every outcome.

The record does not report a statistical analysis plan, analysis populations beyond the treated-set description for the primary outcome, or methods for handling protocol deviations. It gives the primary endpoint's cycle duration separately for Parts A and B and Parts C and D, but does not describe how these differing windows were addressed in the analysis.

These omissions do not establish that the trial team failed to use such procedures; they mean only that the registry record does not report them. Without the analysis methods and outcome-level results, readers cannot assess how missing observations or multiple outcomes might have influenced statistical conclusions.

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: disease progression (66.7%), diarrhoea (33.3%), mycobacterial infection (33.3%), pneumonia (33.3%), respiratory tract infection bacterial (33.3%).

The safety summary reports serious adverse event counts and other adverse event counts separately for each listed group. For instance, Part A: A20P80 reports 2 participants affected by serious adverse events among 3 at risk; Part B: A20P80B7.5 reports 6 among 6; and Part C: A40C6 reports 3 among 9. These are descriptive group summaries. The small denominators mean that a difference of one participant could materially change the apparent pattern.

The serious adverse event terms listed are disease progression at 66.7%, and diarrhoea, mycobacterial infection, pneumonia, respiratory tract infection bacterial and urinary tract infection bacterial at 33.3% each. The registry does not report the denominators or calculation method for these term percentages, so they cannot be interpreted as group-specific incidences. The record also does not report deaths in the safety summary.

Serious adverse events are not interchangeable with dose-limiting toxicities. The latter are defined as events or laboratory abnormalities considered related to treatment during the first cycle; the registry does not state that all serious events met that definition. The safety counts should not be used as a direct estimate of treatment effect or compared as if groups had been randomized.

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

The posted registry information describes an early-phase study designed to assess doses of four afatinib-based combinations in patients with advanced solid tumours. Its primary endpoint was the number of treated participants with a dose-limiting toxicity during the first cycle. That endpoint is relevant to dose selection because it focuses on defined toxicities during an initial treatment period.

The record does not report the primary endpoint result, an estimated maximum tolerated dose, or a statistical analysis of the endpoint. It therefore does not show how many participants experienced a dose-limiting toxicity or how precisely any dose-selection conclusion was supported. The serious adverse event counts provide a separate descriptive safety summary, but they do not fill that gap and should not be substituted for the primary outcome.

The trial was non-randomized and open-label, with several regimens and dose-group labels. These features do not support treating differences between groups as unbiased causal comparisons. The regimen components differ, and the primary observation window differs by part. Group counts also have limited precision when denominators are small.

The record does not provide enough information to conclude that one combination is safer or more effective than another, or to make a comparative judgment against a control treatment. It reports no randomized comparator and gives no efficacy result in the listed primary outcome. The study description and adverse event summaries can characterize what was planned and what was posted, but they do not establish clinical benefit or lack of benefit.

14. Why This Trial Matters Statistically

This trial raises a statistical question common to early-phase research: how to use observed toxicity during an initial treatment cycle to guide dose selection. The primary endpoint is a participant count defined by both an event criterion and treatment-related attribution. That makes the endpoint conceptually important, but interpretation depends on clear definitions, complete observation and a transparent decision procedure.

The study also illustrates why design labels matter. Non-randomized groups with different drug combinations are not equivalent to controlled randomized arms. Counts may describe what occurred within each group, but they cannot isolate the effect of a particular drug or dose when group composition and regimen differ. Open-label conduct is another relevant feature when outcomes include assessment and attribution of adverse events.

Part-specific cycle lengths are an additional interpretive consideration: the primary endpoint uses a 21-day cycle in Parts C and D and a 28-day cycle in Parts A and B. Outcome windows should be understood in context rather than assumed to be identical across regimens.

Finally, the contrast between a clearly named primary endpoint and the absence of its results in the registry record emphasizes the role of reporting. Without outcome counts, analysis methods and uncertainty estimates, readers cannot evaluate the dose-finding result from the registry information. The posted safety figures remain useful descriptive information, but they answer a narrower question than the primary endpoint.

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 main trial-specific limitation is that the registry record does not report results for the primary dose-limiting toxicity endpoint. It therefore does not provide the counts needed to assess the stated dose-finding question, nor does it report a maximum tolerated dose. The record also lists zero analyses, so statistical estimates and uncertainty for that endpoint are unavailable.

The study is non-randomized and open-label. Comparisons among its groups cannot be treated as randomized contrasts, and the four parts use different combinations. The registry record does not report an adjustment strategy for differences among participants or groups. The first-cycle timeframe also differs: 21 days in Parts C and D and 28 days in Parts A and B.

The safety summaries have small group denominators, making descriptive counts sensitive to individual outcomes. The record does not give the denominator or calculation details for the listed serious-event term percentages. It does not report the number of deaths in the safety summary, detailed participant characteristics, event timing, missing-data procedures, or how serious events overlap with the primary endpoint's treatment-related toxicity definition.

The registry describes a treated-set population for the primary outcome but does not report whether every treated participant completed the relevant observation period or how incomplete assessments were handled. It also does not report the analysis plan, multiplicity approach or detailed dose-selection procedure. These are limitations of what the registry record reports; they do not establish what procedures may have been conducted but not recorded.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Trial Exploring Afatinib (BIBW 2992) + Paclitaxel (Part A), Afatinib + Paclitaxel + Bevacizumab (Part B), Afatinib + Carboplatin (Part C) and Afatinib+ Paclitaxel +Carboplatin(Part D) in Patients With Advanced Solid Tumours — NCT00809133.
• Registry record last updated 2016-03-14; status last verified 2016-02.
• Results first posted 2016-03-14.
• 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

NCT00809133 is a completed, non-randomized, open-label Phase I trial sponsored by Boehringer Ingelheim. The registry lists enrollment of 83, a start of 2007-05 and primary completion in 2015-02. The trial examined afatinib with paclitaxel; afatinib, paclitaxel and bevacizumab; afatinib with carboplatin; and afatinib, paclitaxel and carboplatin.

The primary outcome was the number of treated participants with dose-limiting toxicities during the first cycle, used for maximum tolerated dose determination. The registry specifies 21-day cycles for Parts C and D and 28-day cycles for Parts A and B. It does not report the primary outcome results or an analysis. Separate serious and other adverse event counts are listed by group, with serious-event terms also reported as percentages whose denominator details are not stated. The record lists 24 outcome measures and zero analyses.