Study Evaluating SKI-606 (Bosutinib) In Philadelphia Chromosome Positive Leukemias: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study Evaluating SKI-606 (Bosutinib) In Philadelphia Chromosome Positive Leukemias (NCT00261846), a na phase 2 study. The primary outcome is Number of Participants With Dose Limiting Toxicity (DLT).

2. Clinical Question

3. Trial Design

The registry identifies this as a Phase 2 study, while its official title and brief summary describe a Phase 1/2 study with two parts. The record reports a single-group, open-label design, with no masking and allocation marked not applicable. It lists an enrollment of 571. The study is marked completed; its recorded start date is 2006-01-18 and its primary completion date is 2009-09-25.

Part 1 was a dose-escalation study in chronic phase CML. Its stated purpose was to establish a maximum tolerated dose in that population. The primary endpoint listed for the record is the number of participants with dose-limiting toxicity during Part 1, over the period from baseline up to Day 28. Part 2 began after Part 1 was completed and a dose had been established for chronic phase participants. The brief summary describes evaluation of 500 mg daily oral bosutinib in cohorts with different phases of Philadelphia chromosome positive CML and in Philadelphia chromosome positive ALL.

The registry lists separate Part 2 groups, including chronic phase second-line and third-line CML categories, accelerated phase CML, blast phase CML, and Philadelphia chromosome positive ALL. These groups reflect different clinical populations rather than randomized arms. There is no concurrent randomized control group in the design information, so the study cannot provide a randomized comparison of bosutinib against another treatment.

The record lists 41 outcome measures and zero analysis records. It does not report the study's sample-size justification, detailed statistical analysis plan, or a primary endpoint result. The enrollment entry does not by itself identify how many participants contributed to each endpoint or analysis population.

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.

Only the first 6 of 12 groups are shown.

Period 1: Part 1 (Dose Escalation)

Reasons for not completing this period:

Period 2: Part 2 (Efficacy)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety population included all participants who received at least 1 dose of study medication.

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-treated population - included all enrolled participants who received at least one dose of bosutinib.

Only the first 6 of 10 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Dose Limiting Toxicity (DLT), measured over Part 1 Baseline up to Day 28.

The primary endpoint is the number of participants with dose-limiting toxicity (DLT) in Part 1, from baseline up to Day 28. The registry defines DLT as specified clinically relevant non-hematologic toxicities arising during the first 28 days of study medication and considered at least possibly related to the medication. The definition includes any grade 3 or 4 clinically relevant non-hematologic toxicity, or a clinically significant grade 2 non-hematologic toxicity requiring 14 days to resolve to grade 1.

This is a count endpoint: it describes how many participants in the relevant population experienced an event meeting the stated definition. The safety population is defined as participants who received at least one dose of study medication. That population definition matters because the endpoint concerns events after treatment exposure, not all people who may have been screened or enrolled.

In general, dose-limiting toxicity is used in dose-escalation research to characterize short-term tolerability and inform dose selection. The registry summary says Part 1 aimed to establish the maximum tolerated dose in chronic phase CML. The endpoint is limited to the specified event definition and observation period; it is not a summary of every possible adverse event or of longer-term safety. The observed DLT count and any associated uncertainty estimate are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The trial design is described as single-group and open-label. In general, a single-group study observes participants receiving the study intervention without a concurrent randomized control group. It can describe outcomes among participants in the study, but it does not provide the protection against confounding that random assignment can offer in a comparison. Open-label means masking was none in the registry record. Knowledge of treatment can affect reporting, assessment, and decisions about care, although the extent of any such effect cannot be determined from the design label alone.

What does the DLT count represent?

The primary endpoint is a count of participants meeting a defined event criterion during a stated period. It is not a count of all adverse events: the definition specifies particular grades and types of non-hematologic toxicity, a possible relationship to study medication, and the first 28 days of medication. In general, an endpoint definition makes the result interpretable by establishing which events qualify, when they are counted, and who is included. The record sets the primary endpoint population as participants who received at least one dose. The actual count and any uncertainty interval are not reported in the registry record.

Counts are often accompanied by the number of participants at risk or assessed, which supplies a denominator for interpreting how common an event was within a population. The registry lists at-risk and affected counts for serious adverse events in Part 2 groups, but it does not report the observed primary DLT result. Those serious-event entries have different scope from the DLT endpoint and should not be substituted for it. In general, event counts can be unstable when a group is small, and a point estimate alone does not show its precision.

Why does the lack of a randomized comparator matter?

Random assignment tends to balance known and unknown prognostic factors across groups, on average. Without it, differences between observed groups can reflect their starting characteristics as well as treatment or follow-up. Here, the listed Part 2 groups represent distinct CML categories and Philadelphia chromosome positive ALL, rather than randomly assigned comparisons. In general, comparing their outcome summaries descriptively may be useful, but it does not isolate a treatment effect. The registry record does not report a comparator group or a planned causal comparison.

How should uncertainty be understood?

In general, a confidence interval expresses the range of values reasonably compatible with the data under a specified statistical method and assumptions. It helps distinguish an estimate's magnitude from its precision. The registry information does not report an interval for the primary endpoint. No precision claim about the DLT count can therefore be made from the endpoint record. A p-value, when used, addresses compatibility with a statistical null model and is not a measure of clinical importance; no primary endpoint p-value is reported in the registry record.

For time-to-event outcomes, general methods such as Kaplan-Meier estimation account for the timing of events and censoring, where the exact event time may not be observed for every participant during follow-up. The listed secondary outcomes include Kaplan-Meier estimates for maintaining or retaining response at specified years, and time to achieve a response among responders. The presence of these outcome titles does not establish the results, the number of events, or the handling of censoring. Those details are not reported in the registry record.

What is the role of the planning illustration?

In general, sample-size planning asks how many participants would be needed under chosen assumptions to detect a specified effect with a chosen significance level and power. The planning assumptions described in the registry information use a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect expressed as a fraction of an observed effect. They distinguish total events for time-to-event planning from participants per arm for other outcomes. These are planning assumptions, not evidence that the trial used a two-arm randomized design. A planning illustration based on an observed effect is not observed power and is not the trial's original sample-size justification. The original justification is not reported in the registry record.

In general, over-dispersion matters when outcome variability is greater than a simple statistical model assumes; ignoring it can make standard errors too small and intervals too narrow. The primary endpoint is a count, but the registry record does not specify a model for its analysis or report a dispersion estimate. It would be inappropriate to infer that a particular count model or adjustment was used. The record lists zero analysis records, so the endpoint's analysis method is not reported in the registry record.

Statistical interpretation also depends on analysis populations and missing-data procedures. An endpoint may be analyzed in a safety population, an efficacy population, or another prespecified group, and these populations need not contain the same participants. The primary endpoint population is defined, but the record does not describe handling of missing observations or provide population definitions for every secondary outcome. Those methods are 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("Bosutinib 400 mg (Part 1)", "Bosutinib 500 mg (Part 1)", "Bosutinib 600 mg (Part 1)")
n      <- c(3, 3, 12)
events <- c(0, 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  Bosutinib 400 mg (Part 1)  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Bosutinib 500 mg (Part 1)  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Bosutinib 600 mg (Part 1)  12  1  8.3  0.2  38.5  1.5  35.4  1.9  36.0

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 41 outcome measures, including a primary DLT count and secondary measures of cytogenetic response, hematological response, kinase and protein phosphorylation, and response timing or maintenance. When many outcomes are examined, the chance of at least one apparently notable result can increase. In general, multiplicity can be addressed through a prespecified hierarchy, adjustment of significance levels, or a clear distinction between confirmatory and exploratory analyses. The registry record does not report a multiplicity strategy or a detailed statistical analysis plan. No correction or hierarchy should be assumed.

The record lists zero analysis records. It does not report which outcomes were analyzed, whether all prespecified outcomes were reported, or how any subgroup analyses were selected. The presence of an outcome title does not establish that a result was available or that a formal hypothesis test was conducted. Results for the primary endpoint are not reported in the registry record.

Missing-data methods can affect interpretation, especially when outcome availability is related to health status, treatment discontinuation, or follow-up. In general, complete-case analysis, imputation, and other approaches rely on different assumptions. The registry information does not describe missing-data amounts, reasons for missingness, or methods used to address it for the primary or secondary outcomes. It also does not provide analysis-population definitions for each secondary endpoint. The primary safety population is defined as participants who received at least one dose, but this definition alone does not explain how participants with incomplete observations were handled.

The enrollment entry is not a substitute for endpoint-specific denominators or analysis populations. Those details are not reported for the primary endpoint in the registry record.

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: neutropenia (20.0%), febrile neutropenia (16.7%), pneumonia (12.5%), leukocytosis (8.3%), diarrhoea (8.3%).

The serious adverse-event entries are organized by named Part 2 groups. For example, the record lists serious events affecting 81 participants among 195 at risk in the Bosutinib 500 mg, CP2L-CML IM-R group, and 34 among 89 at risk in the Bosutinib 500 mg, CP2L-CML IM-I group. It also lists 43 among 79 at risk for AP-CML Total, 37 among 64 at risk for BP-CML Total, and 17 among 24 at risk for Bosutinib 500 mg, Ph+ ALL. Other listed groups have their own at-risk and affected counts; these should be interpreted separately, not combined into a total.

The record separately lists the most frequent serious-event terms as percentages: Neutropenia, 20.0%; Febrile neutropenia, 16.7%; Pneumonia, 12.5%; Leukocytosis, 8.3%; Diarrhoea, 8.3%; and General physical health deterioration, 8.3%. The denominator for these term percentages is not reported in the registry record. These entries describe serious events and should not be conflated with the primary DLT endpoint, which has a narrower definition and a Part 1 timeframe. Death counts are not reported in the registry record for the listed groups.

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

The result does not establish a primary endpoint finding, because the registry record does not report the number of participants with DLT. It does establish how the endpoint was defined: qualifying toxicity during the first 28 days of study medication, considered at least possibly related to medication, among the stated safety population. This definition identifies what the endpoint was designed to count, but a definition is not an observed result.

The record describes an open-label, single-group study with dose escalation in Part 1 and disease-specific cohorts in Part 2. This design can describe observations in the enrolled groups, but it does not create a randomized treatment contrast. The Part 2 cohorts should not be interpreted as control groups for one another. The stated hypotheses about major cytogenetic response and overall hematological response are study aims, not evidence that those outcomes were achieved.

The serious adverse-event entries provide counts for named groups and percentages for listed terms, but the registry information does not supply the denominator for those term percentages or death counts. Such entries should be read within their recorded group and event definitions. They do not answer the primary DLT question by themselves.

In general, a study result is best interpreted alongside its population, outcome definition, timeframe, uncertainty, and analysis methods. The registry record does not report the primary endpoint estimate, its uncertainty, the original sample-size justification, or the detailed analysis plan. It therefore does not support conclusions about the magnitude or precision of the primary endpoint, or a causal comparison with another treatment. These limits concern what the registry record documents; they do not establish that an unreported analysis was or was not conducted elsewhere.

14. Why This Trial Matters Statistically

This study illustrates why design features and endpoint definitions need to be read together. Part 1's DLT endpoint is a defined count over a specified early treatment period, in a safety population that received at least one dose. That makes the question different from a general tally of all adverse events or a longer-term safety summary. The registry record gives the endpoint definition but does not report its observed count, so the design question is clearer than the result available in the record.

The two-part structure also separates dose escalation from evaluation in disease-specific cohorts. Part 1 aimed to establish a maximum tolerated dose in chronic phase CML. Part 2 evaluated 500 mg daily oral bosutinib across cohorts that included different CML phases and Philadelphia chromosome positive ALL. Keeping those purposes distinct helps prevent a dose-escalation endpoint from being mistaken for a response endpoint.

Statistically, the single-group, open-label design is central to interpretation. The separate cohorts do not supply randomized controls, and their results would not automatically support direct treatment comparisons. The record's many outcome measures also raise the need for a prespecified analysis strategy and careful interpretation of multiple endpoints; such a strategy is not reported in the registry record.

The study is also a useful example of why registry completeness matters. Enrollment, outcome definitions, and safety entries do not replace endpoint results, uncertainty estimates, analysis populations, or missing-data methods. Those details are needed to evaluate the strength and precision of conclusions. The registry identifies many questions the study set out to examine, but the primary result and several analytic details are not reported in the registry record.

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 limitation for interpreting the primary endpoint is that its observed count is not reported in the registry record. No estimate or uncertainty interval for Part 1 DLT can be assessed. The record defines the DLT criteria and safety population, but does not give the endpoint-specific denominator or explain missing observations.

The study is open-label and single-group, with no randomized comparator. That limits causal interpretation and prevents a randomized comparison with another treatment. Part 2 consists of distinct disease and treatment-history cohorts, so differences across groups should not be treated as controlled treatment effects. The record does not report adjustment methods for differences between cohorts.

The registry lists 41 outcomes and zero analysis records. It does not report a detailed statistical analysis plan, multiplicity handling, outcome-specific analysis populations, or missing-data procedures. The original sample-size justification is not reported in the registry record. The stated planning assumptions are an illustration and should not be taken as the study's own design rationale or as observed power.

Safety entries are available for named Part 2 groups, but the record does not report death counts for those groups. The denominator for the listed serious-event term percentages is also not reported in the registry record. These gaps limit interpretation of those entries and make them unsuitable as substitutes for the specifically defined Part 1 DLT endpoint.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study Evaluating SKI-606 (Bosutinib) In Philadelphia Chromosome Positive Leukemias — NCT00261846.
• Registry record last updated 2017-07-27; status last verified 2017-06.
• Results first posted 2013-03-12.
• 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

The registry record describes a completed, open-label, single-group study of bosutinib (SKI-606) in Philadelphia chromosome positive leukemias. It identifies the study as Phase 2, while the official title and summary describe a Phase 1/2, two-part study. Part 1 was dose escalation in chronic phase CML to establish a maximum tolerated dose; Part 2 evaluated 500 mg daily oral bosutinib in separate disease cohorts.

The listed primary endpoint is the number of participants with DLT during Part 1, from baseline up to Day 28, in a safety population defined by receipt of at least one dose. The observed primary endpoint count is not reported in the registry record. The record lists 41 outcome measures and zero analysis records. It also lists serious adverse-event counts for Part 2 groups and selected serious-event terms, but death counts are not reported for those groups.