Safety And Efficacy Study Of Bosutinib In Patients With Philadelphia Chromosome Positive Chronic Myeloid Leukemia Previously Treated With One Or More Tyrosine Kinase Inhibitors: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety And Efficacy Study Of Bosutinib In Patients With Philadelphia Chromosome Positive Chronic Myeloid Leukemia Previously Treated With One Or More Tyrosine Kinase Inhibitors (NCT02228382), a na phase 4 study. The primary outcome is Percentage of Participants With Cumulative Confirmed Major Cytogenetic Response (MCyR) in 2nd and 3rd Line Chronic Phase (CP) Participants.

2. Clinical Question

The study's stated purpose was to fulfill a post-authorization commitment to provide additional safety and efficacy data in patients with high unmet medical need, including people treated in the fourth or later line setting. The registry describes the broader aim, but the specified primary endpoint concerns a subgroup and a particular response measure. That distinction matters: the broad enrollment of 163 is not itself the denominator for the primary endpoint, which uses an evaluable set with valid baseline efficacy assessment. The number in that endpoint population is not reported in the registry record.

3. Trial Design

This was a phase 4 study of bosutinib in people with previously treated chronic myeloid leukemia. The registry lists Pfizer as the sponsor, enrollment of 163, and status as terminated. The recorded study start was 2014-11-07 and primary completion was 2020-10-13. These registry dates describe the study record and do not, on their own, establish when every participant entered or completed treatment.

The design is not a randomized comparison: allocation is listed as NA, and masking is listed as none. Bosutinib is the only intervention named. Consequently, the groups described in the safety record are clinical categories, including chronic-phase treatment lines and disease phases, rather than treatment arms randomized to competing interventions. Differences between these groups should not be read as causal treatment contrasts. They may reflect the populations and disease settings represented in each category.

The study included multiple disease and treatment-history categories. The registry's stated purpose refers to approximately 150 patients, including 75 chronic-phase, accelerated-phase, or blast-phase patients in the fourth or later line setting. The recorded enrollment is 163. The primary outcome, however, was specified for 2nd and 3rd line chronic-phase participants, rather than for every enrolled participant. The registry record does not report the number enrolled in each primary-endpoint subgroup.

The primary endpoint timeframe was up to 1 year (52 weeks). Other listed outcomes include cumulative cytogenetic and hematological responses, response at named follow-up times, molecular response, and a Kaplan-Meier estimate related to retaining complete cytogenetic response at Month 36. The registry lists 16 outcome measures, but no analyses are listed. Protocol details such as the full statistical analysis plan, planned interim analyses, and sample-size justification are not reported in the registry record.

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: A total of 177 participants signed the ICF, 14 participants were screen failure and 163 were enrolled into the study and assigned to study treatment. Reporting arms were based on line of therapy (CP2L, CP3L, CP4L) and disease phase (CP and AP). Data collection and planned analysis on BP participants was not performed because no participants with BP were enrolled in the study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Evaluable set for cytogenetic response: treated participants with valid baseline efficacy assessment (\>=20 metaphases from baseline bone marrow or CCyR with \>=200 cells from FISH or baseline MMR). Data for this outcome measure was not planned to be collected and analyzed for AP CML and Ph- participants and planned to be analyzed for 2nd line and 3rd line population.

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: Safety analysis set included all participants who received at least 1 dose of bosutinib

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Cumulative Confirmed Major Cytogenetic Response (MCyR) in 2nd and 3rd Line Chronic Phase (CP) Participants, measured over Up to 1 year (52 weeks).

The primary endpoint is the percentage of participants with cumulative confirmed major cytogenetic response (MCyR) among 2nd and 3rd line chronic-phase participants, assessed up to 1 year (52 weeks). It is a binary response outcome: each participant is classified as meeting the specified response definition or not meeting it, and the result is expressed as a percentage of participants. The endpoint's stated dispersion measure is a 95% confidence interval.

The definition combines cytogenetic and molecular response conditions. For participants entering without complete cytogenetic response (CCyR), confirmed MCyR means confirmed CCyR or partial cytogenetic response (PCyR) by 1 year. For participants entering with CCyR, it requires maintenance of confirmed CCyR for at least 1 year after starting bosutinib, or at least major molecular response (MMR) by 1 year with a deeper molecular response than at baseline. Participants with baseline PCyR who did not achieve CCyR were counted as nonresponders. Initial cytogenetic responses without MMR required confirmation by 2 consecutive assessments at least 28 days apart.

The registry defines CCyR using Ph+ cell thresholds assessed by conventional cytogenetics or fluorescent in situ hybridization, PCyR as 1 to 35% Ph+ cells, and MMR as no more than 0.1% BCR-ABL1 on the international scale with at least 10,000 ABL1 transcripts assessed by a central laboratory. These criteria make the endpoint more explicit than a general response label, but the registry record does not report the observed percentage, confidence interval, or endpoint denominator. The measure is useful for describing response status under the study's prespecified definition; without a comparator, it does not establish a comparative treatment effect.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a percentage endpoint represent?

A binary percentage outcome counts participants who meet a defined event or response criterion and expresses that count relative to a specified analysis population. In this study, the event is confirmed MCyR according to the detailed entry-status rules and assessment requirements in the registry. The percentage would describe the observed response frequency in the evaluable population, not the probability that any individual will respond in another setting. Its interpretation depends on the population denominator and on how missing or unassessable outcomes are handled. Those details are not fully reported in the registry record.

How should a confidence interval be understood?

A confidence interval is an uncertainty range around an estimated quantity. For a response percentage, it communicates how much statistical uncertainty remains about the underlying response frequency, given the observed data and the method used. A narrower interval generally indicates greater precision, while a wider interval indicates less precision. The registry specifies a 95% confidence interval as the endpoint's dispersion measure, but it does not report an interval estimate. Therefore no conclusion about precision can be drawn from the record's endpoint definition alone.

The confidence interval would not account automatically for every concern about study design. It describes sampling uncertainty under its statistical method; it does not remove possible selection effects, measurement limitations, missing-data concerns, or the absence of a randomized comparator. Statistical precision and design validity are distinct issues.

Why do confirmation rules matter?

The endpoint requires confirmation of initial cytogenetic responses when MMR is absent, with 2 consecutive assessments at least 28 days apart. Such rules aim to distinguish a response that is sustained across assessments from an isolated measurement. The definition also uses different response paths according to baseline status: participants entering without CCyR are assessed for confirmed CCyR or PCyR, while those entering with CCyR are assessed for maintenance or specified molecular response. This approach creates an endpoint tailored to starting response status, but it also means that endpoint classification depends on baseline data and follow-up assessments.

In general, when outcomes require repeated confirmation, incomplete follow-up can affect whether response status is ascertainable. The registry does not report the amount or pattern of missing outcome data, nor does it explain how participants without sufficient follow-up assessments were handled. The resulting effect on the reported endpoint, if calculated, cannot be evaluated from this record.

What does the analysis population imply?

The primary endpoint population is described as an evaluable set: treated participants with valid baseline efficacy assessment. The record lists examples of valid baseline assessment, including a specified number of metaphases from baseline bone marrow, CCyR based on FISH, or baseline MMR. This is not necessarily identical to all enrolled participants or all treated participants. Analysis restricted to people with evaluable baseline data can be appropriate for a defined response assessment, but the count included and the disposition of others are needed to understand the denominator. Those counts are not reported in the registry record.

The endpoint description says analysis was not planned for accelerated-phase and Philadelphia chromosome-negative participants. It does not state in the posted record how the primary analysis population was finalized, whether all eligible participants were analyzed, or whether alternative populations were used. The number of analyses listed is zero. A detailed statistical analysis plan, including any outcome-handling rules beyond the endpoint definition, is not reported in the registry record.

Why does the design matter for inference?

Allocation is listed as NA and masking as none; only bosutinib is named as an intervention. This is not a randomized comparison. In a single-arm study, the response percentage can describe what happened among study participants, but a causal contrast against another treatment is not available from the design described in the registry. Comparisons across disease phases or treatment lines are observational group contrasts, not randomized treatment effects. Differences may reflect the characteristics that distinguish those groups as well as treatment history and disease status.

Randomization and masking address different sources of bias in comparative studies. Random allocation can help balance measured and unmeasured baseline factors between treatment groups, while masking can reduce some forms of influence on treatment delivery or outcome assessment. Their absence does not make descriptive outcome reporting impossible, but it limits what can be inferred about treatment differences. The record does not report additional design features that would support a causal comparison.

How do planning illustrations differ from observed power?

The sample-size assumptions describe a planning illustration computed from an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The illustration is not the study's stated design, and its assumptions do not match the registry's single-arm structure. Required sample sizes for hypothetical planning do not show the probability that the completed study detected an effect, and they are not observed power. Because the primary effect estimate is not reported in the registry record, the planning illustration cannot be related to a posted primary result.

In general, planning calculations depend on assumptions about the effect to detect, outcome variability or event frequency, error rates, and allocation. Changing these assumptions changes the planning result. A planning illustration is most useful as a conditional scenario, not as evidence that a study was adequately or inadequately powered. The registry record does not report the study's own sample-size justification, so the planning illustration should not be mistaken for the original rationale for enrollment.

For time-to-event outcomes, methods and planning quantities differ from those for a binary percentage outcome. The record's general planning description says time-to-event tables use total events, while other illustrations use participants per arm. That convention does not mean the primary endpoint is time-to-event; the primary endpoint is a percentage response. The listed Kaplan-Meier outcome is a separate secondary outcome concerning retention of CCyR at Month 36.

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, Chronic Phase 2nd and 3rd Line Chronic ")
n      <- c(98)
events <- c(75)
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, Chronic Phase 2nd and 3rd Line Chronic   98  75  76.5  66.9  84.5  67.2  83.8  67.2  83.8

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 16 outcome measures, including the primary response measure and secondary cytogenetic, hematological, molecular, and time-to-event outcomes. Testing or estimating multiple outcomes can raise multiplicity concerns because the chance of at least one apparently notable result can increase when many questions are examined. A prespecified hierarchy or adjustment can help define how multiple inferential claims are controlled. The registry record does not report a multiplicity strategy, testing hierarchy, or adjustment procedure. No adjustment should be assumed.

The record lists no analyses. It also does not report primary endpoint results, confidence interval bounds, analysis denominators, or a statistical analysis plan. Although the primary endpoint identifies an evaluable set with valid baseline efficacy assessment, the number in that set and the handling of participants without valid assessments are not reported in the registry record. The treatment of missing follow-up, incomplete confirmation, and withdrawals is also not reported in the registry record.

These omissions matter because endpoint classification depends on baseline response status and follow-up confirmation. Without participant disposition and missing-data rules, readers cannot determine how many participants had response status established, whether the analysis included every eligible participant, or how missing assessments may have affected the estimated percentage. The record does not describe sensitivity analyses addressing such uncertainty.

The broad enrollment and the primary endpoint population are not interchangeable. The registry states that the primary endpoint was for 2nd and 3rd line chronic-phase participants and that data were not planned for accelerated-phase and Philadelphia chromosome-negative participants. The final analysis population and subgroup counts are not reported in the registry record. Thus, neither a denominator nor the extent of outcome availability can be reconstructed from the posted information.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pancytopenia (33.3%), pericardial effusion (33.3%), diabetes mellitus (33.3%), adenocarcinoma of colon (33.3%), lung neoplasm malignant (33.3%).

The registry reports serious adverse-event counts for each listed clinical group. For chronic-phase 2nd line participants, it lists 21 affected among 46 at risk; for chronic-phase 3rd line, 30 among 61; for chronic-phase 4th line, 14 among 49; for accelerated-phase, 1 among 4; and for Philadelphia chromosome-negative participants, 3 among 3. The overall chronic myelogenous leukemia group lists 69 among 163. These are descriptive counts, not comparisons against a control group.

The record also lists deaths as 5, 7, 5, 0, and 2 across those five clinical groups, with 19 in the overall chronic myelogenous leukemia group. The registry does not provide time-to-event context or a comparative analysis for these figures. The listed serious-event terms are pancytopenia, pericardial effusion, diabetes mellitus, adenocarcinoma of colon, lung neoplasm malignant, and pleural effusion, each shown as 33.3%. The denominator and calculation basis for these term percentages are not reported in the registry record.

Group sizes vary, and the accelerated-phase and Philadelphia chromosome-negative groups are especially small. Counts and percentages in small groups are unstable descriptions and should not be treated as comparative risk estimates. The registry record also does not report enough detail to establish event timing, exposure duration, or causal attribution. These figures characterize the posted safety record; they do not establish whether bosutinib caused a given event.

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

The study addresses a clinically important evidence gap described in its stated purpose: additional safety and efficacy data among people with Philadelphia chromosome-positive chronic myeloid leukemia previously treated with tyrosine kinase inhibitors, including those in later treatment lines. Its phase 4 status and enrollment of 163 place the study in a post-authorization setting. The registry's specified primary endpoint focuses on confirmed MCyR in 2nd and 3rd line chronic-phase participants, while the stated broader purpose includes a range of disease phases and later treatment settings.

The posted record does not report the primary endpoint percentage or its confidence interval. Therefore it cannot establish the observed frequency of confirmed MCyR, the precision of that estimate, or whether the response definition was met by a particular proportion of the evaluable participants. The endpoint definition explains what would count as response, but a definition is not a result.

The study is not a randomized comparison, and the registry lists no comparator intervention. Any posted response frequency would be descriptive for the participants who were assessed. It would not establish how outcomes would differ under another treatment, nor would it isolate bosutinib's contribution from the effects of patient selection, disease course, prior treatment, or other factors. Likewise, comparisons among clinical groups cannot be treated as randomized contrasts.

The safety record gives counts of serious adverse events and deaths across the clinical groups, alongside selected event terms. Those figures can describe what the registry records, but they do not by themselves establish causation or comparative safety. The serious-event term percentages lack a reported denominator, and the record does not give full context on event timing or exposure for these counts.

Accordingly, this registry record is informative about the study's purpose, endpoint definition, population categories, and selected safety observations. It is not a complete basis for judging comparative efficacy or safety, and it does not provide the primary response result needed to characterize the main endpoint statistically.

14. Why This Trial Matters Statistically

This study is statistically notable because its intended question spans several clinical settings while its primary endpoint is narrower. The registry describes a commitment to collect additional safety and efficacy information in a population with substantial prior treatment, including later-line treatment. Yet the primary endpoint is defined for 2nd and 3rd line chronic-phase participants. Keeping that distinction clear prevents a broad enrollment figure from being mistaken for the primary analysis denominator.

The response endpoint also illustrates how clinical outcomes can depend on detailed operational definitions. Baseline status determines the response path, initial cytogenetic responses may require confirmation, and baseline PCyR without subsequent CCyR is classified as nonresponse. Such rules can improve consistency in endpoint classification, while making the assessment population and missing follow-up especially important to interpret.

The nonrandomized, unmasked design makes descriptive interpretation central. A single-arm record can contribute information about outcomes and reported safety events in the enrolled population, but it cannot supply the same treatment contrast as random allocation to a comparator. Differences between the listed disease and treatment-line groups should not be mistaken for effects of treatment because those categories are not randomized arms.

Finally, this record illustrates why registry results need both estimates and analysis context. The endpoint definition and intended 95% confidence interval are not enough to assess response without the result, denominator, missing-data handling, and analysis plan. The record lists 16 outcomes but no analyses. Its value for statistical interpretation is therefore constrained by what is not reported, even though it describes the study purpose and several safety counts.

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 central limitation for interpretation is that the primary endpoint result is not reported in the registry record. There is no observed response percentage, confidence interval, or endpoint denominator. The registry also lists zero analyses, which prevents review of the primary result or secondary analyses from the posted record.

The endpoint is restricted to evaluable 2nd and 3rd line chronic-phase participants. The size and composition of that population are not reported, and the record does not provide participant disposition for the endpoint. Although the definition specifies valid baseline efficacy assessments, it does not report the handling of missing follow-up assessments, incomplete confirmation, or participants who could not be classified.

The study has no randomized comparator, with allocation listed as NA and masking as none. This limits causal and comparative interpretation. The clinical groups differ by disease phase and treatment line, and their outcomes cannot be interpreted as like-for-like treatment comparisons. The registry does not report an adjusted analysis that would address differences among groups.

The safety record has additional limits. The event-term percentages are listed as 33.3%, but their denominator and calculation basis are not reported. The record does not provide detailed timing or exposure context alongside these figures. The small accelerated-phase and Philadelphia chromosome-negative groups mean their counts are particularly limited as descriptive evidence. The listed deaths and serious adverse events do not establish treatment causality.

The registry does not report the full statistical analysis plan, sample-size justification, multiplicity approach, interim analysis plans, or sensitivity analyses. The planning assumptions described for illustrations are not the study's own design assumptions and are not evidence of observed power. These limitations leave important questions about analysis conduct and precision unresolved.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety And Efficacy Study Of Bosutinib In Patients With Philadelphia Chromosome Positive Chronic Myeloid Leukemia Previously Treated With One Or More Tyrosine Kinase Inhibitors — NCT02228382.
• Registry record last updated 2021-12-30; status last verified 2021-12.
• Results first posted 2021-12-30.
• 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

This phase 4 study evaluated bosutinib in previously treated chronic myeloid leukemia. Pfizer is listed as sponsor, enrollment is 163, and the registry status is terminated. The recorded study start is 2014-11-07, with primary completion on 2020-10-13. Allocation is listed as NA and masking as none.

The primary endpoint is the percentage with cumulative confirmed MCyR among 2nd and 3rd line chronic-phase participants, up to 1 year (52 weeks). It uses a specified evaluable population and a 95% confidence interval, but the endpoint result, interval, and analysis denominator are not reported in the registry record. The registry lists 16 outcome measures and no analyses.

Safety counts are reported across clinical groups, including serious adverse events and deaths, but the record does not provide a randomized comparator. The listed figures are descriptive, and the denominator for serious-event term percentages is not reported. Overall, the record describes the study aim, endpoint rules, and selected safety data but does not provide the primary statistical result or enough analysis detail for comparative conclusions.