Homoharringtonine (Omacetaxine Mepesuccinate) in Treating Patients With Chronic Myeloid Leukemia (CML) With the T315I BCR-ABL Gene Mutation: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Homoharringtonine (Omacetaxine Mepesuccinate) in Treating Patients With Chronic Myeloid Leukemia (CML) With the T315I BCR-ABL Gene Mutation (NCT00375219), a na phase 2 study. The primary outcome is Percentage of Participants Achieving an Overall Hematologic Response by Subpopulation and Total Population.

2. Clinical Question

The clinical question concerns response in a selected population with a specific mutation and prior treatment history. It is not a comparison of omacetaxine with another treatment. The study sought to evaluate safety and efficacy in achieving a clinical response among participants whose disease was in one of the specified phases at enrollment.

The endpoint combines different hematologic response categories according to phase. For chronic phase, overall hematologic response includes confirmed complete hematologic response (CHR). For accelerated or blast phase, it includes confirmed CHR, no evidence of leukemia (NEL), or return to chronic phase (RCP). This phase-specific definition reflects that clinically meaningful response categories are not identical across the disease phases.

The registry describes the primary endpoint as adjudicated by the Data Monitoring Committee. However, it does not report the numbers of participants achieving each response, response percentages, confidence intervals, or the committee’s adjudication results. The clinical question can therefore be described from the registered definition, but the extent of response cannot be assessed from the registry record.

3. Trial Design

The registry identifies this as a phase II, open-label study with a single-group model. The study has no randomized allocation and no masking. All participants received omacetaxine; there is no concurrent control group for estimating a treatment contrast. The record lists enrollment as 103 and identifies chronic myeloid leukemia as the condition under study.

The target population was people with CML in chronic, accelerated, or blast phase who had failed prior imatinib therapy and had the T315I BCR-ABL gene mutation. Disease phase at enrollment defined the primary endpoint subpopulations. The stated primary analysis population was the intent-to-treat population. The registry record does not give further details about how participants were recruited or how eligibility was verified.

The intervention was subcutaneous omacetaxine mepesuccinate. The arm description states that induction treatment was 1.25 mg/m^2 twice a day for 14 consecutive days every 28 (±3) days, for up to 6 cycles. The description then begins to specify maintenance treatment at 1.25 mg/m^2, but the remainder of the maintenance regimen is not reported in the registry record. The primary endpoint timeframe was Day 1 up to 6 months.

The registry lists the study as completed. The recorded start date is 2006-09-20, and the primary completion date is 2010-03-23. These dates describe the study record and do not supply details about the timing of individual participant follow-up.

Because the study is open-label and single-group, response is assessed without a randomized concurrent treatment comparison. The design can describe observed outcomes among participants in the study, but it cannot by itself separate treatment-associated changes from other influences on outcomes or establish a comparative effect against another therapy. No randomized comparison is 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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Intent to treat 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: Intent to treat population includes all participants who provide written informed consent and receive at least one dose of study medication.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants Achieving an Overall Hematologic Response by Subpopulation and Total Population, measured over Day 1 up to 6 months.

The primary endpoint is the percentage of participants achieving an overall hematologic response, reported by CML phase and for the total population. Its timeframe is Day 1 up to 6 months, and the registry identifies the intent-to-treat population as the analysis population. Primary endpoints adjudicated by the Data Monitoring Committee were used for the primary analyses.

Response categories differ by disease phase. For chronic phase, overall hematologic response means confirmed complete hematologic response (CHR). For accelerated or blast phase, it includes confirmed CHR, no evidence of leukemia (NEL), or return to chronic phase (RCP). A response had to last at least 8 weeks to be considered meaningful. Thus, the endpoint is not simply a transient change: its registered definition requires persistence for the specified duration.

Hematologic response is used as a clinical measure of disease status, while the phase-specific categories allow the endpoint to reflect different response states across the enrolled disease phases. The registry’s stated analysis compared response rates by phase with an a priori value of 2.5%, using a one-sided lower 95% exact binomial confidence limit. The stated criterion was that the lower limit exceed 2.5%.

The registry record does not report the observed response percentages or confidence limits. Consequently, the endpoint definition and intended benchmark can be explained, but whether the registered criterion was met cannot be determined from this record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is a binary participant-level outcome: each participant either meets the registered definition of overall hematologic response within the specified timeframe or does not. The reported measure is the percentage of participants meeting that definition. General statistical explanation: for a binary outcome, an estimated percentage describes the proportion of the analyzed group with the event. Its precision depends on the number of participants contributing outcome information and on how common the event is. The registry record does not report the response counts or denominators for the phase-specific analyses.

Why use an exact binomial confidence limit?

The registered method uses a one-sided lower 95% exact binomial confidence limit for the response rate in each disease phase. The binomial model represents the outcome as a response or no response for each participant. An exact method calculates the confidence limit from the binomial distribution rather than relying on a normal approximation. General statistical explanation: this can be useful when proportions or group sizes make a normal approximation less dependable. The record does not report the phase-specific counts, so the confidence limits cannot be reproduced or independently checked from the registry information.

A one-sided lower confidence limit focuses on the lower plausible bound for the response rate under the specified method. The registered benchmark is 2.5%. The stated decision rule is that the lower limit must exceed that benchmark for the observed response rate to have exceeded the minimum threshold required to demonstrate efficacy. This rule uses a lower bound rather than judging only whether the point estimate is above the benchmark. It is still a statistical criterion, not a guarantee that the true response rate is above the benchmark.

What does the benchmark comparison mean?

The benchmark is not a concurrent control arm. Comparing a response rate with a prespecified value can address whether the observed rate clears a minimum threshold under the registered criterion, but it does not estimate a difference between omacetaxine and another treatment. Because the trial is single-group, there is no randomized treatment contrast in the primary analysis. General statistical explanation: a historical or fixed benchmark may not capture differences in patient selection, outcome assessment, or care across settings. The registry record does not report the basis for selecting the 2.5% benchmark or further justification for it.

The primary endpoint is divided by CML phase at enrollment. Each phase uses its specified response categories: confirmed CHR for chronic phase, and confirmed CHR, NEL, or RCP for accelerated or blast phase. A response must persist for at least 8 weeks. These definitions determine which participant outcomes count as events in the binary analysis. The registry does not provide response adjudication results, phase-specific denominators, or information on how participants with missing assessments were classified.

How should precision and missingness be considered?

A confidence interval communicates sampling uncertainty, but it does not account automatically for every source of bias. General statistical explanation: a confidence interval can be narrow while the study still has limitations related to selection, measurement, or missing outcomes. The registry identifies the intent-to-treat population, but does not report its operational definition, the number analyzed in each phase, or the approach to missing primary endpoint data. Without those details and the endpoint estimates, neither precision nor sensitivity to missingness can be evaluated.

Omitting participants with unavailable outcomes, treating them as nonresponders, or using another missing-data approach can affect a response percentage. General statistical explanation: the consequences depend on why outcomes are missing and on the analysis method. The missing-data method is not reported in the registry record, so no particular approach should be assumed.

What do the planning illustrations represent?

The registry’s sample-size assumptions describe planning illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is described as a stated fraction of the observed effect. For time-to-event outcomes, the assumptions refer to the total number of events; for other outcomes, they refer to participants per arm. These are planning illustrations, not observed power. They do not change the actual trial design, which is recorded as single-group. The registry record does not report the observed primary response effect or the resulting planning values, so no numerical sample-size illustration can be interpreted from the record.

General statistical explanation: a planning calculation asks what scale of study might be needed under specified assumptions; it does not indicate the probability that a completed study has detected a real effect. Power is a design property under assumptions, not a measure of how convincing an observed result is. A planning illustration based on an observed effect can also depend strongly on the chosen fraction of that effect. No trial-specific sample-size justification or design calculation is reported in the registry record.

Multiplicity is also relevant because the registry lists multiple secondary outcome topics alongside the primary endpoint. Testing many outcomes can increase the chance of at least one apparently notable result if no multiplicity strategy is used. General statistical explanation: procedures such as hierarchical testing or adjustment can address this issue, but they may affect interpretation and precision. The registry record does not report a multiplicity adjustment or a hierarchy for secondary analyses. This absence means the handling of multiple outcome comparisons cannot be inferred.

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("CML: Chronic Phase", "CML: Accelerated Phase", "CML: Blast Phase")
n      <- c(62, 20, 21)
events <- c(48, 11, 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  CML: Chronic Phase  62  48  77.4  65.0  87.1  65.6  86.0  65.5  86.0
ARM  CML: Accelerated Phase  20  11  55.0  31.5  76.9  34.2  74.2  34.0  74.3
ARM  CML: Blast Phase  21  2  9.5  1.2  30.4  2.7  28.9  2.9  29.2

11. Multiplicity, Missing Data and Analysis Populations

The registry identifies the intent-to-treat population for the primary endpoint and states that primary endpoint results adjudicated by the Data Monitoring Committee were used in the primary analyses. It does not report how the intent-to-treat population was defined operationally, the numbers analyzed by disease phase, or how participants without an observed endpoint were handled. A missing-data method is not reported in the registry record.

The registry lists multiple secondary outcomes, including cytogenetic response categories, molecular response measured using GUS or ABL, hematologic response categories, response among participants with extramedullary disease at baseline, reduction in T315I-mutated BCR-ABL, and cycles to best response. The multiplicity strategy for evaluating these outcomes is not reported in the registry record. No adjustment method, testing hierarchy, or distinction between confirmatory and exploratory secondary analyses is described.

General statistical explanation: when many outcomes are examined, the chance of a seemingly notable result can rise unless the analysis plan addresses multiplicity. That concern does not establish that a reported result is false; it affects how evidence across several tests should be interpreted. Because the registry does not give outcome estimates or a multiplicity plan, the strength of evidence across the secondary outcomes cannot be assessed.

The record does not report whether interim efficacy analyses were planned or conducted, or whether any stopping rules were used. It also does not report a statistical analysis plan beyond the described primary endpoint criterion. These omissions prevent a fuller assessment of prespecification, missingness, and the relationship among the endpoint analyses.

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: febrile neutropenia (11.7%), thrombocytopenia (11.7%), disease progression (11.7%), bone marrow failure (7.8%), pancytopenia (5.8%).

The registry lists 103 participants at risk for the adverse-event summaries. It records 67 participants with serious adverse events and 100 with other adverse events. These counts describe the omacetaxine group; they are not comparative estimates because the study has no concurrent control group. The registry record does not report the number of deaths.

Selected serious adverse event terms are listed with percentages: febrile neutropenia, 11.7%; thrombocytopenia, 11.7%; disease progression, 11.7%; bone marrow failure, 7.8%; pancytopenia, 5.8%; and anaemia, 4.9%. These percentages are presented as registry safety figures. They should not be added together: participants may have experienced more than one event, and the registry does not report whether the listed terms overlap at the participant level.

General statistical explanation: adverse-event counts and percentages summarize what was recorded during a study, but they do not by themselves establish that treatment caused an event. In a single-group study, there is no randomized comparison for estimating an excess risk relative to another treatment. The registry record does not report event timing, exposure-adjusted rates, or details that would support a more extensive comparison of safety patterns.

The registry lists these figures but does not provide further detail about the definitions or adjudication of the serious event terms. They therefore offer a descriptive account, not a complete causal or comparative safety assessment.

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

The record establishes that a phase II, open-label, single-group study evaluated subcutaneous omacetaxine in people with CML and the T315I BCR-ABL mutation after prior imatinib failure. It specifies a phase-based hematologic response endpoint, a timeframe from Day 1 up to 6 months, an intent-to-treat analysis population, and a benchmark-based decision rule. It also lists selected adverse-event counts and percentages.

The record does not report the primary response counts, response percentages, or confidence intervals. Therefore, it does not show whether the registered response criterion was met, how response rates differed across disease phases, or how precisely any response rate was estimated. The secondary outcome estimates are also not reported in the registry record. The endpoint definitions alone are not evidence that participants achieved those outcomes.

The single-group design does not provide a randomized comparison with another treatment. An outcome observed during the study cannot, from this design alone, be interpreted as a comparative treatment effect. The open-label structure and the absence of detailed information about missing endpoint data and adjudication procedures also limit what can be inferred from the registry record.

The safety figures describe recorded events in the study group, including the listed serious event terms. They do not establish causation or permit a comparative risk assessment. The number of deaths is not reported in the registry record.

General statistical explanation: results should be interpreted in light of both the estimated effect and its precision, as well as design features that affect bias and comparison. Here, the outcome estimates needed to assess effect size and precision are not reported. The appropriate statistical conclusion is therefore limited: the registered question and methods are identifiable, but the primary efficacy result and its uncertainty cannot be judged from this record.

14. Why This Trial Matters Statistically

This trial is statistically notable for combining a phase-specific clinical response definition with a single-group benchmark analysis. The response categories depend on whether participants entered in chronic phase or in accelerated or blast phase, and a response had to last at least 8 weeks. Those choices define what the primary binary endpoint represents and what counts as a response in each subpopulation.

The planned primary criterion is based on a one-sided lower 95% exact binomial confidence limit relative to 2.5%. This places emphasis not only on the estimated response rate but also on whether its lower confidence bound clears the registered minimum threshold. It illustrates how a benchmark-based decision rule can be framed around uncertainty rather than the point estimate alone.

At the same time, the design is open-label and single-group, with no concurrent control. The benchmark analysis is not a randomized comparison, so it answers a different question from a controlled treatment contrast. That distinction is important when interpreting any response estimate, even if the estimate and confidence limit are available.

The registry record also demonstrates why endpoint definitions and outcome results must be considered separately. It describes primary and secondary outcome topics, but does not report the primary response estimates or their confidence intervals. Without those figures, the statistical criterion cannot be evaluated and precision cannot be assessed. The record supports discussion of the trial’s estimand and planned inference, not a conclusion about the observed response.

Finally, the record includes selected adverse-event figures but does not report a concurrent safety comparator, deaths, or a full account of event timing and analysis. This makes the safety information descriptive. Distinguishing descriptive event summaries, benchmark comparisons, and randomized contrasts is central to reading the statistical evidence 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 most direct limitation of the registry record for statistical interpretation is that it does not report the primary response counts, percentages, or confidence intervals. Without these, the stated decision rule relative to 2.5% cannot be assessed. The phase-specific denominators and results are also not reported, so the precision of estimates across chronic, accelerated, and blast phase cannot be compared.

The study is recorded as open-label and single-group, with no concurrent randomized control. This limits estimation of a comparative treatment effect and leaves the benchmark analysis dependent on the appropriateness of the fixed threshold. The registry record does not report the basis for selecting that threshold.

The registry names the intent-to-treat population but does not report the number of participants contributing endpoint data, the handling of missing outcomes, or sensitivity analyses. It states that primary endpoints adjudicated by the Data Monitoring Committee were used, but details of adjudication are not reported. Multiplicity methods, interim analyses, and a fuller statistical analysis plan are also not reported in the registry record.

The intervention description is incomplete: induction dosing is described, but the maintenance regimen details are not reported in the registry record. Selected adverse-event counts and percentages are available, but the number of deaths is not reported, and event timing and comparative safety estimates are not available in the record. These limitations constrain interpretation of both efficacy and safety from the registered information.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Homoharringtonine (Omacetaxine Mepesuccinate) in Treating Patients With Chronic Myeloid Leukemia (CML) With the T315I BCR-ABL Gene Mutation — NCT00375219.
• Registry record last updated 2021-11-15; status last verified 2021-11.
• Results first posted 2014-06-03.
• 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

NCT00375219 is a completed phase II, open-label, single-group study of subcutaneous omacetaxine mepesuccinate in CML with the T315I BCR-ABL mutation after prior imatinib failure. The registry lists enrollment as 103. Participants were described as being in chronic, accelerated, or blast phase. The recorded start date is 2006-09-20, and the primary completion date is 2010-03-23.

The primary endpoint was the percentage achieving overall hematologic response from Day 1 up to 6 months, analyzed by disease phase and for the total population. Response definitions were phase-specific, with a response required to last at least 8 weeks. The stated analysis used a one-sided lower 95% exact binomial confidence limit against a 2.5% benchmark.

Primary response estimates, confidence intervals, missing-data methods, and multiplicity procedures are not reported in the registry record. Safety listings include 67 participants with serious adverse events and 100 with other adverse events; the number of deaths is not reported.