Efficacy and Safety of LBH589 in Adult Patients With Refractory Chronic Myeloid Leukemia (CML) in Chronic Phase: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy and Safety of LBH589 in Adult Patients With Refractory Chronic Myeloid Leukemia (CML) in Chronic Phase (NCT00451035), a na phase 2 study. The primary outcome is Major (Complete/Partial) Cytogenetic Response (MCyR) Rate.

2. Clinical Question

3. Trial Design

This was a phase II, multicentre, single-group study of oral LBH589, also called panobinostat, in adults with chronic-phase chronic myeloid leukemia after resistance following treatment with at least two BCR-ABL tyrosine kinase inhibitors. The registry record lists an enrollment of 29. It records the study start as 2007-02-19 and primary completion as 2008-04-13, and gives the study status as terminated.

The intervention description specifies panobinostat 20 mg orally once a day, three times a week, as part of a 4 week (28 day) treatment cycle. The study was unmasked, and allocation is listed as NA. There is no concurrent control arm in the recorded design. The study therefore describes experience within a treated group rather than a randomized estimate of the difference between treatments.

The primary outcome was the major cytogenetic response rate, comprising complete or partial response, assessed from the percentage of Ph+ metaphases by bone marrow karyotype analysis. The timeframe was from study start to study end, approximately up to 19 Months. The outcome description notes that assessment ideally used a minimum of 20 metaphases in each bone marrow sample. This is an assessment goal in the outcome description, not a reported number of evaluable samples.

Other listed outcomes include hematologic, cytogenetic and molecular response measures, BCR-ABL mutation assessments, progression-free survival, and panobinostat concentration and timing measures. The registry record lists 14 outcome measures but gives no analysis records. It does not report a detailed statistical analysis plan, a sample-size justification, an interim-analysis plan, or the number of participants who received at least one dose. The registry record says the study was terminated due to insufficient clinical efficacy in the targeted 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.

Before assignment: A total of 29 participants were enrolled, of which 29 participants discontinued the study treatment and 17 participants discontinued the study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full Analysis Set (FAS) consisted of all enrolled participants who have received at least one dose of study medication. The outcome measure was not achieved as the study was terminated due to insufficient clinical efficacy in the targeted participants population. Due to insufficient data, this outcome could not be measured.

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: The Full Analysis Set (FAS) consisted of all enrolled participants who have received at least one dose of study medication.

6. Primary Endpoint

The registry lists the primary outcome as Major (Complete/Partial) Cytogenetic Response (MCyR) Rate, measured over From Start of the Study up to End of Study (approximately up to 19 Months).

The primary endpoint was the major cytogenetic response rate, expressed as a count of participants in the outcome description. A major response included either a complete cytogenetic response or a partial cytogenetic response. The classification was based on the percentage of Philadelphia chromosome-positive (Ph+) metaphases in a bone marrow aspirate assessed by karyotype analysis. Complete response was defined as 0% Ph+ metaphases; partial response was defined as 1 to 35% Ph+ metaphases. The outcome description also defines less substantial cytogenetic response categories, but those categories are not part of the primary major-response definition.

Cytogenetic response is used to describe changes in the proportion of sampled marrow cells carrying the Philadelphia chromosome. It provides a laboratory-based response measure for a disease characterized in the record by the BCR-ABL fusion. The outcome description says assessment ideally relied on a minimum of 20 metaphases per sample. In general, response classifications depend on the specimen and the cells that can be evaluated, so the quality and availability of samples matter to interpretation.

The registry record states that the outcome was not achieved because the study was terminated due to insufficient clinical efficacy in the targeted population, and notes insufficient data for the outcome. It does not report how many participants had a major response, the response proportion, or an uncertainty interval. The registry statement should therefore not be interpreted as a reported response count of zero.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a single-group study estimate?

In general, a single-group study follows participants receiving an intervention and describes outcomes in that group. It can report counts, rates, timing, or other measures when those results are available. It does not include a concurrent control group in the recorded design, so it cannot directly estimate how outcomes would have differed under another treatment or under no study treatment. Changes observed in a treated group may have several explanations, and a single-group design cannot separate them in the way a randomized comparison is intended to do.

This study is recorded as single-group, with allocation listed as NA and masking listed as NONE. The registry record does not describe a randomized comparator. The primary outcome record does not give a numerical response result, which means even the descriptive response estimate cannot be examined for magnitude or precision.

What does the response classification mean?

The primary endpoint classifies cytogenetic response using the percentage of Ph+ metaphases in bone marrow, determined by karyotype analysis. Complete response is 0% Ph+ metaphases and partial response is 1 to 35% Ph+ metaphases; together they define a major response. In general, a categorical endpoint converts measurements into groups using specified thresholds. That makes a response count easier to interpret as a clinically recognizable category, while also meaning that measurements near a category boundary can be classified differently from measurements on the other side of that boundary.

The outcome description says assessment ideally used a minimum of 20 metaphases in each bone marrow sample. This is part of the stated measurement approach, not a reported count of samples that met the goal. The registry record does not provide the number of evaluable samples or describe how insufficient or missing samples were handled.

What can a confidence interval add?

In general, a confidence interval expresses the uncertainty around an estimated quantity. A narrow interval indicates greater precision under the statistical method used; a wide interval indicates less precision. An interval does not remove bias from study design or turn an uncontrolled estimate into a randomized comparison. The registry record does not report a primary response estimate or a confidence interval, so the precision of the primary endpoint cannot be evaluated from the record.

How should planning illustrations be read?

General sample-size planning asks how much information may be needed to detect a specified effect under stated assumptions. The planning assumptions recorded for the illustrations include a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. They describe detecting a stated fraction of an observed effect; for time-to-event outcomes, the stated planning quantity is total events, while other outcomes use participants per arm. Such illustrations are planning scenarios, not observations from this study and not observed power.

Those assumptions describe a two-arm planning framework, whereas this trial is recorded as a single-group study. They should not be read as a description of the actual study design or as evidence that participants were assigned equally between arms. The registry record does not report the trial’s own sample-size justification. In addition, the primary response outcome has no reported numerical result, so a reader cannot use the registry record to assess the observed primary effect or its precision.

Why does over-dispersion matter in general?

For count outcomes, a statistical model may assume a particular relationship between the average count and its variability. Over-dispersion means the observed variability is greater than that assumption allows. If a model ignores over-dispersion, its uncertainty estimates can be too small, making results appear more precise than the data warrant. This is a general statistical consideration; the registry record does not report a count model or an over-dispersion assessment for this study.

What is the role of an analysis plan?

In general, a prespecified analysis plan describes how outcomes will be defined, which participants will be included, how missing values will be handled, and how uncertainty and multiple outcomes will be addressed. These choices help readers distinguish planned analyses from decisions made after results are known. The registry record lists outcomes and states that there are no analysis records, but it does not report a detailed statistical analysis plan, interim analyses, or a sample-size justification. Their absence from the registry record does not establish what may have been specified elsewhere; it means those details 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("Panobinostat (LBH589)")
n      <- c(29)
events <- c(0)
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  Panobinostat (LBH589)  29  0  0.0  0.0  11.9  0.0  11.7  0.1  11.6

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 14 outcome measures. These include several related response outcomes—hematologic, cytogenetic and molecular—as well as mutation, progression-free survival, and pharmacokinetic outcomes. When a study evaluates many outcomes, there are multiple opportunities to obtain a notable result by chance. In general, multiplicity methods can control or describe that issue, but the appropriate approach depends on which outcomes were primary, which were secondary, and what claims were intended. The registry record does not report a multiplicity adjustment or a detailed statistical analysis plan.

The primary endpoint description identifies a Full Analysis Set consisting of enrolled participants who received at least one dose of study medication. It does not report the size of that population, the number with evaluable cytogenetic assessments, or how participants with no usable sample were treated in the primary analysis. The record says there was insufficient data for the outcome, but does not give details about the amount or pattern of missing data. Missing measurements can limit both the number of participants contributing to an estimate and the generalizability of that estimate.

The registry record lists no analysis records. It does not describe interim analyses, missing-data methods, or whether any sensitivity analyses were planned or performed. These omissions mean readers cannot determine from the record how the listed outcomes were prioritized, whether formal adjustment for multiple testing was used, or how incomplete endpoint information influenced the reported conclusion. These are gaps in the registry record, not evidence that a particular method was or was not used outside the record.

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: leukocytosis (3.4%), splenic infarction (3.4%), cardiac failure (3.4%), gastrointestinal haemorrhage (3.4%), pyrexia (3.4%).

The posted safety figures list 4 participants affected by serious adverse events among 29 at risk, and 26 participants affected by other adverse events among 29 at risk. The record also lists 3 deaths. These are counts recorded for the panobinostat group; they are not a comparison with an untreated or alternative-treatment group. The registry record does not give details about event timing, duration, severity beyond the serious-event classification, or the circumstances of the deaths.

The listed serious-event terms are leukocytosis, splenic infarction, cardiac failure, gastrointestinal haemorrhage, pyrexia, and electrocardiogram QT prolonged. Each term is shown with a frequency of 3.4%. The record does not establish that every listed term occurred in a different participant, nor does it describe whether participants experienced more than one event. These terms and frequencies should therefore be read as reported safety entries, not as a complete account of individual event histories.

In general, adverse events recorded during a trial do not by themselves establish causation. A single-group design cannot provide a controlled estimate of how event frequencies compare with another treatment or background risk. The registry record does not report an attribution analysis that would determine whether events or deaths were considered related to study medication.

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

The study record documents evaluation of oral panobinostat in adults with chronic-phase chronic myeloid leukemia resistant following treatment with at least two BCR-ABL tyrosine kinase inhibitors. It records enrollment of 29 and describes the intended primary endpoint as major cytogenetic response. It also records termination due to insufficient clinical efficacy in the targeted population. These registry entries describe the study’s setting and its recorded reason for termination; they do not provide a numerical estimate of the primary response rate.

The absence of a primary response count is central to interpretation. The endpoint is marked as not achieved, and the record notes insufficient data for the outcome. This does not mean that the response count was zero. Without an estimate and uncertainty interval, readers cannot assess how large or precise any primary response result might have been. Nor can they make a numerical comparison to another treatment from this single-group study.

The safety entries document serious and other adverse events and deaths among participants in the treated group. They are important descriptions of what the record reports, but they do not show whether panobinostat caused a particular event. There is no concurrent comparison group in the recorded design, and the registry record does not provide detailed attribution or event-level context.

Accordingly, the record does not establish a comparative treatment effect, a causal explanation for adverse events, or a population-wide estimate of response. It does establish that the study was terminated and that the primary endpoint lacks a reported numerical result in the registry record. These limits matter when interpreting any planning illustration or any broad claim about efficacy or safety: planning scenarios are not trial outcomes, and recorded event counts are not causal comparisons.

14. Why This Trial Matters Statistically

This trial is statistically informative in part because it highlights the distinction between a stated endpoint and a reported endpoint result. The protocol-defined primary question concerned major cytogenetic response, but the registry record does not give a response count or rate. It records that the outcome was not achieved and that there was insufficient data for the outcome. Readers therefore need to distinguish the registry’s termination statement from a quantitative estimate of response.

The single-group design also clarifies the boundary between descriptive evidence and comparative evidence. Outcomes observed among participants receiving panobinostat could be described, but no randomized control group is recorded to support a like-for-like contrast. This design limitation applies to safety interpretation as well: adverse-event counts describe the treated group, but do not identify the excess risk attributable to treatment.

The study also illustrates why analysis-population definitions and missing outcome information are consequential. The primary outcome description defines the Full Analysis Set by receipt of at least one dose, but the number in that set and the extent of endpoint data are not reported. When an endpoint is unavailable or incompletely measured, readers cannot evaluate its precision or determine how missing information affected the conclusion.

Finally, the registry record lists numerous outcome measures but no analysis records. Without a detailed analysis plan, readers cannot assess how outcome priority, multiplicity, or missing data were handled. These are not merely reporting details: they shape what can reasonably be inferred from a clinical trial 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 primary limitation is the absence of a numerical result for the major cytogenetic response endpoint. The registry record marks the outcome as not achieved and cites insufficient data, but does not report a response count, rate, or confidence interval. As a result, the magnitude and precision of the primary outcome cannot be assessed from the registry record.

The study was single-group, unmasked, and had no recorded comparator. This limits causal interpretation and prevents a randomized, like-for-like comparison. The record also gives an enrollment of 29, but does not report how many enrolled participants received at least one dose or how many contributed evaluable primary endpoint data. The Full Analysis Set is defined in the endpoint description, but its size is not reported.

The record gives limited detail about missing data, sample evaluability, and the handling of participants without an assessment. It states that the study was terminated due to insufficient clinical efficacy in the targeted population, but does not report a detailed statistical plan, an interim-analysis plan, or a sample-size justification. It lists 14 outcome measures without analysis records, leaving the approach to multiplicity and outcome prioritization unreported.

Safety interpretation is also constrained. Counts of serious adverse events, other adverse events, and deaths are listed, but there is no control group, detailed timing, or event-level context in the record. The listed serious-event frequencies should not be interpreted as causal estimates. These limitations describe what is not reported in the registry record; they do not establish what information may have been collected elsewhere.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Efficacy and Safety of LBH589 in Adult Patients With Refractory Chronic Myeloid Leukemia (CML) in Chronic Phase — NCT00451035.
• Registry record last updated 2021-07-15; status last verified 2021-07.
• Results first posted 2021-07-14.
• 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

The registry record describes a phase II, multicentre, single-group study of oral panobinostat (LBH589) in adults with chronic-phase chronic myeloid leukemia resistant after treatment with at least two BCR-ABL tyrosine kinase inhibitors. Enrollment was 29. The recorded study start was 2007-02-19, primary completion was 2008-04-13, and status was terminated.

The primary endpoint was major cytogenetic response, defined as complete or partial response by bone marrow karyotype assessment. The record says the outcome was not achieved because the study was terminated due to insufficient clinical efficacy in the targeted population and notes insufficient data. It does not report a response count or rate. Safety entries list 4 participants with serious adverse events, 26 with other adverse events, and 3 deaths among the panobinostat group.

The design has no recorded comparator, and the registry record does not report a detailed statistical analysis plan, sample-size justification, or missing-data methods. The posted results are therefore limited for estimating response, precision, comparative effects, and causal safety risks.