Clofarabine and Cytarabine in Treating Older Patients With AML or High-Risk MDS: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Clofarabine and Cytarabine in Treating Older Patients With AML or High-Risk MDS (NCT00839982), a na phase 1, phase 2 study. The primary outcome is Number of Patients With Dose Limiting Toxicity.

2. Clinical Question

The registry describes a phase I/II study in previously treated AML and high-risk MDS, conditions for which the study was intended to examine a combination regimen and its tolerability. Its primary endpoint is a participant count, not a comparison of event rates between treatment groups. The dose-limiting toxicity definition emphasizes specified serious non-hematologic toxicity that is at least possibly related to study drug, with listed exceptions, as well as prolonged grade 2 myelosuppression under stated circumstances.

The treatment description includes alternative schedules for cytarabine. The registry record does not report enough detail to determine how participants were assigned among dose levels or schedules. Nor does the available endpoint information give the observed number meeting the dose-limiting toxicity definition. Thus, the clinical question can be described from the study aims and endpoint, but the posted information does not establish a numerical answer about the primary endpoint or a comparative treatment effect.

3. Trial Design

This was a completed phase I/II study sponsored by Fred Hutchinson Cancer Center. The registry lists enrollment as 35, a single-group model, allocation as NA, and masking as none. The study began in 2008-11, reached primary completion in 2012-12, and has completed status. The trial title and official title describe treatment of older patients with AML or high-risk MDS, including previously treated disease.

Participants in the treatment group received clofarabine by mouth once daily on days 1-5, together with low-dose cytarabine given under one of two described schedules: by subcutaneous injection twice daily on days 1-10 or by subcutaneous injection daily on days 1-14. Treatment was to repeat every 21-28 days for up to 4 courses, unless disease progression or unacceptable toxicity occurred. The registry description does not explain the selection or allocation of the alternative schedules or dose levels.

A single-group design can describe outcomes observed among people receiving the regimen, but it does not provide a concurrent control group for estimating what would have happened under another treatment or under no study treatment. The absence of masking is also relevant when interpreting outcomes that require clinical judgment, although the registry does not describe the assessment procedures in detail. The record does not report a randomization procedure, an allocation method, or further masking details.

The primary endpoint is the number of patients with dose-limiting toxicity by day 30. Treatment response, disease-free survival, and overall survival are listed as secondary outcomes. The registry lists five outcome measures and one analysis, but the available information does not provide the methods or results for every listed measure. The sample-size justification and detailed statistical plan 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.

Overall Study

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.

6. Primary Endpoint

The registry lists the primary outcome as Number of Patients With Dose Limiting Toxicity, measured over Outcomes by day 30.

The primary endpoint counts participants with dose-limiting toxicity by day 30. The registry defines this toxicity as grade 3-4 non-hematologic toxicity at least possibly related to study drug, subject to specified exceptions. The exceptions include neutropenic fever, drug-related fever, alopecia, anorexia, inadequately treated nausea, vomiting and/or diarrhea, and grade 3/4 increases in ALT, AST, or bilirubin that recover to < grade 2 by 7 days. Prolonged grade 2 myelosuppression lasting longer than 49 days is also considered a dose-limiting toxicity for patients who do not proceed to additional cytotoxic therapy.

This type of endpoint is used in early-phase dose evaluation because it captures prespecified toxicities during a defined observation period. The registry states that the maximum tolerated dose or recommended phase II dose is the highest dose level at which no more than 1 patient out of 6 experiences dose-limiting toxicity. That rule describes the dose-selection criterion; it is not itself a report of the observed toxicity count or selected dose.

The endpoint is a participant count, so its meaning depends on the definition, observation window, and population assessed. The posted information does not give the primary endpoint result, the dose levels evaluated, or the number of participants assessed at each level. Those details are needed to understand how the criterion was applied in practice. The number with dose-limiting toxicity is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The main statistical feature is the single-group design. In a controlled comparison, treatment groups can be contrasted to estimate differences in outcomes, subject to the study design and analysis. In this trial, the registry lists a single treatment group and no comparator. The data can therefore describe what was recorded among participants receiving the regimen, but do not furnish a concurrent estimate of outcomes under an alternative strategy. This distinction is central: a group’s event count is descriptive, whereas a treatment effect requires a meaningful comparison.

What does a participant count convey?

The primary endpoint is a count of participants who meet the dose-limiting toxicity definition by day 30. A count is directly interpretable as the number meeting that definition in the assessed population, but its context depends on how many people were evaluated and whether follow-up was complete. The registry lists enrollment as 35, but enrollment is not necessarily the same as the number analyzed for a particular endpoint. The analysis population and the primary endpoint result are not reported in the registry record, so no event proportion or uncertainty interval can be stated from the available information.

The endpoint definition also determines which events qualify. The record specifies grade 3-4 non-hematologic toxicity at least possibly related to study drug, with named exceptions, and includes prolonged grade 2 myelosuppression under a stated condition. These rules promote consistent classification, but application still depends on collection and adjudication procedures. Those procedures are not reported in the registry record. The stated dose-selection criterion is a rule for interpreting dose-level experience; it does not reveal how many people at any dose level had qualifying toxicity.

Why does the single-group design matter?

Without a concurrent comparator, the treatment-group observations cannot establish whether an event was more or less common than it would have been under another treatment. This limitation remains even if an event count is precisely recorded. Differences in disease status, previous treatment, patient characteristics, follow-up, and event ascertainment can all matter when comparing separate groups. The registry does not report a comparative group or an adjustment strategy. Accordingly, statements should describe observed events and avoid attributing them to treatment or claiming a comparative effect.

The registry records masking as none. In general, masking can reduce the influence of treatment knowledge on some assessments or decisions. Its relevance depends on the outcome and assessment process. A count based on explicitly defined criteria may still require clinical evaluation, but the registry does not describe who assessed events or whether any review process was used. The fact that masking was absent does not, by itself, establish that assessments were biased; it identifies a design feature to consider.

What can the adverse-event entries establish?

The safety record distinguishes serious events from other adverse events and reports participants at risk and affected. Seriousness is a classification based on the event’s consequences, not a synonym for high intensity. The posted entries report 24 participants affected by serious adverse events, 0 affected by other adverse events, and 5 deaths. These categories should be kept distinct rather than combined into an overall rate. The listed serious-event terms and percentages add descriptive detail, but do not identify treatment causality or provide a comparison against another group.

Percentages attached to event terms should be interpreted in the context of the registry’s event-reporting conventions. The record does not supply enough detail to reconstruct the derivation of every percentage or determine whether terms represent people, events, or overlapping categories. A participant may have more than one event, so event-term percentages should not be added to create a total. No such total is needed to interpret the listed values individually.

How should uncertainty and planning calculations be understood?

In general, a confidence interval expresses the range of values compatible with data under a specified statistical model and procedure. It conveys uncertainty around an estimate; it does not prove that the true value lies within a particular displayed interval, nor does it turn a descriptive single-group result into a causal comparison. No primary endpoint estimate or interval is reported in the registry record.

The record’s sample-size assumptions describe planning illustrations based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and effects set as stated fractions of the observed effect. Such illustrations are hypothetical design calculations, not the trial’s own design or observed power. The trial itself is single-group, so the assumed equal allocation between two arms is not a description of its allocation. The calculated illustration values and the observed effect are not reported in the registry record, and no new calculation can be inferred from the assumptions alone.

In general, over-dispersion matters when observed variability exceeds what a model assumes; ignoring it can make uncertainty estimates too narrow. This is a general statistical consideration rather than a reported feature of this study. The registry’s primary endpoint is a participant count, and no dispersion parameter is reported. No model specification, interval method, hypothesis test, or detailed analysis plan is reported in the registry record. The count of one analysis does not by itself identify which outcomes, populations, or methods were included.

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("Dose Level 1", "Dose Level 2", "Dose Level 3", "Dose Level 4")
n      <- c(4, 26, 2, 3)
events <- c(0, 4, 2, 2)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Dose Level 1  4  0  0.0  0.0  60.2  0.0  49.0  0.5  52.2
ARM  Dose Level 2  26  4  15.4  4.4  34.9  6.2  33.5  6.3  33.7
ARM  Dose Level 3  2  2  100.0  15.8  100.0  34.2  100.0  29.2  99.2
ARM  Dose Level 4  3  2  66.7  9.4  99.2  20.8  93.9  19.4  93.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists five outcome measures and one analysis. These counts do not reveal which outcomes were analyzed together, which analysis corresponds to the primary endpoint, or whether any secondary outcomes were included in the same statistical procedure. The record does not report a multiplicity adjustment or a prespecified hierarchy for interpreting several outcomes. In general, testing multiple outcomes can increase the chance of a chance-positive finding if results are treated as confirmatory without accounting for the number of tests. That is a general concern, not evidence that a particular error occurred in this study.

The sample-size assumptions describe planning illustrations with a two-sided significance level of 0.05 and equal allocation between two arms. They do not describe the single-group trial’s design, nor do they establish the study’s own sample-size justification. That justification, any interim analyses, and the detailed statistical plan are not reported in the registry record. The number of analyses alone cannot establish whether interim looks occurred or whether the stated significance level governed the trial analysis.

Information about missing outcomes is also absent. The record does not report how many participants were assessed for the primary endpoint, whether anyone was lost to follow-up, how incomplete observations were handled, or which analysis population was used. In general, missingness can affect estimates when the chance that data are unavailable is related to outcomes or participant characteristics. Without the missing-data pattern and analysis approach, the direction or magnitude of any effect cannot be assessed. These omissions limit interpretation; they do not show that data were missing or mishandled.

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 0% reporting threshold.

Most frequent serious adverse event terms

Serious events with the highest arm-level rate: infections (68.6%), bacteraemia (28.6%), febrile neutropenia (22.9%), bacterial infection other than blood (20.0%), septic shock (14.3%).

The registry reports a treatment-group risk count of 35 for serious adverse events and 35 for other adverse events. It records 24 participants affected by serious adverse events, 0 affected by other adverse events, and 5 deaths. These are registry-reported counts. The record does not state that the serious events or deaths were caused by the study drugs, so they should not be read as causal findings.

The listed serious-event terms are Infections at 68.6%, Bacteraemia at 28.6%, Febrile neutropenia at 22.9%, Bacterial infection other than blood at 20.0%, Septic Shock at 14.3%, and Arrhythmia at 8.6%. The percentages are quoted as recorded. Event terms can overlap because a participant may experience more than one type of event; adding the percentages would not yield a meaningful overall figure. The registry record does not provide enough detail to reconstruct the term-level counting conventions.

Seriousness should not be confused with severity. Seriousness classifies events by consequences, while severity indicates intensity. The posted safety entries are descriptive and do not compare risks with another treatment group. They also do not replace the primary endpoint’s specific dose-limiting toxicity definition, which has its own criteria and observation window.

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

The registry record describes a phase I/II study of clofarabine with low-dose cytarabine in previously treated older patients with AML or high-risk MDS. Its primary endpoint is the number of participants with dose-limiting toxicity by day 30, and the registry supplies a definition and dose-selection criterion. This establishes what the study intended to measure, but the primary endpoint count and selected dose are not reported in the registry record.

The safety entries provide descriptive information: 24 participants are recorded as affected by serious adverse events, 0 by other adverse events, and 5 deaths. Several serious-event terms and percentages are also listed. These entries do not show that the drugs caused the events, and without a comparator they do not show whether event occurrence was higher or lower than under another regimen. The numbers should therefore be read as registry-reported observations rather than as a treatment effect.

The record lists treatment response, disease-free survival, and overall survival as secondary outcomes, but their results and analysis details are not reported in the registry record. No conclusion about those outcomes follows from their inclusion in the study record. Nor can enrollment alone establish the number assessed for each outcome or the precision of any estimate.

In general, an early-phase study can contribute descriptive safety and dose-selection information, while claims about comparative effectiveness require evidence suited to that question. This study’s single-group design is not a like-for-like comparison against a control group. The posted information therefore does not establish that the regimen works or does not work, and it does not support medical advice. Its interpretable contribution is bounded by the endpoint definitions and the event information actually recorded.

14. Why This Trial Matters Statistically

This study raises several important statistical interpretation issues in a compact setting. First, its primary endpoint is tied to dose evaluation rather than a direct comparison of treatment outcomes. The registry specifies what counts as dose-limiting toxicity and gives a criterion for selecting a maximum tolerated or recommended phase II dose. That makes the endpoint definition central: changing which events qualify or the period assessed could change the count used for dose decisions.

Second, a single-group design separates descriptive reporting from comparative inference. Counts in the treatment group can document what was recorded, but they do not supply a control experience. This distinction is especially important when a registry also lists clinical outcomes such as treatment response and survival. Outcome names alone do not provide results, and results from a single group cannot by themselves establish what would have occurred under another strategy.

Third, the registry’s safety information illustrates why event categories must be kept distinct. Serious adverse events, other adverse events, the dose-limiting toxicity endpoint, and deaths are not interchangeable measures. Their definitions and reporting rules differ. Reading the figures without those distinctions can create an impression of a single, unified safety measure that the record does not support.

Finally, the listed planning assumptions are not a description of this trial’s single-group design. Planning illustrations can help explore how a future controlled study might be sized under assumptions, but they are not observed power and do not resolve missing outcome details. The sample-size justification, detailed analysis plan, and primary endpoint result are not reported in the registry record. Recognizing these boundaries is essential to keep descriptive evidence, design assumptions, and causal conclusions separate.

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 interpretation is the absence of a comparator group. The registry describes a single-group study, so outcomes cannot be contrasted with a concurrent control experience. Allocation is listed as NA and masking as none. The record does not provide randomization or allocation procedures, and the single-group model offers no basis for attributing observed events or outcomes to the regimen rather than other influences.

The primary endpoint result is not reported in the registry record. The record also does not identify the dose levels evaluated, the number assessed at each level, or the dose selected under the stated criterion. Although the registry lists enrollment as 35, it does not establish how many participants contributed data to each endpoint. Response and survival outcomes are named but their results are not reported.

The treatment description includes alternative cytarabine schedules, but the registry record does not explain how those schedules or dose levels were selected for participants. This leaves uncertainty about the treatment exposure represented by the group as a whole. The record also does not report detailed event ascertainment procedures, analysis populations, missing-data handling, confidence intervals, or the statistical methods used for the listed analysis.

The serious adverse-event counts and term percentages are descriptive, with no comparator for assessing relative risk. The record does not provide enough detail to establish causality or reconstruct every term-level reporting convention. The sample-size assumptions describe illustrations for a two-arm design rather than the study’s single-group structure; the study’s own sample-size justification is not reported in the registry record. These limitations restrict the strength and scope of conclusions that can be drawn from the posted information.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Clofarabine and Cytarabine in Treating Older Patients With AML or High-Risk MDS — NCT00839982.
• Registry record last updated 2017-07-11; status last verified 2017-07.
• Results first posted 2017-07-11.
• 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 describes a completed phase I/II, single-group study sponsored by Fred Hutchinson Cancer Center, with enrollment listed as 35. It began in 2008-11 and reached primary completion in 2012-12. The study examined clofarabine with low-dose cytarabine in previously treated older patients with AML or high-risk MDS.

The primary endpoint was the number of patients with dose-limiting toxicity by day 30. The registry defines the toxicity criteria and gives a dose-selection rule, but the primary endpoint result and selected dose are not reported in the registry record. Treatment response, disease-free survival, and overall survival are listed as secondary outcomes; their results are also not reported.

The safety record lists 24 participants affected by serious adverse events, 0 affected by other adverse events, and 5 deaths. These are descriptive entries and do not establish causality or a comparative treatment effect. With no comparator group and limited reporting of analysis details, the registry supports only a bounded interpretation of the study’s design and posted safety information.