Phase I/II Study of Pentostatin Combined With Tacrolimus and Mini-Methotrexate for GVHD Prevention After MUD BMT: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase I/II Study of Pentostatin Combined With Tacrolimus and Mini-Methotrexate for GVHD Prevention After MUD BMT (NCT00506922), a non-randomized phase 1, phase 2 study. The primary outcome is Number of Patients Without GVHD at 100 Days.

2. Clinical Question

3. Trial Design

This was a Phase I/II study with nonrandomized allocation and no masking. The registry lists a single-group model and enrollment of 150. It describes five groups: no pentostatin and pentostatin at 0.5 mg/m^2, 1 mg/m^2, 1.5 mg/m^2, or 2 mg/m^2. Tacrolimus and methotrexate are named as the accompanying drugs in the study title and summary. The primary objective was to assess efficacy across escalating pentostatin doses for acute graft-versus-host disease prevention in the transplant settings described in the record.

The stated secondary objectives were to assess safety, reduce acute graft-versus-host disease after unrelated-donor transplantation to 40%, and document tacrolimus blood levels when combined with pentostatin. These are objectives, not reported findings. The record does not report whether the stated target was met or provide tacrolimus level results.

The study status is completed. The registry lists a start date of 2000-09 and primary completion of 2009-11. M.D. Anderson Cancer Center is named as sponsor. Because allocation was nonrandomized, differences among the dose groups may reflect more than pentostatin dose; the registry does not establish that the groups were comparable at baseline. The record does not report the method used to assign participants to groups, group-specific enrollment plans, or the rationale for the dose sequence.

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 150 patients were enrolled, and 147 were available for analysis. Two patients assigned to the 1.5 mg/m\^2 arm were removed without receiving treatment (due to ineligibility, and poor donor cell collection). A patient assigned to arm 2.0 mg/m\^2 withdrew consent before being treated.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All analysis was intention to treat (ITT).

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 Without GVHD at 100 Days, measured over 100 days.

The primary endpoint is the number of participants without graft-versus-host disease at 100 days. Its description defines success more fully: a participant must be alive, engrafted, and without acute graft-versus-host disease at that time. In other words, the stated success definition requires all of those conditions, rather than absence of graft-versus-host disease alone. The registry says the analysis population was intention to treat.

This endpoint is relevant to the study objective because it captures an early post-transplant status that combines freedom from acute graft-versus-host disease with being alive and engrafted. In general, a binary endpoint classifies each participant according to whether the defined outcome occurred; it can be summarized as a count and proportion, although no primary endpoint count or proportion is reported in the registry record. The endpoint title is shorter than its description, so interpretation should follow the stated success definition rather than treating “without GVHD” as the only condition.

The timeframe is 100 days. The registry record does not provide a definition of engraftment, a grading system or diagnostic criteria for acute graft-versus-host disease, or details about how participants with incomplete follow-up were classified. Those omissions limit assessment of how consistently the endpoint could be applied.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the study structure imply?

The record describes a Phase I/II study, nonrandomized allocation, no masking, and a single-group model. It also lists five pentostatin dose groups, including a group without pentostatin. These descriptors should be read together: the listed groups allow the study to describe experience at different doses, but nonrandomized allocation does not make them equivalent to randomized arms. In general, random allocation helps balance measured and unmeasured participant characteristics across groups. Without it, a difference between groups cannot automatically be attributed to the intervention or dose. The record does not explain how participants entered each group or report a method to account for possible group differences.

The study summary states that pentostatin doses were being escalated in combination with tacrolimus and methotrexate. General dose-escalation studies examine experience across dose levels, often with safety among their concerns. The registry’s objectives include safety and efficacy, but the specific escalation rules, stopping criteria, and decision process are not reported in the registry record. They should not be inferred from the dose-group labels.

How should the primary endpoint be understood?

The endpoint is binary in kind: each participant either meets the stated success definition at 100 days or does not. The definition requires the participant to be alive, engrafted, and without acute graft-versus-host disease. A composite definition can capture several clinically relevant conditions in one endpoint, but it also means that a participant may fail the composite for more than one possible reason. The registry does not report counts for each component, so the contribution of each condition to the endpoint cannot be separated.

General statistical summaries for binary outcomes include the number meeting the definition and the number assessed, often accompanied by a proportion and uncertainty interval. No such primary outcome result is posted in the registry record. The record identifies intention-to-treat as the analysis population, but does not give endpoint counts or explain how missing 100-day status would be handled. Consequently, the population label alone does not reveal how incomplete outcome information was treated.

What can the group counts establish?

For a nonrandomized study, a raw count within a group is descriptive. It does not by itself show that a dose caused an outcome, nor does it establish that outcomes differ across doses. A comparative analysis would need to address the study’s allocation structure and relevant participant differences; the registry record lists no analyses and reports no adjusted or unadjusted efficacy estimates. It also does not report a statistical model, hypothesis test, confidence interval, or approach to dose-response analysis.

General statistical inference distinguishes an observed estimate from its uncertainty. A confidence interval describes a range of values compatible with the data under the method’s assumptions; it is not a guarantee that the true value lies in that range. No confidence interval is reported for the primary endpoint. A p-value, if one were reported, would address compatibility with a specified null model, not the size or clinical importance of an effect. The registry record does not report a p-value or the test that would have been used.

In general, binary outcomes can be affected by differences in follow-up and by how outcome status is defined or ascertained. The record states the 100-day timeframe and the endpoint conditions, but does not describe assessment schedules, disease grading, adjudication, or handling of loss to follow-up. Those details matter to reproducibility and to judging whether outcome classification could differ across groups.

What does the safety information mean statistically?

Safety counts are descriptive unless their definitions, observation periods, denominators, and comparison methods are clear. The record lists serious-event counts and participants at risk by group, but does not provide serious-event terms. It also lists counts for another adverse-event category without naming its events. General comparisons of safety counts require caution when groups are not randomized and when the time at risk or event-collection methods are not described. The registry record does not provide those methods or a statistical comparison of safety outcomes.

Finally, planning calculations and observed results answer different questions. A planning illustration based on an observed effect is not an observed-power calculation and is not the trial’s original design justification. The registry record does not report the original sample-size justification or a statistical analysis plan. In particular, it does not identify prespecified models, interim analyses, multiplicity procedures, or decision thresholds. These absences mean the posted record cannot establish which analyses were planned or whether the reported objectives were evaluated using a particular inferential framework.

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("Pentostatin")
n      <- c(147)
events <- c(100)
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  Pentostatin  147  100  68.0  59.8  75.5  60.1  75.0  60.1  75.0

11. Multiplicity, Missing Data and Analysis Populations

The registry identifies one primary outcome measure, the number of participants without graft-versus-host disease at 100 days, and lists zero analyses. It also gives secondary objectives covering safety, a stated reduction target for acute graft-versus-host disease after unrelated-donor transplantation, and tacrolimus blood levels. These objectives raise distinct questions, but the registry record does not report a statistical analysis plan or a procedure for controlling multiplicity across outcomes, doses, or analyses. The absence of a posted procedure does not establish that no such procedure was used; it means it is not reported in the registry record.

The primary endpoint population is described as intention to treat. This identifies the stated analysis population but does not explain the operational details: the record does not say how participants with missing 100-day status, withdrawal, protocol deviations, or incomplete follow-up were handled. It also does not report the numbers assessed for the primary endpoint in each group. Missing-data methods and endpoint denominators are therefore unavailable for evaluating how incomplete information could affect the result.

In general, multiplicity matters when several outcomes or comparisons are assessed, because repeated testing can increase the chance of a chance-positive finding if no adjustment or hierarchy is specified. The record does not provide enough detail to determine how many statistical comparisons were planned or how they would be interpreted. Likewise, the record does not report interim analyses, stopping rules, or the original sample-size justification. Those design and analysis details are not reported in the registry record.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 2% reporting threshold.

Most frequent non-serious adverse event terms

The serious adverse-event entries list an affected count of 0 for each group. The corresponding numbers at risk are 27 for no pentostatin, 10 for pentostatin 0.5, 29 for pentostatin 1, 61 for pentostatin 1.5, and 10 for pentostatin 2. These are the posted counts, not estimates of comparative safety. The registry lists no serious adverse-event terms, so the nature of events considered or collected cannot be examined from this record.

The record also lists another adverse-event category. Its affected counts are 28 for no pentostatin, 9 for pentostatin 0.5, 17 for pentostatin 1, 40 for pentostatin 1.5, and 7 for pentostatin 2; the corresponding numbers at risk are 37, 10, 29, 61, and 10. The category’s event terms are not reported in the registry record, so these figures cannot be interpreted as counts for a particular symptom or diagnosis.

Deaths are not reported in the registry record. Zero posted serious-event counts should not be read as evidence that no adverse experiences occurred: the other category has affected participants, and the record does not supply event definitions, observation periods, or collection methods. Because the groups were nonrandomized, these counts also do not establish that one dose had a safer profile than another.

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

This registry record documents a study of pentostatin with tacrolimus and methotrexate in a transplantation setting, with several pentostatin dose groups and a no-pentostatin group. It specifies a primary success definition at 100 days: alive, engrafted, and without acute graft-versus-host disease. It also records the study’s safety and tacrolimus-level objectives. These details show what the study was designed to address, but do not establish what outcomes were observed.

The primary efficacy result is not reported in the registry record. There is no posted count of participants meeting the endpoint, no endpoint estimate by group, and no reported analysis comparing doses. It is therefore not possible from this record to quantify the primary outcome, assess its precision, or determine whether the stated efficacy objective was met. The enrollment figure does not supply those missing outcome results.

The nonrandomized allocation is important to interpretation. The dose groups should not be treated as exchangeable comparison groups: differences between them, if available from another source, could reflect differences other than pentostatin dose. The registry record does not report baseline characteristics or an adjustment strategy that would resolve that concern.

The serious adverse-event counts are posted as zero in each group, but event terms are absent, deaths are not reported, and the other adverse-event category is not named. These entries therefore describe only the limited safety information in the registry. They do not provide a complete account of all possible harms or a comparative safety analysis. The record supports a description of the trial’s aims, design labels, endpoint definition, and posted adverse-event counts; it does not support a conclusion about efficacy or an overall treatment benefit.

14. Why This Trial Matters Statistically

This study illustrates why a registry’s endpoint definition and its outcome results need to be distinguished. The primary endpoint is not merely absence of acute graft-versus-host disease: success also requires being alive and engrafted at 100 days. That definition clarifies the intended interpretation, while the lack of a posted outcome count prevents assessment of how many participants met it.

It also highlights the limits of interpreting dose groups in nonrandomized research. A list of escalating doses can describe how a study was organized, but it does not make the groups a fair causal comparison. Randomization is one way to reduce systematic differences between groups; the registry explicitly identifies this study as nonrandomized and cautions that its arms are not a like-for-like control comparison. Statistical methods cannot automatically remove unknown differences when allocation and relevant covariates are not described.

Finally, the record separates study objectives from evidence of their achievement. It names efficacy, safety, and tacrolimus blood levels as questions of interest, but provides no primary analyses or tacrolimus level results. Safety entries are also limited by missing event terms and unreported death counts. For statistical readers, the central lesson is to identify what is actually measured and reported, then distinguish descriptive counts from comparative inference. A completed study record can document objectives and design without furnishing enough outcome information to judge the size or precision of an effect.

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 for interpretation is that the registry record does not report primary efficacy results, despite naming the endpoint and stating the analysis population. It lists zero analyses and provides no group-specific endpoint counts, estimates, confidence intervals, or tests. As a result, efficacy and precision cannot be assessed from this record.

The design is nonrandomized, and the registry warns that the groups are not a like-for-like control comparison. The record does not report how participants were assigned to dose groups, describe baseline characteristics, or identify an adjustment method. Even if group outcome counts were available, causal interpretation would remain limited without information about potential differences between groups.

Endpoint implementation is also incompletely described. The definition requires being alive, engrafted, and without acute graft-versus-host disease at 100 days, but definitions of engraftment and acute disease, assessment procedures, and handling of missing status are not reported in the registry record. The record does not provide component-specific outcomes, so the reason for endpoint failure could not be separated.

Safety interpretation is constrained by the absence of serious-event terms, the unnamed other adverse-event category, and death counts that are not reported in the registry record. The event observation period and collection methods are also not stated. The record does not report a statistical analysis plan, multiplicity procedure, interim analyses, stopping rules, or original sample-size justification. These limitations concern what can be established from the registry entry; they do not establish what information may exist outside it.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Phase I/II Study of Pentostatin Combined With Tacrolimus and Mini-Methotrexate for GVHD Prevention After MUD BMT — NCT00506922.
• Registry record last updated 2015-04-28; status last verified 2012-08.
• Results first posted 2011-03-28.
• 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, nonrandomized study sponsored by M.D. Anderson Cancer Center, with enrollment of 150 and a single-group model. It lists a no-pentostatin group and four pentostatin dose groups, all in a regimen involving tacrolimus and methotrexate. The primary endpoint is the number of participants alive, engrafted, and without acute graft-versus-host disease at 100 days, with intention-to-treat named as the analysis population.

The study’s secondary objectives concern safety, acute graft-versus-host disease after unrelated-donor transplantation, and tacrolimus blood levels. Serious adverse-event affected counts are listed as 0 in each group, but event terms are absent; deaths are not reported in the registry record. The primary efficacy outcome, analyses, and statistical plan are also not reported, so the record does not permit a quantitative assessment of efficacy or precision.