Vorinostat, Azacitidine, and Gemtuzumab Ozogamicin for Older Patients With Relapsed or Refractory AML: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Vorinostat, Azacitidine, and Gemtuzumab Ozogamicin for Older Patients With Relapsed or Refractory AML (NCT00895934), a non-randomized phase 1, phase 2 study. The primary outcome is Number of Participants With Dose-limiting Toxicity (Phase I).

2. Clinical Question

This study asked whether vorinostat and azacitidine could be combined with gemtuzumab ozogamicin in patients 50 years of age and older with relapsed or refractory non-APL acute myeloid leukemia (AML), using varying schedules and dose levels in Phase 1 and a selected-dose regimen in Phase 2. Its primary endpoint focused on dose-limiting toxicity in Phase 1, so the central question recorded for that phase was about tolerability during the stated 42-day timeframe. The brief summary also describes an interest in whether the combination might increase gemtuzumab ozogamicin's anti-leukemia effect in people, while noting that this was not yet known.

The registry record lists complete remission and disease relapse among the secondary outcomes. However, it does not report outcome results for those measures, nor does it report the number of participants with dose-limiting toxicity. The statistical interpretation must therefore distinguish the questions the study was designed to address from results that can actually be read from the registry record. The study is non-randomized and single-group, with no masking; it does not establish a like-for-like comparison against a control group.

3. Trial Design

The registry record describes a Phase 1/2, non-randomized, unmasked, single-group study sponsored by the National Cancer Institute. It is listed as completed, with enrollment of 52. The recorded start was 2009-05 and primary completion was 2013-07. Those administrative details describe the registered study; they do not, by themselves, establish that all planned outcomes were reported.

The design had a dose-finding phase followed by treatment at a selected dose. Phase 1 varied schedules and dose levels of vorinostat, azacitidine, and gemtuzumab ozogamicin, and included cohorts 1-3. The primary endpoint was the number of participants with dose-limiting toxicity in Phase I, measured over 42 days. The registry record does not give a definition of dose-limiting toxicity, the rules used to select a dose, or the criteria for moving between phases.

For Phase 2, the recorded regimen was vorinostat 400 mg/day on days 1-9, azacitidine 75 mg/m2/day on days 1-7, and gemtuzumab ozogamicin 3 mg/m2/day on days 4 and 8. This describes the registered schedule, not evidence that a particular dose or combination was safe or effective. The record identifies complete remission and disease relapse as secondary outcomes, but does not report their results.

Because allocation was non-randomized and the model was single-group, there is no randomized comparison that separates treatment effects from differences between groups or from changes over time. The lack of masking is also part of the design; the record does not explain whether particular outcome assessments were independently reviewed. Details of any control condition, dose-selection decision process, follow-up beyond the stated primary timeframe, or statistical analysis plan are not reported in the registry record. The enrollment figure and phase-specific safety denominators are described separately in the record, which does not explain how those populations relate to one another.

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.

Dose Escalation

Efficacy of Most Tolerated Dose

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 Participants With Dose-limiting Toxicity (Phase I), measured over 42 days.

The primary endpoint is the number of Phase 1 participants with dose-limiting toxicity during 42 days. It is a count of participants meeting the study's toxicity criterion within the specified timeframe, rather than a measure of how often an event occurred or how severe each event was. The registry record does not state the operational definition of dose-limiting toxicity, so the exact events, severity grades, and attribution rules included in that endpoint cannot be determined from the record.

Dose-limiting toxicity is commonly used in early-phase dose-finding research to help assess whether a regimen can be administered at a given dose and schedule. In general, this kind of endpoint can inform dose selection by focusing attention on toxicities occurring in an agreed observation window. Its meaning depends on the protocol's definitions, monitoring rules, and handling of participants who do not complete the observation period; those details are not reported in the registry record.

The endpoint title identifies the intended measure, but the registry record does not report a result for it. It therefore does not establish how many participants experienced dose-limiting toxicity, how that count differed across dose levels or cohorts, or which dose was selected on the basis of the endpoint. The safety entries listed elsewhere in the record are not a substitute for the primary endpoint: serious adverse events and other adverse events may not match the protocol's dose-limiting toxicity definition.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a single-group design show?

In general, a single-group study describes outcomes among participants who receive the study treatment. It can be useful in early-phase work, where dose and schedule are being explored and a control comparison may not be the central objective. It does not, however, estimate a randomized contrast between treatment and control. Without random allocation, differences among groups can reflect who entered each group, how treatment was selected, or other factors as well as the intervention. The registry record classifies this study as non-randomized and single-group, so the safety and outcome entries should be interpreted descriptively rather than as a causal comparison.

Here, Phase 1 involved varying schedules and dose levels, while Phase 2 used treatment at a selected dose. These phases serve different purposes. A dose-finding phase explores tolerability across regimens; a subsequent phase may describe outcomes at a selected regimen. The registry record does not describe the dose-selection rule or say how participants moved between phases. It also does not explain the relationship between the overall enrollment of 52 and the Phase 1 and Phase 2 safety denominators. Those missing details prevent a reconstruction of participant flow from the record.

What does the primary endpoint count?

The primary endpoint is a participant count: the number of Phase 1 participants with dose-limiting toxicity over 42 days. A count communicates how many participants met the endpoint, but its interpretation depends on both the number assessed and the exact event definition. A proportion would additionally express the count relative to an eligible or evaluable group, but the registry record does not report the primary endpoint count or define the evaluability rules. No estimate of its precision can be read from the record.

In general, a confidence interval expresses the range of values reasonably compatible with the observed data under a statistical model. Wider intervals indicate less precision; narrower intervals indicate more precision, conditional on the model and data. A confidence interval for a participant count or event proportion would require the relevant result and denominator. Since the primary endpoint result is not reported in the registry record, no interval for that endpoint can be interpreted from the posted information.

How should adverse-event counts be read?

Adverse-event summaries often count participants who experienced one or more events, while separate listings may count event episodes. Those are not interchangeable quantities. A participant with repeated episodes might contribute once to a participant count but more than once to an event count. The record labels the safety summaries in terms of participants, so the listed group counts should be read as participants affected, not as totals of all episodes. The registry record does not provide episode counts or further counting rules.

Serious adverse events are a safety category and should not be treated as synonymous with dose-limiting toxicity. In general, seriousness is based on defined regulatory criteria, while a dose-limiting toxicity endpoint depends on the study protocol's criteria and time window. An event can be serious without meeting a protocol's dose-limiting definition, and a dose-limiting event need not be captured by a summary in the same way. The record does not report the dose-limiting toxicity definition, so the serious adverse event counts cannot be used to reconstruct the primary endpoint.

Over-dispersion is a general concern when event counts vary more than a simple statistical model expects. It can arise when participants differ in their underlying event risk or when repeated events cluster within participants. If a model assumes less variation than the data contain, its uncertainty estimates may be too small. The registry record does not report a statistical model for adverse events or event-level data with which to assess over-dispersion. The posted participant counts should therefore be treated as descriptive summaries, not as model-based estimates.

What do planning assumptions mean?

In general, a sample-size calculation describes how much information a future study might need under specified assumptions. It is not a measure of the probability that the completed study found a true effect, and it is not observed power. The record describes planning illustrations based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. For non-time-to-event outcomes, the stated planning quantity is participants per arm; for time-to-event outcomes, it is a total number of events using the Schoenfeld method. Illustrations at fractions of an observed effect represent hypothetical planning targets, not additional trial findings.

Those assumptions describe a hypothetical two-arm planning framework and should not be confused with this trial's recorded single-group, non-randomized design. They do not turn the trial into a randomized comparison, and they do not establish that the original study was designed to achieve a particular power. The registry record does not report a sample-size justification for the trial's own design. Any planning illustration also depends on the reliability of the observed effect used as its starting point; no effect estimate for the primary endpoint or secondary outcomes is reported in the registry record.

Finally, a p-value and a confidence interval answer different questions in general. A p-value measures how unusual data would be under a specified null model, while a confidence interval gives an estimate with an associated range of uncertainty under a model. Neither replaces careful attention to design, endpoint definitions, missing observations, or clinical context. The registry record lists 0 analyses, and it does not report p-values, confidence intervals, or analysis details for the named outcomes.

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 1", "Dose 2", "Dose 3", "Dose 4")
n      <- c(3, 3, 3, 6)
events <- c(0, 0, 0, 1)
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 1  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Dose 2  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Dose 3  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Dose 4  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9

11. Multiplicity, Missing Data and Analysis Populations

The record identifies a primary endpoint for Phase 1 and lists complete remission and disease relapse as secondary outcomes. It also indicates 4 outcome measures overall, but does not provide the results or full descriptions of all those measures in the information recorded. When a study examines several outcomes, there is a general multiplicity concern: the more statistical questions considered, the greater the chance that at least one result appears noteworthy by chance if each is tested separately. How investigators address that concern depends on the prespecified analysis plan. An adjustment strategy, hierarchy, or other multiplicity procedure is not reported in the registry record.

The registry record lists 0 analyses. It does not report outcome-specific statistical models, effect estimates, confidence intervals, p-values, or a plan for handling multiple comparisons. The absence of those details in the registry record does not establish what analyses may have been conducted outside the record; it means that their methods cannot be evaluated from the posted information.

Missing-data handling and analysis populations are also not reported in the registry record. It does not state how participants with incomplete follow-up, treatment discontinuation, or unevaluable toxicity assessments were handled, or define an intention-to-treat, safety, or evaluable population for the outcome analyses. These matters affect denominators and interpretation. In general, excluding participants without complete assessments can produce a different result from retaining all enrolled participants under a prespecified approach. Without the population definitions and missing-data rules, the reported safety denominators cannot be assumed to be the analysis denominators for the primary endpoint or secondary outcomes.

The phase-specific safety counts are available, but the record does not reconcile those counts with total enrollment or describe participant overlap between phases. It also does not report a participant flow account. That uncertainty limits assessment of who was included in each summary and whether any observations were omitted.

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 (13.3%), sepsis (9.3%), hypoxia (6.7%), hypotension (6.7%), infection with neutropenia (6.7%).

The registry record lists safety counts separately for Phase 1 Dose-Finding and Phase 2. In Phase 1 Dose-Finding, 6 participants with serious adverse events are listed among 15 at risk, while 9 participants with other adverse events are listed among 15 at risk. In Phase 2, 13 participants with serious adverse events are listed among 43 at risk, and 43 participants with other adverse events are listed among 43 at risk. These are phase-specific descriptive entries; they are not randomized comparisons and should not be read as evidence that one phase was safer or less safe than the other.

The listed serious event terms include febrile neutropenia at 13.3%, sepsis at 9.3%, hypoxia at 6.7%, hypotension at 6.7%, infection with neutropenia at 6.7%, and death, NOS at 6.7%. The record does not give further detail on event onset, duration, severity grading, recurrence, attribution to study drugs, or the denominator and counting convention for these term percentages. The death term does not provide a separate death count in the phase-specific safety summaries, where deaths are not listed.

In general, an adverse event occurring during a study is not automatically caused by the study treatment. Attribution requires information about timing, alternative explanations, and investigator assessment. Serious adverse events are also distinct from the primary endpoint of dose-limiting toxicity; the registry record does not provide the protocol definition needed to map one category to the other.

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

The study record establishes that a Phase 1/2 investigation of vorinostat, azacitidine, and gemtuzumab ozogamicin was conducted for patients 50 years of age and older with relapsed or refractory non-APL AML. It describes a dose-finding phase and a Phase 2 regimen at a selected dose. It also records safety summaries for each phase and lists complete remission and disease relapse as secondary outcomes. These details describe the study's structure and the information registered about it.

What the record does not establish is the primary result: the number of Phase 1 participants with dose-limiting toxicity during 42 days is not reported. The record also does not report complete remission or disease relapse results. Without those results, the posted information cannot answer whether the combination achieved particular toxicity or disease outcome rates. The presence of a completed status does not fill those reporting gaps.

The adverse-event entries show that serious and other adverse events were recorded in both phase-specific groups. They do not establish that the study drugs caused those events, and they do not provide a controlled estimate of how event risk compares with another treatment or no treatment. The non-randomized, single-group design further limits causal conclusions. The record does not provide a like-for-like control comparison, a complete statistical analysis, or the details needed to assess precision for the primary endpoint.

In general, a clinical trial can contribute useful descriptive evidence even when it cannot provide a randomized treatment-effect estimate. But the conclusions should match the available design and reported outcomes. For this record, the defensible statistical reading is that the study investigated dose and schedule, registered the stated regimen and safety summaries, and identified remission and relapse as secondary outcomes. The results needed to quantify the primary endpoint and those secondary outcomes are not reported in the registry record. No treatment recommendation or conclusion about efficacy follows from these posted entries alone.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of how early-phase and later-phase questions can sit within one registered study while requiring distinct interpretations. The Phase 1 portion varied schedules and dose levels and used dose-limiting toxicity over 42 days as its primary endpoint. Phase 2 treated participants at a selected dose. Separating those purposes matters: a dose-finding endpoint is not the same as a disease outcome, and a selected-dose phase does not automatically supply a controlled estimate of treatment effect.

The design also illustrates why allocation and masking details belong in the interpretation. A non-randomized, single-group study can document outcomes among participants receiving a regimen, but it cannot by itself provide a randomized contrast against a control. Differences among dose-finding cohorts and a selected-dose group may reflect how participants and regimens were assigned or selected, as well as the effects of treatment. The record does not report enough detail to evaluate those processes.

The safety entries emphasize another statistical distinction: participant counts with serious or other adverse events are not interchangeable with a protocol-defined dose-limiting toxicity outcome. They also do not establish causation. A careful reading keeps the endpoint definition, timeframe, denominator, and attribution question separate rather than treating every safety summary as an answer to the same question.

Finally, the record demonstrates the importance of reporting results and analysis methods alongside a trial's design. It records a completed study, enrollment, a regimen, safety counts, and secondary outcome names, but lists 0 analyses and does not report the primary or secondary outcome results. Without those elements, readers cannot assess estimates, precision, missingness, multiplicity, or the relation between results and prespecified questions. Statistical importance rests not only on a study's question, but also on whether the results needed to answer it are accessible and interpretable.

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.

Several limitations specific to this record constrain interpretation. First, the central Phase 1 endpoint is named but its result is not reported. The record also does not report the results for complete remission or disease relapse. Thus, it is not possible to quantify the primary toxicity outcome or the named secondary outcomes from the registered information.

Second, the dose-limiting toxicity definition is not reported. The timeframe is stated as 42 days, but the record does not describe event criteria, severity thresholds, attribution requirements, or how incomplete assessments were handled. Without these definitions, readers cannot determine precisely what counted toward the primary endpoint or whether the listed serious adverse events overlap with it.

Third, the study was non-randomized, unmasked, and single-group. It therefore does not offer a randomized control comparison. The record does not report a statistical analysis plan, analysis populations, missing-data procedures, multiplicity handling, or outcome estimates with measures of uncertainty. The record lists 0 analyses, which limits assessment of how outcomes were modeled or compared.

Fourth, overall enrollment is 52, while the Phase 1 and Phase 2 safety entries list 15 and 43 participants at risk, respectively. The registry record does not explain how these group denominators relate to total enrollment, whether participants could be represented in more than one phase, or how participants were selected for Phase 2. No participant flow information is reported in the record.

Finally, the serious adverse event term percentages are listed without further detail on their denominator or counting method, and deaths are not separately quantified in the phase-specific summaries. Event attribution, timing, recurrence, and severity detail are not reported. These gaps mean the safety entries should be treated as limited descriptive summaries, not as a complete characterization of harms or a treatment-effect estimate.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Vorinostat, Azacitidine, and Gemtuzumab Ozogamicin for Older Patients With Relapsed or Refractory AML — NCT00895934.
• Registry record last updated 2019-05-23; status last verified 2019-05.
• Results first posted 2015-02-06.
• 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 completed, non-randomized, unmasked, single-group Phase 1/2 study sponsored by the National Cancer Institute, with enrollment of 52. It studied vorinostat, azacitidine, and gemtuzumab ozogamicin in patients 50 years of age and older with relapsed or refractory non-APL AML.

Phase 1 varied schedules and dose levels; Phase 2 used vorinostat 400 mg/day on days 1-9, azacitidine 75 mg/m2/day on days 1-7, and gemtuzumab ozogamicin 3 mg/m2/day on days 4 and 8. The primary endpoint was the number of Phase 1 participants with dose-limiting toxicity during 42 days. Complete remission and disease relapse were listed as secondary outcomes.

The registry record lists phase-specific serious and other adverse event counts, but does not report the primary endpoint result or the secondary outcome results. It also does not report outcome analyses, analysis populations, missing-data methods, multiplicity procedures, or the operational definition of dose-limiting toxicity. The available results therefore support only a limited descriptive reading of the registered safety entries.