Phase I Dose-Escalation Study Of Azacitidine In Combination With Temozolomide: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase I Dose-Escalation Study Of Azacitidine In Combination With Temozolomide (NCT00629343), a na phase 1 study. The primary outcome is Maximum Tolerated Dose of Temozolomide.

2. Clinical Question

In a dose-escalation study, investigators assess tolerability as treatment is given at different dose levels. The aim is to identify a dose suitable for further study, using safety observations from the regimen under investigation. That goal differs from estimating whether one treatment improves an outcome relative to another: without a control group, the registry data cannot provide a randomized estimate of comparative effect.

The study concerned advanced soft tissue sarcoma or malignant mesothelioma and tested azacitidine with temozolomide. The registry does not report how participants were distributed between the two conditions, nor does it give the detailed characteristics needed to judge how representative the enrolled group was. The primary endpoint’s timeframe was up to 26 weeks for each dosing cohort. That defines the period associated with the endpoint in the record; it does not, by itself, specify how often participants were assessed or how dose decisions were made.

3. Trial Design

The registry classifies this as a Phase I, single-group trial with no masking. Its brief summary describes it as a single-center, open-label, single-arm dose-escalation study. Enrollment was 27, and the study status is completed. The recorded start was 2007-10 and primary completion was 2012-10. The registry does not report a randomized allocation or a parallel control group.

Participants received azacitidine in combination with temozolomide. The adverse-event groups are labeled Azacitidine 25 mg, Azacitidine 50 mg, and Azacitidine 75 mg. These labels describe dose groups within the study, not independent randomized arms. Since dose assignment is part of an escalation study, apparent differences between these groups should not be interpreted as if participants had been randomly assigned to competing treatments under otherwise comparable conditions.

The primary outcome was the maximum tolerated dose of temozolomide when combined with azacitidine. Its timeframe was up to 26 weeks for each dosing cohort. The registry also lists two outcome measures, but does not provide a numerical primary endpoint result in the record summarized for this analysis. The number of analyses reported is zero.

The study summary describes evaluations that included history and physical examination, laboratory studies, biopsy, and imaging of measurable disease. These details describe planned or conducted assessment activities in the summary; the registry does not provide participant-level results for those assessments. Nor does it report the dose-escalation rules, criteria defining dose-limiting toxicity, the number of participants treated at each temozolomide dose, or the rationale for the planned enrollment. Those details are important for reconstructing how the dose decision was reached, and should not be inferred from the group labels alone.

Because the design is single-arm and open-label, the study is suited to descriptive dose-finding and safety reporting, not a blinded comparison of treatment effects. The registry does not report a separate comparator or a statistical analysis plan for efficacy comparisons. Its safety counts must therefore be read as observations within the study regimen and dose groups, rather than as evidence that one group caused more or fewer events than 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.

Before assignment: 27 participants signed a consent form and four were determined to be ineligible, resulting in 23 assigned to treatment.

Dose Level 1: Azacitidine 25mg

Dose Level 2: Azacitidine 50 mg

Dose Level 3: Azacitidine 75mg

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 Maximum Tolerated Dose of Temozolomide, measured over Up to 26 weeks for each dosing cohort.

The primary endpoint is the maximum tolerated dose of temozolomide when it is used in combination with azacitidine. In dose-finding research, this endpoint is intended to identify a dose that can be taken forward for further evaluation while considering treatment-related toxicity. The endpoint is not itself a measure of tumor response, survival benefit, or comparative efficacy.

The registry gives the unit as mg/m^2 and specifies a timeframe of up to 26 weeks for each dosing cohort. It records the endpoint as a number, but does not report the numerical value of the maximum tolerated dose in the record. It also does not report the operational definition of dose-limiting toxicity, the observation window used to classify such toxicity, or the escalation and stopping rules. Without those details and the numerical endpoint result, readers cannot reconstruct the dose-finding decision from the registry record alone.

Using a tolerability endpoint is appropriate to the aim of a Phase I dose-escalation study: early evaluation is focused on how a regimen is tolerated and what dose merits additional study. However, the endpoint’s meaning depends on the prespecified toxicity criteria and dose-decision procedure. Those methods are not reported in the registry record. The endpoint should therefore be understood as the study’s stated dose-finding target, not as a complete account of the safety profile or evidence that a particular dose is effective.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a dose-escalation design estimate?

In general, dose-escalation studies evaluate tolerability across dose levels to identify a dose for further investigation. They do not typically answer the same question as a randomized efficacy trial. A dose-finding conclusion relies on rules for escalation, stopping, and defining dose-limiting toxicity. Those rules determine how observed events translate into a dose decision. The registry record does not report those rules for this trial, so the stated maximum-tolerated-dose endpoint cannot be independently reconstructed from the posted counts.

The safety groups are labeled by azacitidine dose, whereas the primary endpoint concerns temozolomide dose in combination with azacitidine. That distinction matters: the group labels alone do not tell the reader what temozolomide doses were used in each cohort or how those doses changed. The record does not report that mapping. It is therefore not possible to infer the temozolomide escalation sequence from the azacitidine labels.

How should a confidence interval be understood?

In general, a confidence interval describes the statistical uncertainty around an estimate, under the assumptions of the method used. A narrow interval indicates more precision than a wide interval, but neither guarantees that the estimate is unbiased or that the model is appropriate. Confidence intervals are especially useful alongside event counts because a count alone does not convey the full uncertainty about an underlying event rate.

The registry record does not report confidence intervals for the primary endpoint or the safety counts. No interval can be inferred from the posted summaries without making additional assumptions, and no such recalculation is appropriate as a substitute for the sponsor’s analysis. The absence of reported intervals means that the precision of these estimates is not documented in the registry record.

Why does the single-group structure matter?

In general, a control group helps distinguish the outcome observed under a study treatment from outcomes that might occur without that treatment or under another treatment. Randomization can balance measured and unmeasured prognostic factors on average, while masking can reduce some forms of assessment or reporting bias. This trial is described as single-group and open-label, with no masking. It therefore has no randomized contrast that can isolate the treatment’s effect from the natural course of disease, supportive care, or other influences.

The dose groups should not be treated as substitutes for randomized arms. Participants entering different dose cohorts may differ for reasons related to dose escalation or study timing. Without an allocation mechanism that supports exchangeability, a difference in observed event counts does not establish that dose caused the difference. The registry explicitly describes no allocation and a single-group model.

What do the adverse-event counts capture?

Adverse-event summaries report counts among people at risk and counts affected, organized by event category and dose group. They provide a useful overview of events recorded during the study, but their interpretation depends on the event definitions, ascertainment window, exposure duration, and rules for linking events to treatment. The registry record lists participants at risk, participants affected, and deaths. It does not provide detailed event-level data, exposure time, or a complete description of the event-collection methods.

Serious adverse events should not be conflated with all adverse events. The record separately reports serious and other adverse-event counts. The zero values for other adverse events in the listed groups do not establish that no non-serious symptoms or events occurred in every sense; they describe the posted category and reporting. Similarly, a serious event’s appearance in the record does not by itself demonstrate causation by study treatment.

How do planning illustrations differ from observed results?

In general, sample-size planning calculations describe how many participants might be needed under specified assumptions to detect an effect with a chosen statistical procedure. They are prospective illustrations, not measurements of what happened in a trial. A planning calculation based on an observed effect is especially dependent on that effect estimate and its uncertainty; it should not be presented as observed power or as proof that the study was adequately powered.

The registry record describes planning assumptions for illustrative calculations, including a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. Those assumptions do not describe this single-group dose-escalation design, and the record does not report a randomized two-arm comparison. The illustrations should therefore not be used to infer the trial’s design or its ability to answer the primary dose-finding question. The record does not report a sample-size justification for the trial itself.

More broadly, statistical interpretation requires alignment between the design, endpoint, analysis, and question. Here, the stated primary endpoint is dose-finding, while the posted numerical data are safety counts. With no reported endpoint value, no reported analyses, and no randomized comparator, the registry supports a narrow descriptive reading rather than a causal efficacy estimate. General statistical principles can clarify those boundaries, but they cannot supply missing trial-specific methods or results.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists two outcome measures and no analyses. It does not report a statistical analysis plan, a hierarchy of endpoints, or a procedure for addressing multiplicity. In general, when several outcomes or repeated comparisons are tested, the chance of a false-positive finding can increase unless the analysis plan accounts for the testing structure. That general concern does not establish that this trial conducted multiple hypothesis tests; the number and nature of analyses are not reported.

The primary endpoint is identified as maximum tolerated dose of temozolomide, but the record does not report a numerical endpoint result or the method used to derive it. It also does not specify whether any secondary outcomes were prespecified, how they were analyzed, or whether any interim reviews occurred. Interim analyses and dose-escalation decision procedures are not reported in the registry record and should not be assumed.

Missing-data methods and analysis populations are also not reported in the registry record. The summary does not state how participants who discontinued, missed assessments, or lacked evaluable toxicity information were handled. It does not define an intention-to-treat, safety, or dose-limiting-toxicity population. These omissions matter because the interpretation of event counts depends on who was considered at risk and evaluable, and on how incomplete follow-up was treated.

The group-level counts do identify numbers at risk for the listed adverse-event categories, but they do not describe the completeness of follow-up or the handling of missing observations. The record therefore permits a description of the posted counts, not a reconstruction of the full statistical approach or the potential effect of missing data.

11. 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

Serious events with the highest arm-level rate: death due to progression of disease (88.2%).

The registry reports serious adverse events, other adverse events, and deaths separately for groups labeled Azacitidine 25 mg, Azacitidine 50 mg, and Azacitidine 75 mg. In the 25 mg and 50 mg groups, 3 were at risk for serious events in each group and 0 were affected; 3 were at risk for other events in each group and 0 were affected. Deaths were 0 in both groups. In the 75 mg group, 17 were at risk for serious events and 15 were affected; 17 were at risk for other events and 0 were affected; deaths were 15.

The registry lists “Death due to progression of disease” as the leading serious-event term, at 88.2%. This is a reported event term, not a standalone estimate of treatment causality. The record does not provide detailed event-level information or explain how the percentage was calculated. The counts should be read as descriptive observations within the listed dose groups, not as randomized comparisons of safety.

The adverse-event categories and the deaths count are not interchangeable. A serious adverse event is a reporting category; the death count is separately listed. These summaries do not show exposure duration, timing, attribution, or the clinical circumstances for each event. They cannot establish whether treatment caused an event or distinguish treatment effects from disease progression.

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

The record establishes that this was a completed Phase I, open-label, single-arm dose-escalation study of azacitidine with temozolomide in patients with unresectable or metastatic soft tissue sarcoma or malignant mesothelioma. It identifies maximum tolerated dose of temozolomide in combination with azacitidine as the primary endpoint and reports safety counts by azacitidine dose group. Those features define the scope of the evidence available from the registry.

The record does not report the numerical maximum tolerated dose, despite naming it as the primary endpoint. It also reports no analyses. The available adverse-event counts do not fill that gap: they describe events in dose groups but do not specify the temozolomide dose sequence, the dose-limiting toxicity criteria, or the rules used to choose a dose. Therefore, a reader cannot determine the study’s final dose-finding conclusion from the record alone.

The single-group design also limits what can be inferred about efficacy and causality. There is no concurrent control group, randomization, or masking. The registry does not report a comparative estimate of tumor response, survival, or another efficacy outcome. The posted safety counts cannot establish that the combination caused the recorded events, and they cannot be compared as though dose groups were randomized groups.

These limitations do not make the record uninformative. It identifies the regimen, population, design, endpoint, timeframe, and reported safety counts. It also makes clear that the numerical results available in the registry are not a complete report of the dose-finding analysis. The appropriate conclusion is descriptive: the record documents safety observations and the intended dose-finding question, but does not provide enough information to quantify the primary endpoint or support comparative claims about benefit or harm.

13. Why This Trial Matters Statistically

This trial illustrates why a Phase I dose-finding endpoint should be read in the context of its design and decision rules. The stated aim is not a randomized efficacy comparison, but identification of a maximum tolerated dose for temozolomide in combination with azacitidine. That endpoint depends on toxicity definitions, observation periods, and escalation procedures. When those methods and the numerical endpoint result are absent from the registry record, readers cannot reproduce the central dose-finding conclusion from the available information.

It also demonstrates the importance of distinguishing dose cohorts from comparative treatment arms. The safety data are organized by azacitidine dose, but the trial is single-group and nonrandomized. A numerical contrast between groups would not automatically be a causal dose effect. Cohort membership, exposure, disease course, and other factors may differ, and the registry does not provide the information needed to assess those influences.

Finally, safety counts need context. Counts alone do not communicate event timing, duration of exposure, attribution, or the treatment status of each participant at the time of an event. The listed deaths and serious-event term make the safety profile important to examine, but do not independently identify cause. Clear reporting of definitions, analysis populations, missing-data handling, and dose-decision methods would be needed for a fuller statistical assessment.

The statistical lesson is not that the trial answers no questions. It does answer a design-level question by identifying the regimen and intended dose-finding purpose, and it provides descriptive safety observations. But a registry record with no reported endpoint value or analyses cannot support a complete reconstruction of how the primary question was answered. Keeping that distinction explicit prevents descriptive counts from being mistaken for comparative evidence.

14. 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 registry record does not report the numerical result for maximum tolerated dose of temozolomide, the primary endpoint. It also does not state the criteria for dose-limiting toxicity, the escalation and stopping rules, or which temozolomide doses corresponded to the azacitidine-labeled groups. These missing details prevent independent review of the dose-finding decision.

The trial was single-group, open-label, and without masking. It had no randomized control group, so the posted counts cannot support a controlled treatment comparison. The study concerned unresectable or metastatic soft tissue sarcoma or malignant mesothelioma, but the record does not report how many participants had each condition or provide detailed baseline characteristics. Generalizability to other populations cannot be assessed from the registry summary alone.

The safety record provides group-level counts but not event-level narratives, timing, duration of exposure, attribution to study treatment, or detailed follow-up. It does not report how missing assessments or discontinuations were handled, or define the analysis populations. The reported serious-event term concerning death due to disease progression does not by itself explain the circumstances of individual deaths or establish whether treatment contributed.

The record lists two outcome measures and zero analyses, without a statistical analysis plan, multiplicity procedure, or explanation of the endpoint calculation. It does not report a sample-size justification for the trial. The planning assumptions associated with illustrative sample-size calculations do not replace the trial’s own design rationale or analysis plan. These limitations leave the posted data useful for a narrow descriptive account, but insufficient for a complete statistical evaluation of the primary dose-finding result or comparative clinical effects.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Phase I Dose-Escalation Study Of Azacitidine In Combination With Temozolomide — NCT00629343.
• Registry record last updated 2025-06-05; status last verified 2025-05.
• Results first posted 2025-06-05.
• 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.

18. Record Summary

NCT00629343 is a completed Phase I, single-center, open-label, single-arm dose-escalation study of azacitidine with temozolomide. It enrolled 27 patients with unresectable or metastatic soft tissue sarcoma or malignant mesothelioma. The recorded study start was 2007-10, and primary completion was 2012-10.

The primary endpoint was maximum tolerated dose of temozolomide in combination with azacitidine, with a timeframe of up to 26 weeks for each dosing cohort. The registry does not report the numerical endpoint result or any analyses. Safety counts are reported for azacitidine groups labeled 25 mg, 50 mg, and 75 mg; the registry also lists death due to progression of disease at 88.2% as the leading serious-event term.

Because there was no randomized comparator and the record lacks key dose-finding and analysis details, the reported counts should be interpreted descriptively. They do not establish comparative efficacy or treatment causality.