Azacitidine and Entinostat in Treating Patients With Recurrent Advanced Non-Small Cell Lung Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Azacitidine and Entinostat in Treating Patients With Recurrent Advanced Non-Small Cell Lung Cancer (NCT00387465), a randomized phase 1, phase 2 study. The primary outcome is (Phase I) Maximum Tolerated Dose (MTD) of Azacitidine When Given Together With Entinostat as Determined by Number of Participants Experiencing Dose-limiting Toxicity (DLT).

2. Clinical Question

3. Trial Design

This was a phase I/II study of azacitidine and entinostat in recurrent advanced non-small cell lung cancer. The registry lists the study as completed, with enrollment of 94, a start date of 2006-08, and primary completion in 2014-05. The sponsor is the National Cancer Institute (NCI). These study-level details describe the registry record; they do not establish how many participants contributed to each outcome.

The Phase I component evaluated azacitidine at 30mg/m2 and 40mg/m2 alongside entinostat 7mg. The arm descriptions specify administration on days 3 and 10 of each cycle for both Phase I dose groups. The primary endpoint was restricted to Phase I participants and concerned dose-limiting toxicity. The registry's reported maximum tolerated dose was 40.

The Phase II arm used azacitidine 40mg/m2 subcutaneously on days 1-6 and 8-10, plus entinostat 7mg by mouth on days 3 and 10. Treatment was to repeat every 28 days in the absence of disease progression or unacceptable toxicity. The registry records this arm, but the posted primary endpoint results give it a participant count of 0 and no endpoint value. Thus, the primary endpoint result pertains to the Phase I arms, not to a reported Phase II primary endpoint estimate.

The design descriptors require care. Allocation is recorded as randomized, masking as none, and the model as single group. Dose-level arms are listed, but the registry record does not explain the relationship between randomized allocation and the single-group model. It also does not report a distinct control group or a randomized treatment-effect estimate for the primary endpoint. Details of sequence generation, allocation concealment, stratification, and the rationale for the design 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.

Before assignment: 49 subjects did not start the study due to screen failure or PI decision.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Only participants in the Phase I arms were analyzed for this outcome measure

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 (Phase I) Maximum Tolerated Dose (MTD) of Azacitidine When Given Together With Entinostat as Determined by Number of Participants Experiencing Dose-limiting Toxicity (DLT), measured over Up to 28 days.

The primary endpoint asks for the maximum tolerated dose (MTD) of azacitidine when given with entinostat. It is assessed by counting participants who experienced dose-limiting toxicity (DLT) during up to 28 days. The registry defines DLT by reference to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0. The record does not give further operational detail about which specific events or grades qualified as a DLT in this study.

In general, a dose-finding endpoint based on DLT is used to help identify a dose level that can be taken forward for study while monitoring treatment-related toxicity. That is a different question from estimating whether the regimen improves a cancer outcome compared with another treatment. The endpoint itself is a count of participants with the event, not a measure of tumor response or survival.

The posted Phase I counts are 0 among 3 participants in the 30mg/m2 azacitidine group and 0 among 6 participants in the 40mg/m2 group. The sponsor-reported analysis gives an MTD of 40. The registry does not provide a confidence interval for the MTD, a detailed dose-selection algorithm, or an uncertainty estimate for the observed DLT counts. The endpoint therefore offers a concise record of the observed toxicity events and the reported dose conclusion, but not a precise estimate of the range of doses that might be suitable in other settings.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The main statistical task for this endpoint is descriptive: count the Phase I participants who experienced DLT during the specified observation period. The registry reports counts of 0 among 3 participants at 30mg/m2 and 0 among 6 participants at 40mg/m2. It describes the endpoint as a count of participants, and specifies a timeframe of up to 28 days. These counts are not a comparison of treatment benefit against a control group.

What does a count of participants measure?

A participant count records how many people in an analysis population had the event being defined. The denominator is needed to interpret that count because the same event count can mean different things in groups of different sizes. Here, the record gives both the Phase I counts and their group sizes. It does not provide a DLT percentage or an uncertainty interval. A count should not be mistaken for a complete description of risk, especially when the group is small.

In general, a confidence interval describes a range of values compatible with the observed data under a specified statistical method. It expresses sampling uncertainty; it is not a guarantee that the true value lies within that range. No confidence interval is reported for the DLT counts or for the MTD. Consequently, the registry does not quantify the precision of these estimates using interval bounds.

How should the MTD result be read?

The registry reports a maximum tolerated dose of 40 for azacitidine given with entinostat. This is the sponsor-reported dose conclusion, not a between-group effect estimate. The posted counts show no DLTs in either recorded Phase I dose group, but the record does not describe the dose-selection algorithm or give a model linking dose to toxicity. It is therefore not possible to reconstruct from the posted information how the MTD value was selected or how uncertainty in that selection was assessed.

In general, dose-finding studies use prespecified rules to balance observed toxicity against the aim of selecting a dose for further study. Different rules can lead to different conclusions from the same observed counts. The protocol’s detailed rules, any prior assumptions, and any sequential decisions are not reported in the registry record. No statistical model or test is specified for the MTD result.

Is there a comparative analysis?

The record lists randomized allocation, no masking, and a single-group model. It also lists Phase I dose groups and a Phase II arm. These fields do not, by themselves, establish that the primary endpoint was analyzed as a randomized comparison. The registry reports no primary-outcome contrast, test statistic, p-value, or confidence interval comparing the dose groups. It specifically indicates that values are missing or not estimable for a two-arm comparison of this binary endpoint.

In general, a comparison of binary outcomes may estimate a difference or ratio between groups, with an uncertainty interval and, where appropriate, a statistical test. Such an estimate requires a clear comparison population and analysis method. Those results are not reported. A reader should not infer comparative effectiveness from the separate DLT counts.

Why does analysis population matter?

The endpoint description says that only participants in the Phase I arms were analyzed. That qualification defines the population to which the primary result applies. The Phase II arm has a reported count of 0 and a missing endpoint value in this outcome record. The registry does not explain the absence of a Phase II primary-outcome value or provide a flow of participants from enrollment through analysis. In general, missing outcome data can affect interpretation when the reason for missingness is related to participant characteristics or outcomes; no missing-data method is reported for this endpoint.

Planning calculations, when used, are not observed results. The stated sample-size assumptions describe an illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. Such assumptions do not establish the trial’s original design plan or its achieved ability to detect an effect. The registry record does not report a sample-size justification, an original power calculation, or interim analysis procedures for this primary endpoint. Any planning illustration should therefore remain distinct from the observed Phase I DLT counts and from the sponsor’s MTD conclusion.

Overall, the available method information supports a narrow descriptive reading: the registry records the DLT counts and states an MTD. It does not supply enough detail to reproduce the dose-selection analysis, calculate a comparative primary-outcome estimate, or assess the precision of the MTD conclusion.

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("Phase I - 30mg/m2 Azacitidine", "Phase I - 40mg/m2 Azacitidine")
n      <- c(3, 6)
events <- c(0, 0)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Phase I - 30mg/m2 Azacitidine  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Phase I - 40mg/m2 Azacitidine  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0

11. Analyses Reported by the Sponsor

The registry reports the sponsor’s primary analysis as a maximum tolerated dose of 40 for azacitidine given with entinostat. The analysis record does not include a confidence interval, p-value, or detailed statistical method for that conclusion. The Phase I arm results list 0 DLTs among 3 participants at 30mg/m2 and 0 among 6 participants at 40mg/m2.

No separate recalculated comparative estimate is available for this binary endpoint: the registry indicates that values are missing or not estimable for a two-arm comparison. The sponsor’s reported MTD is therefore the relevant posted analysis to describe, not a result that can be checked against an unadjusted treatment-effect calculation from the registry values. The record does not flag a discrepancy for this outcome.

In general, a sponsor-reported dose conclusion may rely on dose-selection rules and study procedures that are not visible in a brief results record. Those rules are not described in detail. The reported value should be attributed to the registry’s analysis, while recognizing that the posted record does not show the supporting calculation or quantify uncertainty around the selected dose.

12. Multiplicity, Missing Data and Analysis Populations

The registry identifies 11 outcome measures and records 9 secondary outcomes as posted. The secondary outcomes include response after subsequent chemotherapy, overall survival, progression-free survival, DNA methylation and response, and pharmacokinetic measures. Multiple outcomes create the possibility of many statistical questions being examined. In general, when many hypotheses are tested, the chance of finding a nominally notable result by chance can increase. Methods such as prespecified outcome hierarchies or multiplicity adjustments can address that issue, but whether they were used is not reported in the registry record.

The primary endpoint has a defined analysis population: only Phase I participants were analyzed. The record gives 0 DLTs among 3 participants at 30mg/m2 and 0 among 6 at 40mg/m2. It does not provide a participant flow, a detailed accounting of exclusions, or reasons for any missing primary outcome data. The Phase II arm’s endpoint entry has a participant count of 0 and no value. The registry does not explain that entry, so it should not be interpreted as a complete account of Phase II enrollment or follow-up.

In general, missing-data methods matter because excluding participants with unavailable outcomes can change the population represented by the analysis. The registry does not state whether the primary endpoint used an intention-to-treat, per-protocol, or other analysis population beyond its explicit restriction to Phase I participants. It also does not describe imputation, sensitivity analyses, or rules for handling participants whose DLT status was unknown.

The registry does not report an interim-analysis plan, stopping rules, or a prespecified statistical analysis plan. Those details are important for understanding how outcomes were prioritized, how dose decisions were made, and whether results were examined repeatedly. Their absence from the registry record does not establish that the study lacked such procedures; it means they cannot be assessed from the posted record. The primary result is best read as the reported Phase I count and MTD, without assuming unreported multiplicity or missing-data procedures.

13. 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

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: lymphopenia (4.8%), neutropenia (2.4%), pericardial tamponade (2.4%).

For the serious adverse event summary, the group titled Azacitidine 40mg/m2 and Entinostat has 42 participants at risk and 2 participants with a serious adverse event; deaths are recorded for 2. For the Phase I - 30mg/m2 Azacitidine group, 3 participants are listed as at risk, with 0 serious adverse events and 0 deaths. These are separate registry safety entries and should not be combined or treated as a randomized safety comparison.

The registry also lists 36 participants with other adverse events among 42 at risk in the Azacitidine 40mg/m2 and Entinostat group, and 0 among 3 in the Phase I - 30mg/m2 Azacitidine group. Serious and other adverse events are distinct categories in the record; the counts should not be added together. The registry does not provide enough information to determine overlap among categories or to compare rates under a defined statistical method.

The listed leading serious adverse event terms are lymphopenia at 4.8%, neutropenia at 2.4%, and pericardial tamponade at 2.4%. The record does not specify the denominator or observation window for those term percentages in the information summarized. These figures describe reported safety events, not a causal comparison between regimens. They do not establish that the same event profile would occur in another population or setting.

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

The primary result establishes what the registry reports for the Phase I dose-finding endpoint: no DLTs were recorded among 3 participants at azacitidine 30mg/m2 or among 6 participants at 40mg/m2, and the reported MTD was 40. It does not provide an uncertainty interval or a detailed dose-selection analysis. The result is therefore a limited description of the posted Phase I findings.

It does not establish a comparative treatment effect. There is no reported control-group estimate for the primary endpoint, and no comparative effect measure, confidence interval, or p-value is posted. Although the allocation field says randomized, the model field says single group, and the record does not clarify that design combination. The primary result should not be reinterpreted as proof that the regimen is superior, equivalent, or inferior to another treatment.

It also does not establish that DLTs cannot occur. In general, observing no events in a study group is compatible with uncertainty about the event rate beyond the observed participants. The registry does not quantify that uncertainty. Nor does the primary endpoint measure tumor response, progression-free survival, or overall survival; those appear as separate outcomes in the registry.

The Phase II arm regimen is described, but the primary outcome entry reports no Phase II participant count or endpoint value. This does not provide a Phase II estimate of dose-limiting toxicity. Other safety figures are separately reported, including serious adverse events, other adverse events, and deaths, but the registry entries do not support a causal comparison across groups.

In general, a registry result is most informative when read alongside the endpoint definition, analysis population, method, and uncertainty. Here, the definition references NCI CTCAE v3.0 and limits the primary endpoint to Phase I participants, but further DLT rules and statistical methods are not reported. The meaning of the result is consequently bounded by those omissions: it documents the sponsor-reported MTD and the observed Phase I event counts, without establishing a broader clinical conclusion.

15. Why This Trial Matters Statistically

This trial raises a useful statistical distinction between dose-finding and treatment-effect estimation. The primary endpoint asks about the maximum tolerated dose of azacitidine with entinostat, using dose-limiting toxicity in Phase I participants. It is not a direct measure of whether the combination changes response or survival relative to another treatment. Keeping those questions separate prevents a dose-selection result from being mistaken for comparative evidence.

The posted counts also illustrate why event counts need context. The registry reports no DLTs in either listed Phase I dose group, but the group sizes are limited and no uncertainty intervals are provided. In general, a zero observed count is not the same as certainty that the event risk is zero. Reporting uncertainty and the method used to select a dose would make the statistical strength of a dose conclusion easier to evaluate.

Design labels are another point of interest. Randomized allocation and a single-group model are both recorded, while dose-level arms and a Phase II arm are described. The registry does not reconcile those features or report a primary comparative estimate. This illustrates how registry fields can require cautious interpretation when their relationship is unclear.

Finally, the record includes many outcome domains, from toxicity to response, survival, and pharmacokinetics. Multiple outcomes can raise questions about prioritization and multiplicity, while incomplete reporting of analysis populations and missing-data procedures limits reproducibility. These are general statistical concerns, not evidence that a particular method was or was not used in the study. The trial matters statistically because it shows how much interpretation depends not only on a point result, but also on the design, endpoint scope, uncertainty, and analysis details made available.

16. 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 principal limitation for interpreting the primary outcome is the small Phase I analysis recorded for DLT: 0 events among 3 participants at 30mg/m2 and 0 among 6 at 40mg/m2. The registry does not report confidence intervals or another measure of uncertainty for those counts or for the MTD. Without such information, the precision of the dose conclusion cannot be judged from the posted result alone.

The record reports an MTD of 40 but does not provide the dose-selection algorithm, statistical model, or full criteria used to classify DLT. The endpoint references NCI CTCAE v3.0, but the study-specific operational definition is not reported in the registry record. The result cannot therefore be independently reconstructed from the listed counts.

There is also ambiguity in the design description: allocation is listed as randomized, while the model is listed as single group. The record does not explain this combination, identify a control treatment for the primary outcome, or give a comparative estimate. The Phase II arm is described, but its entry for the primary endpoint has a participant count of 0 and no value. The record does not explain that entry.

Other limitations include the absence of reported details on the analysis plan, interim analyses, multiplicity adjustment, missing-data handling, and participant flow for the primary endpoint. The record lists secondary outcome domains, but their results and analysis methods are not included in the registry record for this endpoint. Safety figures are reported separately, but the observation windows and context needed for a comparative safety analysis are not reported. These gaps restrict reproducibility and the scope of conclusions; they do not establish that the underlying study lacked additional procedures or data.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Azacitidine and Entinostat in Treating Patients With Recurrent Advanced Non-Small Cell Lung Cancer — NCT00387465.
• Registry record last updated 2019-05-09; status last verified 2019-04.
• Results first posted 2019-05-09.
• 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.

20. Record Summary

The registry describes a completed phase I/II study of azacitidine with entinostat for recurrent advanced non-small cell lung cancer. It lists enrollment of 94 and identifies the National Cancer Institute (NCI) as sponsor. The primary endpoint was the Phase I maximum tolerated dose of azacitidine with entinostat, assessed through DLT during up to 28 days and defined by reference to NCI CTCAE v3.0.

The posted Phase I endpoint counts are 0 among 3 participants at 30mg/m2 and 0 among 6 at 40mg/m2. The sponsor-reported MTD is 40. The record provides no confidence interval or comparative estimate for this primary outcome. It lists randomized allocation and a single-group model, without explaining how these descriptors relate to one another.

The Phase II regimen is described, but no Phase II primary endpoint value is posted. Statistical details including dose-selection rules, missing-data handling, multiplicity procedures, and interim analyses are not reported in the registry record. The findings are therefore best interpreted as a limited Phase I dose-finding result rather than a comparative treatment-effect estimate.