Phase I/II of Oral Vorinostat Combination With Erlotinib in NSCLC Patients With EGFR Mutations With DP After Erlotinib.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase I/II of Oral Vorinostat Combination With Erlotinib in NSCLC Patients With EGFR Mutations With DP After Erlotinib. (NCT00503971), a na phase 1, phase 2 study. The primary outcome is Progression Free Survival Rate at 12 Weeks.

2. Clinical Question

The trial concerned people with stage IIIB or IV non-small-cell lung cancer (NSCLC) with EGFR mutations whose disease had progressed after erlotinib treatment. It investigated adding oral vorinostat to erlotinib in that setting. The registry describes a sequential study with a dose-finding phase followed by a phase intended to assess safety and efficacy. It does not report the primary endpoint result, so the record cannot establish the observed progression-free survival rate at 12 weeks.

3. Trial Design

This was an open-label, non-randomized, sequential Phase I/II trial with a single-group model. The registry lists enrollment of 33 and identifies the condition as non-small-cell lung cancer. The study began in 2008-05, had a primary completion date of 2011-12, and is recorded as terminated. The reason for termination is not reported in the registry record.

The first part was a phase I dose-finding study intended to identify a maximum tolerated dose. It was planned for three hospitals. The registry lists vorinostat plus erlotinib dose-level groups for phase I, followed by a phase II group. In phase II, participants were to receive oral erlotinib 150 mg daily and oral vorinostat according to the phase I results. The brief summary says treatment continued until disease progression, unacceptable toxicity, or consent withdrawal, at the principal investigator’s discretion.

The phase II aims were to assess safety and efficacy. Safety and response rate were described as primary endpoints in the brief summary; clinical benefit rate, time to progression, time to response, response duration, and progression-free survival were described as secondary endpoints there. The separately listed primary outcome is progression-free survival rate at 12 weeks. The registry record does not explain the relationship between these descriptions of endpoint priority.

Because there was no random allocation or concurrent control group, the design does not provide a randomized treatment comparison. Differences among dose-level groups should not be read as controlled comparisons: those groups belong to sequential dose finding, and the record does not establish that their participants were comparable. The registry does not report the protocol’s sample-size justification or a detailed statistical analysis plan.

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: Screening details: Histologically confirmed NSCLC Diagnosis of advanced stage IIIB with pleural effusion or IV NSCLC Previous disease progression after \>= 3 months treatment with Erlotinib. Must tolerate erlotinib dose of 150 mg daily during the prior month. Have demonstrated mutations at epidermal growth factor receptor (EGFR) at Exon 19 or Exon 21

Overall Study

Analysis population for the primary outcome, as defined in the registry: Efficacy analysis PFSR12w population: all patients who have received at least one dose of study medication have been included.

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 Progression Free Survival Rate at 12 Weeks, measured over From date of first day of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 12 weeks.

The primary outcome is the progression-free survival rate at 12 weeks, expressed as a percentage of participants. Progression-free survival was defined as time from first treatment until disease progression or death from any cause. The stated assessment period runs from the first day of treatment until the first documented progression or death, assessed up to 12 weeks. The efficacy population included all patients who received at least one dose of study medication.

A rate at a specified time point gives a clinically interpretable snapshot of the proportion of the defined population that has not experienced either event by that time. Combining progression and death means that either event counts as a failure to remain progression-free. This type of endpoint can summarize disease control over a defined interval, but it does not describe how long each participant remained progression-free beyond that interval. Nor does it distinguish the contribution of progression from the contribution of death.

The registry record does not report the observed percentage, the number of participants progression-free at the assessment point, or a confidence interval for the primary outcome. It therefore gives the endpoint definition and population but not the result or its precision. The recorded definition also does not state how censoring or missing assessments were handled.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Several statistical ideas help clarify what the registry does and does not report. The distinction between an endpoint definition and an endpoint result is central: the record defines progression-free survival rate at 12 weeks and identifies the efficacy population, but does not give the corresponding estimate. A clearly specified measure does not by itself tell readers what was observed.

What does a percentage endpoint describe?

A percentage describes the share of a defined population meeting a specified status or experiencing a specified event. For this primary outcome, the relevant status is being alive without documented progression by the 12-week assessment point. The registry identifies the population as patients who received at least one dose. It does not report the numerator or the percentage, so no rate can be interpreted from the record.

A percentage at a fixed assessment time is not the same as a complete account of time to progression. It compresses follow-up into a status at the chosen time. Participants may have different follow-up histories, and their event times can contain more information than a single rate. The record does not report the statistical procedure used to estimate the rate or how incomplete follow-up was treated.

What would a confidence interval add?

A confidence interval communicates uncertainty around an estimated quantity under the assumptions of the statistical method used. It is not a guarantee that the true value lies within the particular interval. Its width is affected by the amount of information and by the variability in the observations. For a percentage endpoint, an interval would help readers judge how precisely the rate was estimated. Although the outcome definition lists a 95% confidence interval as its dispersion measure, the numerical interval is not reported in the registry record.

Without an estimate and its interval, neither the magnitude of the primary result nor its statistical uncertainty can be assessed. A significance test or a confidence interval would also not resolve limitations arising from the absence of randomization or a concurrent control group. Precision and causal interpretation are different issues: a precise estimate from a single group still does not by itself establish what would have occurred under another treatment strategy.

Why does the design matter?

Random allocation can help balance measured and unmeasured participant characteristics between treatment groups. This trial is recorded as non-randomized and single-group, with no concurrent control. Phase I dose levels are part of sequential dose finding; the registry does not describe them as randomized comparison groups. Thus, comparisons among those groups cannot automatically be interpreted as estimates of the effect of changing the dose. Differences could reflect the sequence of enrollment, participant characteristics, follow-up, or other factors not addressed in the record.

Open-label means that masking was absent. Knowledge of assigned treatment can affect some aspects of care, reporting, or assessment, depending on the outcome and procedures. The registry does not report details that would permit assessment of how outcome assessment was conducted or whether safeguards were used.

How should safety counts be understood?

For the phase II group, the registry reports 25 participants at risk for serious adverse events and 16 affected. It separately reports 25 at risk for other adverse events and 22 affected, with 1 death. These are descriptive counts. They do not provide a controlled comparison, and the record does not provide enough detail to infer event timing, duration, recurrence, or causal attribution. A count of affected participants is also not necessarily a count of all event episodes.

The phase I dose-level groups are reported with their own at-risk and affected counts. Keeping the groups separate preserves the registry’s reporting structure. Pooling them would require decisions about which participants and events to combine, and no such combined analysis is reported. The listed percentages for serious adverse event terms should be read cautiously because the denominator is not reported in the registry record.

What do the sample-size illustrations mean?

Planning calculations based on an observed effect are not the same as the trial’s original sample-size justification. The registry’s description of those illustrations specifies assumptions including two-sided significance level 0.05, equal allocation between two arms, and a normal approximation. It also says that the target effect is a stated fraction of the observed effect, and distinguishes participant counts per arm from total event counts for time-to-event calculations. These are planning assumptions, not features of this single-group trial’s design and not observed power.

The observed primary effect and numerical planning results are not reported in the registry record. Therefore, the assumptions alone do not permit an interpretation of a sample-size estimate. In general, such calculations explore how much information a hypothetical comparison might require under specified assumptions. They cannot establish that the trial was adequately sized, and they do not substitute for an analysis of the observed outcome.

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("Vorinostat Plus Erlotinib Phase II")
n      <- c(22)
events <- c(6)
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  Vorinostat Plus Erlotinib Phase II  22  6  27.3  10.7  50.2  13.2  48.2  13.2  48.4

11. Multiplicity, Missing Data and Analysis Populations

The registry describes several outcomes across the brief summary and the outcome listings. It identifies response rate and safety as primary endpoints in the brief summary, while the separately specified primary outcome is progression-free survival rate at 12 weeks. The brief summary also mentions clinical benefit rate, time to progression, time to response, response duration, and progression-free survival as secondary endpoints. Overall survival and time to progression are listed as secondary outcomes. The registry record does not explain how these descriptions were prioritized or how they relate to the four outcome measures recorded.

When a study examines multiple outcomes, repeated tests can increase the chance that at least one result appears statistically noteworthy by chance. Statistical plans may address this through prespecified endpoint hierarchies, adjustment procedures, or other approaches. No multiplicity strategy is reported in the registry record. The record also does not report inferential analyses, so there are no posted p-values or confidence intervals across outcomes to assess in this regard.

The primary endpoint population is defined as all patients who received at least one dose. This is a reported population definition, but it does not resolve missing data or follow-up. The registry does not report how many participants lacked an assessment, how progression or death dates were verified, whether participants were censored, or how withdrawals were handled in the endpoint analysis. The brief summary says treatment could end with progression, unacceptable toxicity, or withdrawal of consent, but does not state the statistical handling of those events or subsequent missing observations.

These omissions limit assessment of completeness and potential bias. They do not establish that data were missing or that a particular analysis method was used. The detailed statistical plan, including its handling of multiplicity, missing data, and analysis populations, is not reported in the registry record.

12. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: fatigue (50.0%), diarrhea (50.0%), mucositis (50.0%), rash (33.3%), anorexia (20.0%).

The registry reports safety counts separately for the phase II group and each phase I dose level. In the phase II group, 25 participants were at risk for serious adverse events and 16 were affected. For other adverse events, 25 were at risk and 22 were affected; the group also lists 1 death. The phase I dose-level entries give their own at-risk and affected counts: dose level 1 lists 3 at risk and 0 affected for serious events, dose level 2 lists 3 at risk and 1 affected, and dose level 3 lists 2 at risk and 2 affected. The other-adverse-event counts are listed separately for those same groups.

These are descriptive registry counts, not comparative estimates. The phase I groups are not a randomized control comparison, and the single-group design supplies no concurrent control for phase II. The record does not state whether the listed death was considered treatment-related, nor does it report event timing, severity grading details, or the criteria for attribution.

The serious-event term list reports fatigue at 50.0%, diarrhea at 50.0%, mucositis at 50.0%, rash at 33.3%, anorexia at 20.0%, and fever at 4.0%. The denominator and further breakdown for these percentages are not reported in the registry record. They should not be used to infer individual risk or to compare this group with another population.

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

The registry record establishes that a sequential Phase I/II study of oral vorinostat plus erlotinib was conducted in people with advanced NSCLC and EGFR mutations after progression on erlotinib. It describes dose finding in phase I and safety and efficacy aims in phase II, reports enrollment of 33, and records the study as terminated. It also provides a definition for the primary progression-free survival outcome and an efficacy population definition.

The record does not report the primary progression-free survival rate at 12 weeks. As a result, readers cannot assess the observed rate, its precision, or whether it met any prespecified target. The outcome definition alone is not a result. The registry also does not report a reason for termination, the protocol’s sample-size justification, or detailed statistical methods.

The reported adverse-event counts and serious-event term percentages are descriptive. They do not establish a causal relationship between the combination and an event, and they do not provide a comparison with another treatment. The percentages have no denominator stated in the registry record. The phase I dose groups should not be interpreted as randomized comparators.

More generally, a single-group study can describe outcomes among enrolled participants, but without a concurrent control it cannot distinguish the effect of the treatment from other influences on those outcomes. That limitation remains even if an outcome estimate is precise. Conversely, the absence of a reported efficacy result does not show that the intervention had no effect; it means the registry record does not provide that result for evaluation.

Accordingly, the defensible interpretation is limited: the registry documents the trial’s design, intended outcome, population definition, enrollment, status, and selected safety summaries. It does not support a conclusion about the efficacy of the combination or a comparative safety judgment.

14. Why This Trial Matters Statistically

This trial illustrates why registry entries need to be read as records of design and reporting, rather than as complete trial reports. The primary outcome is named and defined, including the assessment time and the population intended for analysis. Yet the registry record does not report the primary estimate or its confidence interval. Readers can understand what was meant to be measured without being able to judge the observed result.

It also demonstrates the interpretive limits of a sequential, non-randomized, single-group design. Phase I dose finding and phase II assessment serve different purposes. Dose-level groups from the dose-finding part do not create a randomized control comparison, and the phase II group has no concurrent comparator in the record. Such distinctions matter when considering whether an observed outcome can be attributed to an intervention.

The adverse-event summaries provide another statistical lesson: counts and percentages are informative only when their denominators, definitions, and context are clear. The registry gives at-risk and affected counts for safety categories, but the denominators for the listed serious-event term percentages are not reported. These summaries can describe what was recorded without supplying a comparative risk estimate.

Finally, the record lists multiple outcome concepts but does not report how multiplicity, missing observations, or analysis populations beyond the primary efficacy definition were addressed. These details affect how readers assess the reliability and completeness of results. In this record, the most important statistical conclusion is not a treatment effect estimate; it is that the primary outcome result and key analysis details are unavailable.

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 trial-specific limitations restrict interpretation of the registry information. The study is explicitly non-randomized, open-label, and single-group. No concurrent control group is described, so the record cannot support a direct estimate of how outcomes differed from an alternative treatment or from no combination. The phase I dose-level groups are part of dose finding and should not be treated as control arms.

The primary progression-free survival rate at 12 weeks is defined but its result is not reported in the registry record. The numerical confidence interval is also not reported. Consequently, the primary efficacy finding and its precision cannot be assessed. Response and other efficacy outcomes mentioned in the brief summary are not accompanied by results in the record.

The record is marked terminated, but the reason is not reported in the registry record. It does not state whether all planned participants were enrolled or whether follow-up and outcome collection were complete. Although enrollment is listed as 33, the primary analysis population is defined by receipt of at least one dose; the number in that population is not reported.

Further details needed to evaluate the analyses are absent, including handling of censoring, missing assessments, withdrawals, and multiplicity. The registry does not give the denominator for the serious adverse event term percentages or details of attribution for the listed death. These omissions limit assessment of both efficacy and safety and should not be filled by assumptions.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Phase I/II of Oral Vorinostat Combination With Erlotinib in NSCLC Patients With EGFR Mutations With DP After Erlotinib. — NCT00503971.
• Registry record last updated 2025-03-07; status last verified 2025-02.
• Results first posted 2025-03-07.
• 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 an open-label, non-randomized, sequential Phase I/II single-group trial of vorinostat plus erlotinib in patients with stage IIIB or IV NSCLC with EGFR mutations after progression on erlotinib. Enrollment is listed as 33; the study status is terminated, with no reason stated in the registry record.

The primary outcome is progression-free survival rate at 12 weeks, defined from first treatment until progression or death from any cause. The efficacy population includes patients who received at least one dose. The primary result and its confidence interval are not reported in the registry record.

Safety counts are listed for phase II and phase I dose-level groups. The record does not provide a concurrent control comparison, detailed analysis methods, or the handling of missing data and multiplicity. Its information therefore supports a description of trial design and selected safety reporting, but not a conclusion about comparative efficacy.