Carboplatin and Paclitaxel With or Without Vorinostat in Treating Patients With Advanced Non-Small Cell Lung Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Carboplatin and Paclitaxel With or Without Vorinostat in Treating Patients With Advanced Non-Small Cell Lung Cancer (NCT01413750), a randomized phase 2 study. The primary outcome is Progression-free Survival (PFS).

2. Clinical Question

The clinical question was whether adding vorinostat to carboplatin and paclitaxel was associated with a different progression-free survival (PFS) profile than giving the same chemotherapy with placebo in patients with advanced non-small cell lung cancer. The registry describes eligible disease as stage IIIA, stage IIIB, or stage IV non-small cell lung cancer under AJCC v7.

The experimental arm received paclitaxel and carboplatin together with vorinostat. The comparator arm received paclitaxel and carboplatin together with placebo. The registry describes the study as a randomized, quadruple-masked, parallel phase II trial. Its stated primary endpoint was PFS, a time-to-event measure that captures time until disease progression or death due to any cause.

The record reports median PFS of 4.1 months for the vorinostat arm and 7.3 months for the placebo arm. These are descriptive estimates from the posted phase II groups, which had reported arm counts of 4 and 7, respectively. The registry also states that early termination meant the phase II portion did not reach planned accrual. The estimates therefore come from a limited set of participants and should not be treated as a definitive comparison of the regimens.

The central statistical question is how much information these medians provide about a randomized treatment contrast. The registry record does not report a hazard ratio, a formal between-arm test, or a complete confidence interval for either median. As a result, the posted medians alone do not quantify the precision of the difference between treatment groups or establish whether the observed contrast is compatible with a wide range of underlying effects.

3. Trial Design

This was a randomized, parallel-group phase II study sponsored by the National Cancer Institute. The registry describes masking as quadruple. The phase II comparison assigned participants to one of two regimens: paclitaxel and carboplatin with vorinostat, or paclitaxel and carboplatin with placebo. The chemotherapy was the same in both arms; the randomized contrast was whether vorinostat or placebo accompanied it.

In the vorinostat arm, paclitaxel was administered intravenously over 3 hours and carboplatin intravenously over 30 minutes on day 0. Vorinostat was taken orally once daily on days -2 to 2. In the placebo arm, paclitaxel and carboplatin were administered as in the other arm, with oral placebo once daily on days -2 to 2. The registry also lists laboratory biomarker analysis as an intervention.

The trial record gives enrollment as 23 and status as terminated. It states that the phase II portion ended early and did not reach planned accrual. The posted phase II PFS results give arm counts of 4 for vorinostat and 7 for placebo. The record does not explain how those endpoint counts relate to total enrollment, or why the study was terminated. These details limit interpretation of how representative the reported endpoint groups are of the intended study population.

The registry also describes phase I dose-level groups and lists dose-limiting toxicity and maximum tolerated dose as secondary outcomes. Those phase I elements are distinct from the randomized phase II efficacy comparison. The record does not report the planned target accrual, the statistical design assumptions behind that target, or whether any interim analyses were planned or conducted. Randomization helps structure a comparison, but it cannot compensate for the limited information in very small endpoint groups or for the absence of a reported inferential treatment comparison.

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.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Due to early termination phase II portion of the study did not reach planned accrual.

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 (PFS), measured over From first day of treatment to the first observation of disease progression or death due to any cause, assessed up to 1 year.

The primary endpoint was progression-free survival (PFS), measured in months. It is a time-to-event outcome: the registry defines it as time from randomization to disease progression or death due to any cause. The timeframe description separately says measurement began on the first day of treatment and was assessed up to 1 year. This difference in the stated time origin is not resolved in the registry record.

Progression was defined using RECIST v1.0: an increase of 20% in the sum of the longest diameters of target lesions, a measurable increase in a non-target lesion, or the appearance of new lesions. The endpoint therefore combines radiographic evidence of progression with death from any cause. Combining these events can capture clinically important deterioration without requiring progression to be the only event of interest.

Time-to-event outcomes are useful when the timing of an event matters and participants may have different lengths of follow-up. Kaplan–Meier estimation, named in the registry, can estimate the event-free survival pattern while accounting for censoring under its assumptions. The median is the time at which the estimated event-free proportion reaches the midpoint of its distribution. It does not describe every participant’s experience, and it does not by itself measure the size or precision of a treatment contrast.

The reported median PFS values are 4.1 months for vorinostat and 7.3 months for placebo. The corresponding registry entries give lower confidence limits of 0.5 and 0.4 months, but do not report upper limits. The incomplete intervals, together with the small phase II groups, leave the precision of these median estimates difficult to assess.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry says PFS was estimated with the product-limit method of Kaplan and Meier. This is a standard method for summarizing time-to-event data. Rather than reducing follow-up to a simple event count, it uses the timing of observed events and accounts for participants whose event time is not observed during their available follow-up. Such participants are commonly called censored. A Kaplan–Meier estimate depends on assumptions about censoring and follow-up; details about how censoring occurred or was handled are not reported in the registry record.

What does the median PFS describe?

The median is a summary of the estimated time-to-event distribution. It marks the point at which the estimated proportion remaining free of progression or death reaches one half. It is not the average time to an event, and it does not indicate that every participant experienced the event at that time. The registry reports a median of 4.1 months for vorinostat and 7.3 months for placebo. With small endpoint groups, the median can be sensitive to the timing of a small number of events and to censoring.

A median also compresses the survival curve into one number. Two groups can have different patterns of events over time even when their medians are similar, or similar patterns near the median but different patterns elsewhere. The registry does not report the complete Kaplan–Meier curves as numerical data, event counts, or a hazard ratio. It is therefore not possible to reconstruct the treatment comparison from the medians alone.

How should the confidence limits be read?

A confidence interval is an uncertainty summary for an estimate, constructed using a statistical procedure. In general, a wider interval indicates less precision, while a narrow interval indicates greater precision under the procedure’s assumptions. Here, the registry identifies the interval as a 95% confidence interval, but lists only the lower limit for each arm: 0.5 months for vorinostat and 0.4 months for placebo. The corresponding upper limits are not reported in the registry record. Without both limits, the interval’s width and full range cannot be assessed.

Confidence intervals for each arm’s median would not themselves be a confidence interval for the contrast between arms. A direct treatment comparison needs its own estimate and uncertainty measure. No such comparison is reported in this record. The posted medians should therefore be read as separate arm summaries, not as a fully quantified randomized effect.

Why does the time origin matter?

The endpoint description defines PFS from randomization to progression or death, while the timeframe statement says follow-up starts on the first day of treatment. Time-to-event results depend on their origin: changing the start point can alter the time assigned to an event. The registry record does not clarify whether these phrases refer to the same operational date in this trial. It is not appropriate to assume that they are interchangeable.

The timeframe also says assessment continued up to 1 year. This describes the stated assessment window, but the record does not give the distribution of follow-up or the number still under observation at particular times. The assessment window alone cannot establish how complete the event information was.

What can randomization and masking contribute?

Random allocation is intended to make treatment groups comparable in expectation, reducing systematic differences in who receives each regimen. Masking can limit some influences on treatment delivery, assessment, or reporting. The registry identifies the trial as randomized and quadruple-masked, but does not describe the specific people covered by that masking term or report enough procedural detail to evaluate how allocation was implemented. These design features support a structured comparison, but do not guarantee balance in a small sample or overcome incomplete outcome reporting.

The record does not report the randomization method, allocation concealment procedure, statistical analysis plan, or the model used for a treatment-effect estimate. General concepts about those methods cannot establish what the investigators actually did. In particular, no hazard ratio or associated confidence interval is posted for this PFS comparison, and no formal significance test is reported.

What is not possible to infer from the posted summaries?

It is not possible to calculate a valid time-to-event treatment effect from the two medians alone. Such a calculation would require information not reported in the registry record, including the event and censoring experience over time and a specified analysis approach. Nor should the group counts be used to infer unreported outcomes or missing participant data. The registry’s total enrollment and its endpoint counts are different reported quantities, and the record does not explain the relationship between them.

These methods explain why the medians are useful as descriptive summaries but insufficient as a complete efficacy analysis. Their interpretation depends on study size, event timing, censoring, follow-up, and the uncertainty around each estimate. With small phase II groups, incomplete confidence intervals, and no reported between-arm analysis, the data provide limited precision about the randomized contrast.

10. Multiplicity, Missing Data and Analysis Populations

The registry record does not report a statistical analysis plan or explain how multiple outcomes or comparisons were handled. It lists PFS as the primary outcome and lists dose-limiting toxicity and maximum tolerated dose as secondary outcomes associated with the phase I portion. The record also states that there were three outcome measures, but the available information does not establish a multiplicity adjustment or a hierarchy for interpreting tests. Since no inferential PFS comparison is posted, there is no reported p-value set from which to assess multiplicity handling.

The record does not describe its analysis populations, such as whether the PFS analysis followed an intention-to-treat principle or used another defined group. It does not explain how participants who were randomized but are not represented in the posted endpoint arm counts were handled. The total enrollment is 23, while the PFS arm counts are 4 and 7; no accounting of the difference is reported. It would be inappropriate to assume that those not reflected in the endpoint counts had a particular outcome or reason for exclusion.

For a time-to-event endpoint, incomplete follow-up and censoring affect the information available, but censoring counts, reasons, and follow-up details are not reported. The registry gives lower confidence limits for both medians but no upper limits. It also does not report missingness for the endpoint or an approach for handling missing outcome information. The absence of such details prevents assessment of whether missing data could have influenced the estimates.

Because the study terminated early and did not reach planned accrual, the available results should be understood as incomplete relative to the planned phase II study. The reason for termination, any rules that led to it, and whether results were examined during the study are not reported in the registry record. No interim analysis or stopping procedure should be inferred from early termination alone.

11. 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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: neutrophil count decreased (57.1%), lymphocyte count decreased (28.6%), white blood cell decreased (28.6%), dehydration (28.6%), nausea (25.0%).

The registry reports serious adverse event figures for four groups: phase I dose level 1, phase I dose level 2, phase II vorinostat, and phase II placebo. For serious adverse events, the counts reported as affected are 3 of 6 at phase I dose level 1, 3 of 6 at phase I dose level 2, 3 of 4 in phase II vorinostat, and 5 of 7 in phase II placebo. These are group-specific counts, not a direct estimate of the randomized treatment effect.

The registry also reports other adverse events in all participants listed at risk in each group: 6 of 6 at each phase I dose level, 4 of 4 in phase II vorinostat, and 7 of 7 in phase II placebo. Serious and other adverse event categories should not be conflated. The record lists no death counts for these groups.

Listed serious adverse event terms include neutrophil count decreased at 57.1%, lymphocyte count decreased at 28.6%, white blood cell decreased at 28.6%, dehydration at 28.6%, nausea at 25.0%, and vomiting at 25.0%. The registry does not specify the denominator or group attribution for these term percentages in the available record. They should not be assigned to a particular arm or interpreted as rates in a defined analysis population.

These figures are descriptive. The small group counts and the inclusion of both phase I and phase II cohorts make broad comparisons difficult. They do not, by themselves, establish that one regimen has a higher or lower risk than the other.

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

The results establish what the registry reports: median PFS was 4.1 months in the phase II vorinostat arm and 7.3 months in the phase II placebo arm. The trial was randomized and quadruple-masked, but its phase II portion terminated before reaching planned accrual. The endpoint groups were small, and the record reports only the lower confidence limits for the medians. These circumstances constrain the strength and precision of conclusions that can be drawn.

The medians do not establish that adding vorinostat caused a change in PFS. A randomized design aims to support causal comparisons, but a treatment-effect estimate and its uncertainty are needed to interpret the contrast. The record does not report a hazard ratio, a formal between-arm test, or a complete confidence interval for the treatment comparison. The numerical ordering of two arm medians is not sufficient evidence of a treatment effect.

Nor do these results establish equivalence or lack of effect. A finding of no reported inferential comparison is not evidence that the regimens perform identically. The incomplete median intervals and absence of a comparative uncertainty estimate mean that the record does not show how compatible the observed data are with different possible effects.

The registry also does not report enough information to reconstruct the time-to-event analysis or assess the endpoint population. It describes PFS as beginning at randomization but gives the timeframe as beginning on the first day of treatment. The relationship between those definitions is unclear. Follow-up details, event counts, censoring information, and the analysis population are not reported.

The appropriate interpretation is therefore descriptive and cautious: the posted medians summarize the reported phase II groups, but the incomplete accrual and limited statistical reporting do not support a dependable estimate of the treatment contrast. No clinical recommendation follows from these figures alone.

13. Why This Trial Matters Statistically

This trial illustrates why an endpoint estimate and a treatment comparison are not the same thing. Median PFS offers a compact description of each arm’s time-to-event experience, but it does not quantify the randomized contrast or its uncertainty. A comparative hazard ratio or another suitable treatment-effect estimate, accompanied by an uncertainty measure, would be needed to address that question more directly. The registry record does not report such a comparison.

It also illustrates the importance of accrual and precision. The registry reports phase II endpoint counts of 4 and 7 and says that early termination prevented the phase II portion from reaching planned accrual. In small groups, the estimate can be influenced by a small number of event times, and confidence limits can be especially important for judging uncertainty. Here, only the lower limits for the median confidence intervals are reported.

Time-to-event methods require more than a stated endpoint and a median. The definition of the time origin, event criteria, follow-up, and censoring all shape interpretation. The record includes a difference between the stated PFS time origin and the timeframe wording, and it does not provide event and censoring details that would let readers evaluate the estimated curves.

Finally, early termination should not be mistaken for a particular statistical stopping rule. The registry does not report why termination occurred, whether any interim analysis took place, or what analysis plan governed the efficacy comparison. Separating details in the record from unreported design details is essential. The study can be described accurately without claiming more than its incomplete results support.

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 most direct limitation is that the registry says the phase II portion did not reach planned accrual because of early termination. The record gives total enrollment as 23, but does not state the planned phase II target or explain the reason for termination. It does not report whether the decision was related to recruitment, safety, efficacy, operations, or another consideration; none of these possibilities should be inferred.

The reported PFS groups are small: 4 in the vorinostat arm and 7 in the placebo arm. The record does not explain how these endpoint counts relate to total enrollment or describe the analysis population. It is therefore not possible to determine from the registry record why other enrolled participants are not reflected in these arm counts or how they were handled.

Uncertainty reporting is incomplete. Although the interval type is given as a 95% confidence interval, the upper limit is not reported for either median. There is no reported hazard ratio, comparative confidence interval, or formal test. Event counts, censoring information, and detailed follow-up are also absent, limiting independent assessment of the Kaplan–Meier estimates.

The endpoint’s time origin is described in two ways: the definition starts at randomization, while the timeframe starts on the first day of treatment. The record does not clarify the relationship between these dates. Analysis populations, missing-data handling, and multiplicity procedures are not reported. These limitations are specific to interpreting this registry record and prevent a fuller assessment of the randomized PFS comparison.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Carboplatin and Paclitaxel With or Without Vorinostat in Treating Patients With Advanced Non-Small Cell Lung Cancer — NCT01413750.
• Registry record last updated 2024-11-12; status last verified 2024-10.
• Results first posted 2015-08-18.
• 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

The registry describes a randomized, quadruple-masked, parallel phase II study of carboplatin and paclitaxel with either vorinostat or placebo in advanced non-small cell lung cancer. It reports enrollment of 23 and a terminated status, noting that the phase II portion did not reach planned accrual.

The primary endpoint was PFS, estimated by the Kaplan–Meier product-limit method. Reported medians were 4.1 months for vorinostat and 7.3 months for placebo, with endpoint arm counts of 4 and 7. The registry lists lower 95% confidence limits of 0.5 and 0.4 months, respectively, but does not report upper limits or a comparative treatment-effect analysis.

Phase I dose-limiting toxicity and maximum tolerated dose are listed as secondary outcomes. The record does not report the reason for termination, the analysis population, the relationship between enrollment and endpoint counts, or details needed to fully assess follow-up and censoring. The PFS estimates are therefore descriptive and imprecise evidence for the randomized comparison.