Ph II Erlotinib + Sirolimus for Pts w Recurrent Malignant Glioma Multiforme: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Ph II Erlotinib + Sirolimus for Pts w Recurrent Malignant Glioma Multiforme (NCT00672243), a non-randomized phase 2 study. The primary outcome is 6-month Progression-free Survival (PFS).

2. Clinical Question

3. Trial Design

This was a phase 2, nonrandomized, single-group study with no masking. The registry lists Duke University as sponsor and describes the study as completed. Enrollment was 32. The recorded start was 2007-04, and primary completion was 2008-09. These dates describe the registry record; they do not establish the duration of follow-up for every participant.

All participants were assigned to the erlotinib-plus-sirolimus treatment group; there was no randomized allocation or control arm. The intervention was administered daily on a 28-day cycle. Doses differed according to whether a participant was taking concurrent enzyme-inducing anti-epileptic drugs: the record lists 150 mg of erlotinib and 5 mg of sirolimus without those drugs, and 400 mg of erlotinib and 10 mg of sirolimus with them. Further details of dose modification, treatment duration, adherence, or discontinuation are not reported in the registry record.

The primary objective focused on 6-month PFS. Secondary objectives were to further define safety and tolerability and to evaluate PFS, radiographic response, and overall survival. The listed secondary outcomes include median PFS, median overall survival, best radiographic response, and the number of participants experiencing at least Grade 3 treatment-related non-hematologic toxicity. Although the record lists five outcome measures, it does not include analysis entries. Numerical results for the primary endpoint and the secondary outcomes are not reported in the registry record.

A single-group phase 2 design can describe outcomes observed during treatment and can support assessment of whether further study is warranted. It does not provide a concurrent comparison that controls for differences in prognosis or changes over time. The registry record does not report a protocol-level statistical plan or a sample-size justification, so the intended precision or decision threshold for the study cannot be established from this 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: Patients were excluded for any of the following: prior therapy with either an EGFR or mTOR antagonist; uncontrolled intercurrent illness including active infection, symptomatic congestive heart failure, unstable angina, grade 3 or greater hyperlipidemia or significant gastrointestinal, renal or liver disease, pregnancy or nursing

Overall Study

Analysis population for the primary outcome, as defined in the registry: Intent to treat (ITT)

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 6-month Progression-free Survival (PFS), measured over 6 months.

The primary endpoint is 6-month PFS, expressed as a percentage of participants. The registry defines PFS as time from the date study treatment began to the first documented progression under the Macdonald criteria, or death from any cause. For this endpoint, progression includes at least a 25% increase in the sum of the products of perpendicular diameters of enhancing lesions, any new lesion, or clinical deterioration. A participant is counted as progression-free at 6 months only if neither progression nor death has occurred by that time.

PFS is used in oncology studies because it captures time without documented progression or death, combining radiographic and clinical aspects of disease course. As a general statistical concept, a fixed-time PFS percentage can make a time-to-event outcome easier to communicate at a particular follow-up point. It does not describe how long each participant remained progression-free, and it does not by itself explain the pattern of events over the full follow-up period.

The endpoint names an ITT population. The registry record does not report the observed 6-month PFS percentage, its confidence interval, the number of participants included in the calculation, or the method used to handle participants whose 6-month status was not known. Thus, the endpoint definition is available, but its numerical result and precision are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The study is described as phase 2, nonrandomized, and single-group. These design features define what statistical conclusions can be drawn. A single-group study can report the distribution of outcomes in the enrolled treatment group, but it cannot estimate a randomized between-group contrast. Because there is no allocation to a control treatment, comparisons with other populations or historical expectations would require assumptions that are not described in the registry record.

What does the primary endpoint count?

The primary outcome is a percentage at a specified time point: the percentage of the ITT population alive without progression at 6 months after treatment initiation. The registry definition treats either documented progression or death from any cause as an event for PFS. Progression is defined using Macdonald criteria, including a threshold increase in enhancing lesions, a new lesion, or clinical deterioration. This definition matters because the outcome depends on both the timing of events and the criteria used to classify progression.

As a general statistical concept, a time-to-event endpoint uses the time from a defined starting point until an event occurs. Participants who have not experienced an event by the end of their observed follow-up may contribute information up to that point, depending on the analysis method. The statistical handling of such incomplete follow-up is often called censoring. The registry record does not state the censoring rules or the method used to estimate the 6-month PFS percentage, so no particular method should be attributed to this study.

How should uncertainty be understood?

The primary endpoint specifies a 95% confidence interval, but the numerical interval is not reported in the registry record. As a general explanation, a confidence interval expresses statistical uncertainty around an estimate under the assumptions of the analysis. Its width depends on factors including the amount of information available and the method used. A point estimate alone would not communicate that uncertainty; in this record, neither the point estimate nor its interval is available.

The registry record does not report a hypothesis test, p-value, or a prespecified statistical comparison for the primary endpoint. Nor does it state how the endpoint was estimated or whether covariate adjustment was used. Those details cannot be inferred from the fact that the study is phase 2 or from the endpoint definition.

What can the secondary outcomes add?

The listed secondary outcomes cover time-to-event measures, response, and toxicity. Median PFS and median overall survival summarize the time-to-event distributions using their respective event definitions. Best radiographic response describes the strongest response category recorded during the assessment period, although the response categories and assessment procedures are not reported in the registry record. The toxicity outcome is the number of participants experiencing at least Grade 3 treatment-related non-hematologic toxicity. The record does not provide results for these outcomes or describe the methods used to assess them.

As a general statistical point, different endpoints answer different questions. A fixed-time PFS percentage concerns status at a particular point, whereas a median time-to-event measure concerns the middle of an event-time distribution. A response measure concerns radiographic change, and a toxicity measure concerns harms. Results across these measures are not interchangeable. The registry record does not give enough analysis detail to evaluate how these outcomes were defined operationally or whether assessments were conducted consistently.

What do the sample-size illustrations mean?

The record describes sample-size calculations as planning illustrations based on an observed effect, with two-sided significance level 0.05, equal allocation between two arms, and a normal approximation. It states that the effect to detect is a specified fraction of the observed effect, and that time-to-event illustrations use a total event count while other illustrations use participants per arm. These are general planning assumptions, not evidence that the trial randomized participants between two arms. The actual study was single-group and nonrandomized.

A planning calculation asks how much information might be needed to detect a chosen effect under stated assumptions. It is not the same as the observed power of a completed study. Because no observed efficacy estimate or numerical planning outputs are reported in the registry record, the illustrations cannot be interpreted as evidence about the magnitude of an effect or the precision achieved in this study. The registry also does not report its own sample-size justification, so the relationship between any planning illustration and the original study design is not established.

What is not documented?

The registry record lists no analysis entries and does not report the statistical analysis plan, missing-data procedures, interim analyses, or adjustments for multiple outcomes. These omissions are important because analysis choices can affect estimates and their uncertainty. The absence of those details does not establish that no such procedures were used; it means they are not reported in the registry record. The sponsor's analysis cannot be evaluated against any recalculation because no numerical efficacy summaries or analysis results are reported.

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("Erlotinib + Sirolimus")
n      <- c(32)
events <- c(1)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Erlotinib + Sirolimus  32  1  3.1  0.1  16.2  0.6  15.7  0.7  15.8

11. Multiplicity, Missing Data and Analysis Populations

The record names a primary endpoint and several secondary outcomes, but it does not report how statistical testing across these outcomes was handled. When multiple outcomes or repeated tests are considered, the chance of at least one apparently unusual result can increase. As a general statistical concept, multiplicity procedures may control that risk, but their use and details must be documented to assess their effect on interpretation. No multiplicity adjustment or testing hierarchy is reported in the registry record.

The primary endpoint specifies an ITT population. This identifies the intended population for the primary outcome, but it does not, by itself, explain how participants with missing endpoint status were handled. The registry record does not report the number of participants with missing follow-up, the reasons for missingness, imputation methods, censoring rules, or sensitivity analyses. It also does not report the number included in each outcome analysis. Enrollment of 32 should not be assumed to equal the analysis denominator for every endpoint.

The record lists five outcome measures and no analysis entries. No statistical analysis plan, interim analysis, or prespecified rules for handling multiple outcomes are reported in the registry record. These limitations prevent an assessment of whether the posted outcomes, if available elsewhere, would reflect prespecified analyses or how missing data and multiple testing might affect their uncertainty. They do not establish that such procedures were absent; their status is not reported in the registry record.

12. Safety Results

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

Other (non-serious) adverse events

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

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: fever (6.2%), seizure (6.2%), abdominal pain (3.1%), colitis (3.1%), mucositis oral (3.1%).

The adverse-event record lists 32 participants at risk for serious adverse events and 4 affected. It also lists 32 at risk for other adverse events and 26 affected. These are separate registry categories. The record does not provide enough detail to determine whether participants could be counted in both categories, so the counts should not be added together.

The listed serious-event terms and percentages are fever, 6.2%; seizure, 6.2%; abdominal pain, 3.1%; colitis, 3.1%; mucositis oral, 3.1%; and skin infection, 3.1%. They describe reported serious events, but the record does not give event counts alongside each percentage, detailed definitions, timing, or participant-level overlap. The percentages should therefore be read as registry entries, not as a complete account of all safety outcomes or as a comparison between treatments.

The record lists deaths as not reported. This does not mean that no deaths occurred; the number of deaths is not reported in the registry record. There is no control group for a comparative safety assessment, and the registry does not report the complete safety analysis or follow-up duration. The listed figures describe what the record contains, not the full balance of potential benefits and harms.

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

The study addresses a clinically relevant statistical question: what proportion of participants with recurrent GBM remained alive without documented progression 6 months after starting erlotinib plus sirolimus? The registry defines this endpoint and identifies an ITT population. It also describes a 32-participant, nonrandomized, single-group phase 2 study and lists safety, survival, and radiographic outcomes.

However, the registry record does not report the numerical primary outcome, its confidence interval, or numerical results for the secondary outcomes. The outcome definitions alone cannot establish what was observed. Without an estimate and its uncertainty, the magnitude and precision of the 6-month PFS result cannot be assessed from this record.

Even if a single-group outcome estimate were available, it would describe the treated group rather than provide a randomized comparison. No concurrent comparator is described, so the record cannot establish how outcomes would have differed under another treatment or no study treatment. The design also does not permit a like-for-like causal comparison based solely on observed outcomes.

The safety entries report affected-participant counts and selected serious-event terms, but they do not provide a complete comparative safety assessment. Definitions, event-level details, and death counts are not reported in the registry record. The listed adverse-event figures should not be treated as proof that the regimen is safe or unsafe.

Overall, the record documents the study question, intervention, design, endpoint definition, and selected safety data. It does not report the efficacy estimates or analysis details needed to judge the primary result, its precision, or the robustness of the statistical conclusions. These are limits of what the registry record documents, not evidence that unreported findings did or did not occur.

14. Why This Trial Matters Statistically

This trial is statistically instructive because the study question is framed around a time-to-event outcome but reported as a percentage at a fixed time point. Understanding the definition is essential: PFS begins at treatment initiation and ends at documented progression under the stated criteria or death from any cause. Different rules for determining progression or handling follow-up could affect an estimate, so transparent reporting of those methods is important.

The nonrandomized, single-group design also illustrates the distinction between describing outcomes and estimating a comparative treatment effect. A study can document what happened in a treated group, but without a concurrent comparator it cannot separate treatment-associated outcomes from other influences using randomization. This distinction remains important even when a study has a clearly defined endpoint and a stated ITT population.

Another statistical lesson is that endpoint definitions and results are not substitutes for one another. The record describes the primary measure and names secondary outcomes, yet numerical outcome estimates and their uncertainty are not reported. Without those estimates, readers cannot evaluate precision, compare the primary and secondary findings, or judge whether the observed evidence aligns with the stated objectives.

Finally, the record demonstrates why planning assumptions should be kept separate from completed-study results. Its sample-size description refers to planning illustrations, whereas this study is documented as a single-group trial. Such calculations are not observed power and do not supply missing outcome estimates. Clear reporting of the analysis population, missing-data handling, multiplicity procedures, and uncertainty would be needed to support a fuller statistical interpretation.

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.

The main limitation for interpretation is that the registry record does not report numerical efficacy results. The primary endpoint is defined, but its 6-month percentage and 95% confidence interval are absent. Numerical results for median PFS, median overall survival, best radiographic response, and the listed toxicity outcome are also not reported. Consequently, no estimate of efficacy or precision can be assessed from this record.

The design had no randomized comparator and no masking. The record therefore offers no concurrent control comparison, and it does not describe procedures that might reduce assessment bias. Further information about eligibility, baseline characteristics, previous treatment, follow-up, treatment exposure, dose changes, and reasons for discontinuation is not reported in the registry record. These details would be relevant to understanding the enrolled group and the completeness of outcome ascertainment.

The registry specifies an ITT population for the primary endpoint, but the analysis denominator, missing-data procedures, and censoring rules are not reported. The record does not describe the statistical analysis plan, methods for estimating time-to-event outcomes, multiplicity handling, or interim analyses. It also does not provide a trial-specific sample-size justification. The planning assumptions listed in the record do not establish what analysis was used in the completed study.

Safety reporting is also limited. The record gives affected-participant counts, selected serious-event terms, and percentages, but does not report event-level detail, overlap between categories, the death count, or a comparative safety analysis. Taken together, these limitations mean that the registry documents important design and endpoint features but does not permit a complete evaluation of efficacy, uncertainty, or safety.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Ph II Erlotinib + Sirolimus for Pts w Recurrent Malignant Glioma Multiforme — NCT00672243.
• Registry record last updated 2013-08-07; status last verified 2013-07.
• Results first posted 2013-04-04.
• 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

NCT00672243 is a completed phase 2, nonrandomized, single-group study sponsored by Duke University. The registry records enrollment of 32 and dates of 2007-04 for study start and 2008-09 for primary completion. Participants received daily erlotinib plus sirolimus on a 28-day cycle, with dosing described according to concurrent use of enzyme-inducing anti-epileptic drugs.

The primary objective was 6-month PFS in patients with recurrent GBM. The endpoint is defined as the percentage alive without progression from treatment initiation, using the stated Macdonald criteria and including death from any cause as an event. Secondary objectives and outcomes concern safety, PFS, overall survival, radiographic response, and toxicity.

The registry record does not report numerical efficacy results, the primary confidence interval, or analysis details. It lists selected adverse-event figures, but deaths are not reported in the registry record. The single-group design does not provide a randomized comparator.