Phase (Ph) II Bevacizumab + Erlotinib for Patients (Pts) With Recurrent Malignant Glioma (MG): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase (Ph) II Bevacizumab + Erlotinib for Patients (Pts) With Recurrent Malignant Glioma (MG) (NCT00671970), a na phase 2 study. The primary outcome is 6 Month Progression-free Survival.

2. Clinical Question

This is a question about an outcome within a treated group, not a direct estimate of how the combination compares with another treatment or with no treatment. A proportion alive and progression free at a specified time describes the share of participants who met both conditions at that time. It does not, by itself, identify what would have happened to the same participants under a different treatment.

The stated secondary objectives broadened the inquiry to safety and tolerability, radiographic response, erlotinib pharmacokinetics, and relationships between clinical response and tumor biomarkers. The listed biomarker topics include EGFR, EGFR vIII, PTEN, phosphorylated AKT, and phosphorylated MAPK. These additional questions are distinct from the primary progression-free survival objective and require their own outcome definitions and analyses.

3. Trial Design

The registry identifies this as a Phase II trial with a single-group model and no masking. Allocation is recorded as not applicable. The intervention is bevacizumab plus erlotinib, and the listed conditions are glioblastoma and gliosarcoma. Enrollment is recorded as 57. The trial status is completed.

Because there is no separate control arm, the design can describe outcomes among participants treated with the combination, but it cannot make a randomized, within-trial comparison against another treatment. Differences between outcomes in this group and outcomes reported elsewhere would not be protected by random allocation and could reflect differences in participants, care, outcome definitions, or follow-up. The record explicitly indicates that the arms are not a like-for-like control comparison; in this trial, the listed design is single group.

The record lists a start date of 2007-02 and a primary completion date of 2008-11. These dates identify the trial timeline recorded in the registry, but they do not establish how long each participant was followed. Participant-level follow-up duration and the handling of censoring are not reported in the registry record.

The primary objective was estimation of 6-month progression-free survival probability. Secondary objectives included radiographic response, safety and tolerability, erlotinib pharmacokinetics, and biomarker associations. The record lists Cmax and AUC for pharmacokinetics and associations with one-year survival for several biomarkers. Details needed to reproduce these analyses, including the analysis populations, adjustment methods, and endpoint-specific missing-data rules, are not reported in the registry record.

The record does not report the protocol’s statistical analysis plan, sample-size justification, interim analyses, or any prespecified decision threshold for interpreting the primary result. Those items should not be inferred from the Phase II label or from the study objectives.

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

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, measured over 6 months.

The primary endpoint is the proportion of participants alive and progression free at 6 months. It combines two conditions at a fixed time: a participant must be alive and must not have experienced disease progression by that point. The registry describes the endpoint as a proportion and lists a 95% confidence interval as its dispersion measure.

This type of endpoint is used to express disease control over a clinically defined period in a form that can be interpreted as a group-level probability. It is different from radiographic response: a response endpoint generally asks whether tumor measurements meet a response definition, whereas progression-free survival also accounts for whether progression has occurred and whether the participant is alive at the specified time. The registry record does not report the detailed criteria used to determine progression or the assessment schedule.

A confidence interval communicates the statistical uncertainty around an estimated proportion. In general, a narrower interval indicates greater precision, while a wider interval indicates less precision. It does not describe the range of outcomes for individual participants, and it does not account automatically for design limitations such as the absence of a control group.

The numerical 6-month estimate and its 95% confidence interval are not reported in the registry record. The record therefore identifies what the primary endpoint was intended to measure, but does not permit a numerical interpretation of the result.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

A proportion is a summary of how many people in an analyzed group meet a specified outcome definition. For this trial, the target outcome was being alive and progression free at 6 months. The registry lists the primary measure as a proportion of participants and specifies a 95% confidence interval. The estimate itself, the interval limits, and the analysis denominator are not reported in the registry record.

What does the confidence interval convey?

In general, a confidence interval expresses uncertainty associated with an estimate under the statistical method used. It helps readers distinguish a relatively precise estimate from one that remains uncertain. It is not a guarantee that the true value lies inside the reported interval, and it does not correct for bias from study design, outcome measurement, or missing follow-up. Since the primary interval is not reported in the registry record, its precision cannot be assessed.

What does a single-group design allow?

A single-group study estimates outcomes in participants who received the intervention. Without a concurrent control group, it cannot isolate the effect of treatment from the course of disease, participant selection, other care, or differences in follow-up. General statistical principle: random allocation is one way to make comparison groups more similar on average, but this trial is not recorded as randomized and has no like-for-like control comparison. A descriptive estimate and a comparative treatment effect answer different questions.

How should planning calculations be read?

The registry’s sample-size assumptions describe planning illustrations based on a fraction of an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. These are planning assumptions, not a description of the actual single-group design. The illustrations are not observed power and should not be treated as outcomes from the trial. The registry record does not report the trial’s own sample-size justification. Since the primary effect estimate is not reported in the registry record, no numerical planning interpretation based on that effect can be made from the information available.

In general, power is a design-stage probability under specified assumptions, not a measure of whether a completed study has produced a reliable result. A post hoc calculation based on an observed effect does not substitute for reading the estimate and its uncertainty. Planning calculations also do not resolve the lack of a control group or establish that the assumptions match the trial’s design.

Why do analysis details matter?

For a time-to-event outcome, interpretation depends on how progression and death are defined, how the timing of events is recorded, and how participants without a known event at the analysis point are handled. In general, censoring allows participants with incomplete event information to contribute follow-up up to the point their status is last known, but the assumptions and implementation matter. The registry record does not report the progression criteria, censoring rules, estimator, or analysis population used for the primary endpoint.

Likewise, a reported proportion can depend on whether all enrolled participants are included or whether the calculation uses a narrower analysis population. The registry record does not report the primary analysis denominator or how missing endpoint assessments were handled. It is therefore not possible to determine from the record whether the endpoint was analyzed in all enrolled participants or under another rule.

How should the safety summaries be interpreted statistically?

Safety summaries describe recorded events in the monitored group. A count of participants affected is not the same as a count of event episodes, because an individual may experience more than one event. The registry record does not provide event-level detail sufficient to determine how repeated events are represented. Percentages for named serious-event terms describe the registry entries, but do not provide a controlled comparison of event risk. General principle: event rates can be difficult to compare across studies when definitions, follow-up, ascertainment, or participant characteristics differ.

Over-dispersion is a general statistical issue that arises when variation in event counts exceeds what a simple model assumes. It can make standard errors too small if a model fails to account for that extra variation. The registry record does not report a count-model analysis or an over-dispersion adjustment for this trial; this concept should not be read as evidence that such a method was used.

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("Who Grade III", "WHO Grade IV")
n      <- c(32, 25)
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  Who Grade III  32  0  0.0  0.0  10.9  0.0  10.7  0.1  10.6
ARM  WHO Grade IV  25  0  0.0  0.0  13.7  0.0  13.3  0.1  13.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists multiple secondary questions spanning radiographic response, erlotinib pharmacokinetics, and biomarker associations with one-year survival. When several outcomes or associations are examined, the chance of at least one apparently notable result can increase if each is assessed separately without accounting for the number of analyses. General statistical approaches to this issue include prespecifying a primary outcome, adjusting for multiple comparisons, or treating secondary findings as exploratory. Which approach was used in this trial is not reported in the registry record.

The record does not report a multiplicity strategy, a hierarchy among secondary outcomes, or whether particular analyses were designated exploratory. The listed primary objective identifies the main question, but does not establish how the statistical analysis plan handled the secondary outcomes.

Missing-data methods also affect interpretation. For the 6-month endpoint, participants may have incomplete progression or survival status at the relevant time; in general, the handling of such information can affect both the estimate and its uncertainty. The registry record does not report missing-data counts, reasons for missingness, imputation procedures, or sensitivity analyses. It also does not report the analysis populations for the primary or secondary outcomes.

These omissions limit reproducibility and make it difficult to assess whether the reported analyses, if any, followed prespecified rules. They do not establish that data were missing or that an inappropriate analysis was conducted; the relevant information 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: seizure (8.8%), headache (5.3%), thromboembolic event (5.3%), nausea (3.5%), vomiting (3.5%).

The registry lists an all-patients safety group with 57 at risk and 20 affected in the serious adverse event fields. The top serious-event terms and recorded percentages are seizure, 8.8%; headache, 5.3%; thromboembolic event, 5.3%; nausea, 3.5%; vomiting, 3.5%; and Death NOS, 3.5%. These are registry summaries and should be read as descriptions of recorded events, not as proof that the treatment caused them.

The record also lists 52 affected among 57 at risk in the other adverse-event fields. The registry information does not explain the event definitions or the relationship between these fields and the serious-event summaries. Do not add the affected counts together: the record does not establish that they represent separate participants.

A serious adverse event is a safety classification, while the listed event term describes what was recorded. The Death NOS term is part of the serious-event listing; the separate deaths field is not reported. The registry record does not provide timing, severity details beyond the serious classification, duration, relatedness assessments, or event-level counts. Without a control group and comparable ascertainment, these summaries cannot show whether the frequency differs from another treatment.

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

The record identifies the intended primary measure: the proportion of participants alive and progression free at 6 months after treatment with bevacizumab plus erlotinib. It also identifies a Phase II, single-group design and reports selected safety information. The primary numerical estimate and its 95% confidence interval are not reported in the registry record, so the magnitude and precision of the primary finding cannot be evaluated from the record.

Even if the primary proportion were available, a single-group result would describe outcomes among participants in that group. It would not establish a comparative treatment effect, because there is no randomized control group in the recorded design. General statistical principle: comparison with an external group is vulnerable to differences in eligibility, disease status, care, follow-up, and outcome assessment. The single-group estimate also cannot establish what would have happened to the same participants under another treatment.

The safety summaries identify recorded serious adverse events and other adverse-event entries, but they do not establish causality. They lack the detail needed to interpret event timing, relatedness, or differences from a comparator. The record’s listed secondary aims likewise do not establish that particular radiographic, pharmacokinetic, or biomarker findings were statistically supported; detailed results and analysis methods are not reported in the registry record.

The absence of a numerical primary result is not evidence that the result was favorable, unfavorable, or null. It is a limit on what can be concluded from the registry record. The record can be used to understand the trial’s design, intended endpoint, and selected safety summaries, but not to quantify the primary outcome or make a controlled comparison.

14. Why This Trial Matters Statistically

This trial illustrates why the endpoint, design, and result need to be interpreted together. A 6-month progression-free survival proportion is a defined clinical summary, and a confidence interval would communicate uncertainty around that estimate. Yet the registry record does not report the estimate or interval. Without them, readers cannot assess either the observed level of progression-free survival or the statistical precision of the primary result.

The single-group design also clarifies the boundary between description and comparison. An outcome in a treated group can be clinically and statistically informative as a description, but it cannot by itself answer how outcomes would differ under another treatment. This distinction is central when interpreting Phase II studies: the study objective is an estimation question, while a comparative claim requires a valid basis for comparison.

The record’s secondary objectives show how a trial can address several kinds of evidence, including tumor response, drug exposure, safety, and biomarker relationships. These questions require different outcome definitions and statistical methods. When the analysis plan, multiplicity approach, and analysis populations are not reported, the strength and reproducibility of secondary findings cannot be evaluated from the registry record.

Finally, the safety summaries demonstrate the value of separating event descriptions from causal conclusions. Recorded percentages and affected counts can help characterize what was reported during the study, but interpretation also depends on follow-up, ascertainment, event definitions, and a suitable comparator. Statistical reading is therefore not only about the numerical estimate; it is also about what design and reporting permit the estimate to mean.

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 interpreting the primary objective is that the 6-month progression-free survival estimate and 95% confidence interval are not reported in the registry record. The primary analysis denominator, progression criteria, assessment schedule, and handling of incomplete follow-up are also not reported. These omissions prevent assessment of the result’s numerical size, precision, and reproducibility.

The single-group design has no concurrent control comparison. It can describe outcomes among treated participants but cannot separate treatment effects from other explanations for those outcomes. Masking is recorded as none, and the registry does not report additional measures that might clarify how outcome assessment was standardized.

Further trial-specific details are not reported in the registry record, including dosing, treatment duration, eligibility criteria, statistical analysis plan, sample-size justification, interim analyses, missing-data methods, and analysis populations. The record lists secondary questions, but detailed results and methods for those questions are not available in the information.

The safety record contains affected counts and named serious-event terms, but does not report event-level timing, relatedness, duration, or the details needed to distinguish repeated events from participants affected. The separate deaths field is not reported. These limits mean the safety summaries should be treated as descriptive registry entries rather than causal or comparative estimates.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Phase (Ph) II Bevacizumab + Erlotinib for Patients (Pts) With Recurrent Malignant Glioma (MG) — NCT00671970.
• Registry record last updated 2013-05-13; status last verified 2013-03.
• Results first posted 2013-05-13.
• 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 identifies NCT00671970 as a completed Phase II trial of bevacizumab plus erlotinib for recurrent malignant glioma, including glioblastoma and gliosarcoma. It is recorded as a single-group, unmasked study with allocation not applicable and enrollment of 57.

The primary objective was to estimate the proportion of participants alive and progression free at 6 months. The primary estimate and 95% confidence interval are not reported in the registry record. Secondary objectives covered safety and tolerability, radiographic response, erlotinib pharmacokinetics, and biomarker associations.

Safety entries include 20 affected among 57 at risk for serious adverse events and named serious-event terms with recorded percentages. These summaries do not establish causality. The single-group design does not provide a randomized comparison, and key analysis details, including missing-data methods and the statistical plan, are not reported in the registry record.