VEGF Trap in Treating Patients With Recurrent Malignant Gliomas That Did Not Respond to Temozolomide: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for VEGF Trap in Treating Patients With Recurrent Malignant Gliomas That Did Not Respond to Temozolomide (NCT00369590), a na phase 2 study. The primary outcome is Progression-free Survival (PFS) at 6 Months.

2. Clinical Question

The clinical question concerns disease control after recurrence in a population described as resistant to temozolomide. The primary endpoint focuses on progression-free survival at a fixed time point, rather than on a comparison of treatment strategies. The registry describes response criteria based on imaging and clinical worsening, and states that participants not known to be progression-free at the 6-month scan (24weeks) were considered to have experienced treatment failure.

The record also describes a criterion for considering the agent promising for further study in glioblastoma: at least 10pts (24%) progression-free at 6months. That is a stated decision threshold, not evidence that the threshold was reached. The record does not report the observed six-month progression-free proportion, so the clinical question cannot be answered from the posted results described in the registry entry.

3. Trial Design

This was a completed phase II, single-group trial sponsored by the National Cancer Institute (NCI). The registry lists enrollment of 58 and dates of 2006-08 for study start and 2011-12 for primary completion. Allocation was listed as not applicable, and masking as none. With no concurrent comparator, the study was not designed as a randomized, masked comparison of ziv-aflibercept against another treatment.

All study patients were assigned to receive VEGF Trap (ziv-aflibercept) intravenously over 1 hour on day 1, with treatment repeating every 14 days in the absence of disease progression or unacceptable toxicity. The registry also lists pharmacological study and laboratory biomarker analysis. Its brief description says the treatment may stop tumor growth by blocking blood flow to the tumor; this is the proposed rationale, not a reported clinical finding.

The primary endpoint was progression-free survival (PFS) at 6 months, expressed as a percentage of participants. The entry lists response rate, PFS rate for subjects with radiographic response, and overall survival among the secondary outcomes. It reports six outcome measures in total but no outcome analyses. The registry record does not report the observed primary endpoint value or the results of the secondary outcomes.

The endpoint description specifies MRI assessments at screening and at the 3rd and 5th cycles, then every 8 weeks until progression. Response was assessed using modified MacDonald Criteria. The description includes definitions for complete response, partial response, stable disease, and progression, including imaging changes and clinical worsening. These details explain the recorded assessment framework; they do not establish how many participants met any response category.

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: pts not known to be progression free at time of the 6-month scan (24weeks) were considered to experienced treatment failure. If at least 10pts (24%) are progression-frree at 6months (GBM) the agent will be considered promising for futher study. The 3 pts in Arm 2 were treated at 2nd recurrence and were excluded from final efficacy analysis

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.

Population: 16 patients were anaplastic gliomas and 42 were glioblastomas all underwent central pathologic review

6. Primary Endpoint

The registry lists the primary outcome as Progression-free Survival (PFS) at 6 Months, measured over 6 months.

The primary endpoint, PFS at 6 months, is the percentage of participants considered progression-free at the specified follow-up time. Progression-free survival combines the timing of disease progression with the status of participants who have not progressed by the assessment point. At a fixed time point, reporting the percentage makes the endpoint interpretable as the proportion meeting the progression-free definition at that time.

The registry description says participants had MRI assessments at screening and at the 3rd and 5th cycles, followed by assessments every 8 weeks until progression. It defines response with modified MacDonald Criteria. Complete response requires disappearance of measurable and evaluable disease and no new lesions, with no steroids. Partial response requires a decrease of at least 50% in the sum of products of perpendicular diameters of measurable lesions, with no progression of evaluable lesions or new lesions, and a steroid-dose condition. Stable disease and progression are also described; progression includes a 25% increase in the sum of products of measurable lesions over the smallest sum observed, or clear clinical worsening.

A fixed-time PFS endpoint is useful for describing disease control at a clinically specified follow-up point. It does not, by itself, provide the full pattern of time to progression or survival. The registry record does not report the observed six-month PFS percentage, its uncertainty interval, or the participant-level information needed to assess follow-up and censoring.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a single-group phase II study with a binary primary outcome: the percentage of participants with an event, where the event for this endpoint is being progression-free at 6 months. In a single-group design, the primary analysis would ordinarily summarize the outcome within the treated group. The record does not report the observed count, percentage, confidence interval, or test result, so the analysis itself cannot be reconstructed from the registry entry.

What does a fixed-time percentage represent?

A fixed-time percentage expresses the share of the analysis population meeting the endpoint definition at a specified time. Here, the time point is 6 months. The percentage is meaningful only alongside a clear definition of progression-free status and a clear account of who was included in the denominator. The registry describes the imaging schedule and response criteria, but does not report the observed numerator and denominator for the primary endpoint.

In time-to-event settings, some participants may not have a recorded event before their last assessment. A time-to-event method can use their follow-up information while accounting for censoring, subject to assumptions about censoring and follow-up. A fixed-time percentage may instead rely on a specified classification at the time point. The registry says that participants not known to be progression-free at the 6-month scan (24weeks) were considered to have experienced treatment failure. It does not report further details about missing scans, censoring, or alternative handling of incomplete follow-up.

How should the design statements be read?

The endpoint description says the design yields 85% power to detect a true 30% six-month PFS rate, while maintaining .91 probability of rejecting for a true 15% six-month PFS rate. These statements describe planned operating characteristics under assumptions; they are not observed power and do not show that the trial reached a particular result. The registry record does not report the statistical test, its significance threshold, or a fuller statistical analysis plan. Those details are not reported in the registry record.

Power is a property of a design under specified assumptions about the underlying outcome and decision rule. It is not the probability that a treatment is effective, nor a measure of how likely the observed result is to be true. A trial can be designed with a stated power and still produce an imprecise or inconclusive estimate. Because the observed endpoint result is not reported, the design statements cannot substitute for an estimate and its uncertainty.

Why does the absence of a comparator matter?

A single-group study estimates outcomes in the enrolled group under the study regimen. It cannot separate the treatment’s contribution from other influences using a concurrent randomized comparison. Historical rates, if used, may differ in eligibility, disease status, follow-up, imaging schedules, or supportive care. The registry record does not specify a historical control analysis. As a result, the posted design alone supports no direct estimate of a treatment-versus-control contrast.

Response criteria are part of the measurement method. The registry lists modified MacDonald definitions for complete response, partial response, stable disease, and progression, with imaging and clinical components. Consistent application matters because changes in assessment or interpretation can change who is classified as progression-free. The entry does not report independent review, assessor masking, or procedures for resolving disagreements; these are not reported in the registry record.

What do planning illustrations mean?

Planning sample sizes based on an observed effect are hypothetical illustrations, not results from the trial and not observed power. They describe how a future study might be planned under stated assumptions. They do not alter the actual enrollment, provide missing outcome data, or establish whether the primary endpoint was met. The record does not report a full trial-specific sample-size justification beyond the design statements in the endpoint description.

Overall, the statistical information in the registry is sufficient to identify the endpoint, the intended assessment schedule, and some design targets. It is not sufficient to reproduce the primary analysis or evaluate its precision. The analysis method, handling of missing endpoint data beyond the stated treatment-failure rule, and detailed analysis population are not reported in the registry record.

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("Arm I - Anaplastic Glioma", "Arm 2 - Glioblastoma")
n      <- c(16, 39)
events <- c(4, 3)
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  Arm I - Anaplastic Glioma  16  4  25.0  7.3  52.4  10.2  49.5  10.3  49.9
ARM  Arm 2 - Glioblastoma  39  3  7.7  1.6  20.9  2.7  20.3  2.8  20.4

11. Multiplicity, Missing Data and Analysis Populations

The registry lists six outcome measures, including the primary PFS endpoint and secondary outcomes concerning response rate, PFS for subjects with radiographic response, and overall survival. It reports no outcome analyses. The statistical plan for controlling the chance of false-positive findings across multiple outcomes or analyses is not reported in the registry record. Without that information and without analysis results, the secondary outcomes cannot be used to confirm or qualify the primary endpoint.

The record states that participants not known to be progression-free at the 6-month scan (24weeks) were considered to have experienced treatment failure. This gives one rule for classifying uncertain six-month status, but the registry does not report how many participants had missing scans, incomplete follow-up, or other unavailable endpoint data. It also does not describe sensitivity analyses or alternative missing-data assumptions.

The analysis population is not described in sufficient detail to establish whether all enrolled participants were included in the primary endpoint denominator or whether another population was used. Although enrollment is listed as 58, the observed endpoint denominator is not reported in the registry record. The handling of treatment discontinuation, missed assessments, and other post-enrollment events is likewise not reported.

These omissions affect interpretation because a fixed-time percentage depends on both the endpoint classification and the population counted. The stated treatment-failure rule provides some context, but does not replace a complete account of missingness, analysis populations, and sensitivity to assumptions. The registry record does not provide enough information to assess those issues or the consequences for the reported endpoint.

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 1% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: ischemia cerebrovascular (3.4%), oral hemorrhage (1.7%).

The registry records safety figures for the group titled “All Study Patients.” It lists 58 at risk in the serious adverse event category and 3 affected, and 58 at risk in the other adverse event category and 35 affected. These are safety counts, not efficacy outcomes. The record does not define in the displayed information whether the affected count represents people, events, or another reporting unit, so the figures should be read in the terms recorded rather than converted into a rate.

The listed serious adverse event terms include ischemia cerebrovascular at 3.4% and oral hemorrhage at 1.7%. These percentages describe the terms as recorded; they do not establish that ziv-aflibercept caused the events. The registry record does not report deaths in the safety summary. A missing death value should not be interpreted as evidence that no deaths occurred.

Safety counts need context about collection period, event definitions, severity, attribution, and follow-up. Those details are not reported in the registry record excerpt. The counts also do not support a comparative safety conclusion because the study had no concurrent control group. The record lists unacceptable toxicity as a reason treatment could stop, but does not report how many participants stopped for that reason.

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

The registry record identifies a phase II study of ziv-aflibercept in recurrent malignant or anaplastic gliomas that did not respond to temozolomide. It specifies a single-group treatment regimen and a six-month progression-free survival endpoint. It also gives the imaging schedule, response definitions, and a stated threshold for considering the agent promising for further study in glioblastoma.

The posted information does not include the observed primary endpoint result. It therefore cannot show what proportion of participants was progression-free at 6 months, how precise that estimate was, or whether the stated threshold was met. The design statements about 85% power, a true 30% rate, and a true 15% rate describe planned properties, not observed treatment outcomes.

Because there was no concurrent comparator, the study design cannot by itself establish how outcomes would differ under another treatment or without ziv-aflibercept. A result from a single group may be useful for describing outcomes and informing further research, but it does not provide the same evidence as a randomized comparison. The registry entry does not report a comparative estimate.

The listed safety figures describe reported serious and other adverse event categories, alongside two serious adverse event terms. They do not establish causation or comparative safety. The record also does not report deaths in the safety summary, which is distinct from reporting that no deaths occurred.

In short, the record describes the question and methods of a completed trial but does not report enough outcome information to answer the primary clinical question. No conclusion about benefit, lack of benefit, or treatment choice follows from the design description alone.

14. Why This Trial Matters Statistically

This trial is statistically notable for the way it frames a fixed-time endpoint in a single-group phase II setting. Six-month PFS offers a focused measure of disease status at a planned time point, while the response definitions and assessment schedule indicate how progression-free status was intended to be evaluated. The record also states a threshold for further study in glioblastoma, making the planned decision framework visible.

The design highlights a distinction between a study’s operating characteristics and its observed evidence. The stated power and assumed rates describe design targets; they do not show what happened among participants. This distinction matters whenever a registry description includes a sample-size or decision rationale but does not post endpoint results.

The absence of a concurrent comparator also clarifies what the design can establish. A single-group trial can describe outcomes under a regimen, but cannot directly estimate a randomized treatment contrast. That limitation is especially important when a decision threshold is interpreted: reaching a within-group benchmark would not by itself show that outcomes were caused by the study treatment.

The record also makes missing-data rules relevant to interpretation. Participants not known to be progression-free at the six-month scan were classified as treatment failures, but detailed completeness and analysis-population information is not reported. Those details can shape the denominator and the meaning of a fixed-time proportion.

Finally, the entry illustrates why outcome reporting is essential. Without the observed endpoint estimate and its uncertainty, readers cannot evaluate whether the design target was reached or how informative the result is. The registry describes the study rationale and framework, but the posted outcome information is insufficient for that statistical assessment.

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 central limitation of the registry record is that it does not report the observed result for the primary endpoint, despite identifying the study as completed. The six-month PFS percentage, its numerator and denominator, and an uncertainty interval are not reported. The registry also lists no outcome analyses, so the primary analysis cannot be evaluated from the entry.

The single-group design has no concurrent control, making comparative interpretation unavailable from the design alone. Allocation is listed as not applicable and masking as none. The record does not describe a historical comparison or an adjusted analysis. Therefore, any within-group outcome, if available elsewhere, would need cautious interpretation as a description rather than a randomized estimate of treatment effect.

The endpoint description includes an explicit rule treating participants not known to be progression-free at the 6-month scan (24weeks) as treatment failures. However, the record does not report missing assessments, follow-up completeness, an analysis population, or sensitivity analyses. This leaves uncertainty about how the rule affected the endpoint classification and denominator.

The record specifies modified MacDonald response criteria and an imaging schedule but does not report whether assessments were independently reviewed, whether assessors were masked, or how classification disagreements were handled. Such procedures are not reported in the registry record. The description of the 3 pts in Arm 2 is incomplete and does not support subgroup interpretation.

Safety information is also limited: the record lists counts and selected serious adverse event terms, but does not provide the context needed to assess attribution, duration, or comparative risk. The death value is not reported. The record’s design statements do not replace the absent clinical outcome results or detailed statistical analysis plan.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: VEGF Trap in Treating Patients With Recurrent Malignant Gliomas That Did Not Respond to Temozolomide — NCT00369590.
• Registry record last updated 2015-10-02; status last verified 2015-08.
• Results first posted 2015-10-02.
• 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 a completed phase II, single-group trial sponsored by the National Cancer Institute (NCI), with enrollment of 58. It studied ziv-aflibercept in recurrent malignant or anaplastic gliomas that had not responded to temozolomide. Treatment was scheduled intravenously over 1 hour every 14 days, unless progression or unacceptable toxicity occurred.

The primary endpoint was PFS at 6 months, assessed under modified MacDonald Criteria. The entry includes design statements, a stated further-study threshold for glioblastoma, and selected safety counts. It lists six outcome measures and no outcome analyses.

The observed primary endpoint result, its precision, and details of the analysis population and missing data are not reported in the registry record. With no concurrent comparator, the design does not provide a randomized treatment comparison.