Ph. 2 Sorafenib + Protracted Temozolomide in Recurrent GBM: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Ph. 2 Sorafenib + Protracted Temozolomide in Recurrent GBM (NCT00597493), 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 study of sorafenib plus protracted temozolomide in recurrent glioblastoma multiforme. The registry lists a single-group model, non-randomized allocation, and no masking. Enrollment was 32, and the study status is completed. The study began in 2007-09, with primary completion in 2009-02.

All participants were assigned to the combination regimen rather than to separately randomized treatment groups. The listed dose was 400mg of sorafenib twice daily alongside 50mg/m^2 of temozolomide once daily. The registry says treatment continued until a listed stopping circumstance, including progressive disease, unacceptable toxicity, non-compliance with study guidelines, or withdrawal of consent. The description ends with an incomplete reference to an intercurrent non-cancer-related event, so the full stopping criteria are not reported in the registry record.

The design can describe outcomes and safety observations among participants receiving the combination. Without a concurrent control group, it does not provide a randomized estimate of how outcomes would differ under another treatment. The absence of masking also means that treatment assignment was not concealed from participants or investigators, as recorded by the registry. The record does not report additional design details such as eligibility criteria, recruitment procedures, or a statistical analysis plan.

The stated primary objective was to evaluate activity using 6-month PFS. Secondary objectives concerned safety and toxicity, and the pharmacokinetics of sorafenib when combined with temozolomide in participants taking and not taking concurrent EIAC medications. The listed pharmacokinetic outcomes include C-max, T-max, and AUC-24. Results for those secondary outcomes are not reported in the registry 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.

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 (PFS), measured over 6 months.

The primary endpoint is 6-month progression-free survival (PFS), expressed as a percentage of participants. The registry defines it as the percentage surviving six months from the start of study treatment without progression. PFS is measured from treatment initiation to the first documented progression according to the Macdonald criteria, or to death due to any cause.

This endpoint combines two ways of reaching an event: documented disease progression and death. A participant who has neither event by the six-month point contributes to the endpoint as progression-free at that time, under the stated definition. The endpoint therefore describes disease control over a specified period, rather than overall survival or tumor response alone.

As a general statistical point, a fixed-time PFS percentage can make an endpoint easier to interpret than a summary of the full time-to-event distribution, because it addresses the proportion meeting a defined status at a particular time. It does not, by itself, show how outcomes compare with another treatment. Precision also matters: a confidence interval describes the uncertainty around an estimated percentage, with wider intervals generally indicating less precision. Although the registry lists a 95% confidence interval as the endpoint's dispersion measure, neither the observed percentage nor its interval is reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies the primary outcome as a percentage and specifies a 95% confidence interval as its dispersion measure. It does not report a calculated percentage, confidence interval, or analysis description for that endpoint. The methods below explain general statistical concepts relevant to this kind of outcome; they should not be read as a claim that a particular method was used in this trial.

What does a confidence interval communicate?

As a general statistical explanation, a confidence interval presents a range of values compatible with an estimate under a specified statistical procedure. The interval communicates precision as well as the central estimate: a narrower interval indicates greater precision than a wider interval. It is not a guarantee that the true value lies within a particular interval, and it does not describe the range of outcomes expected for individual participants. The registry names a 95% confidence interval for 6-month PFS, but the interval itself is not reported in the registry record.

What does a fixed-time PFS percentage represent?

The endpoint is a proportion defined at a fixed time after treatment initiation. Its event definition treats documented progression or death from any cause as a PFS event. In general, interpreting a fixed-time estimate requires clarity about how participants without documented status at the target time are handled, how follow-up is incorporated, and which participants are included in the analysis. The registry record does not report those analytical details. It also does not report the number included in the primary endpoint analysis or the outcome estimate.

Although the endpoint is expressed as a percentage, PFS is defined using time from treatment initiation to progression or death. Methods for time-to-event outcomes can account for differing follow-up times and incomplete observation, but the registry record does not identify the method used for the primary analysis. It would therefore be inappropriate to assert that a particular survival estimator, censoring rule, or variance calculation was applied.

Why does study design shape interpretation?

The listed design is single-group and non-randomized, with no masking. As a general statistical point, random allocation can help balance known and unknown prognostic factors between groups, while a concurrent control group allows a direct within-trial treatment comparison. Neither feature is present in the design recorded. A single-group outcome can describe what happened among participants receiving the regimen, but it cannot by itself show what would have happened to comparable participants under a different treatment.

Absence of masking is also a design characteristic that can matter for outcomes involving investigator assessment, participant reporting, treatment decisions, or follow-up. The primary outcome includes documented progression according to specified criteria. The registry record does not describe safeguards for assessment or whether outcome assessors were independent. No further inference about assessment procedures is warranted.

What can be said about planning calculations?

The record describes sample-size calculations as planning illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; it also says the effect to detect is a stated fraction of the observed effect. It specifies that time-to-event illustrations give a total number of events and other illustrations give participants per arm. These are planning assumptions, not a description of the trial's original design, and such illustrations are not observed power. The registry record does not report a sample-size justification for the trial itself. The observed primary endpoint effect is also not reported in the registry record, so the planning assumptions should not be mistaken for a reported efficacy result.

As a general statistical point, power is a design-stage probability tied to assumed effect size, variability, significance level, allocation, and analysis method. A post hoc calculation based on an observed estimate does not establish the probability that the study detected a true effect. Small or imprecise studies can have uncertain estimates regardless of a retrospective power value. The planning language recorded for this study should be understood in that context.

How do event counts and rates differ?

For safety outcomes, a count records how many participants were reported as affected, while a percentage expresses the frequency relative to a stated denominator. These summaries do not convey when events occurred, whether a participant had repeated events, or how long an event lasted. The registry lists serious adverse event figures and terms, but it does not provide the detailed participant-level event history needed to assess those dimensions. As a general point, adverse-event summaries should be interpreted alongside definitions, follow-up duration, severity, and ascertainment procedures.

The registry lists 32 participants at risk for both serious and other adverse events. It records 4 affected for the serious category and 28 affected for the other category. The record does not define in further detail how the categories were constructed or whether the categories can overlap. These are descriptive safety figures, not comparative estimates.

What is not established by the record?

The registry record lists no analyses and does not report the primary endpoint estimate, its confidence interval, the missing-data approach, an analysis population, or the detailed statistical plan. It also does not report interim-analysis procedures. These omissions limit independent assessment of how the endpoint was calculated and how uncertainty was handled. They should not be filled in by assuming standard practice: statistical methods vary, and the registry record does not identify which choices were made.

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("Sorafenib + Temozolomide")
n      <- c(32)
events <- c(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  Sorafenib + Temozolomide  32  3  9.4  2.0  25.0  3.2  24.2  3.4  24.3

11. Multiplicity, Missing Data and Analysis Populations

The primary endpoint is identified as 6-month PFS. The registry also lists secondary outcomes concerning safety and toxicity and pharmacokinetic measures C-max, T-max, and AUC-24. A study that evaluates multiple outcomes raises a general multiplicity question: when many hypotheses are tested, the chance of at least one apparently notable result can increase. The registry record does not report a multiplicity adjustment, a hierarchy among secondary outcomes, or a statistical plan specifying how multiple outcomes were to be interpreted. It also does not report analyses for these outcomes.

Missing data can affect interpretation when participants do not have outcome status available at the relevant time or leave follow-up. As a general statistical point, conclusions can depend on why data are missing and on the assumptions used to handle them. The registry record does not report how missing PFS information, loss to follow-up, or incomplete pharmacokinetic measurements were handled. It does not report a sensitivity analysis for missing data.

The record does not describe the primary analysis population or provide a participant flow accounting for inclusion in the endpoint analysis. Enrollment is listed as 32, but the registry does not report how many participants contributed to the primary endpoint estimate. The record also does not report interim analyses or stopping rules beyond the treatment stopping circumstances described in the regimen. These items are not reported in the registry record and should not be inferred from the Phase 2 designation or the completed status.

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: pancreatitis (6.2%), lipase increased (6.2%), serum amylase increased (6.2%), seizure (6.2%), lung infection (3.1%).

The registry records 4 participants affected by serious adverse events, with 32 at risk in the Sorafenib + Temozolomide group. For the other adverse event category, it records 28 affected, with 32 at risk. These are descriptive counts from the treatment group, not estimates of excess risk relative to another treatment. No control group is listed.

The serious adverse event terms and percentages reported include pancreatitis (6.2%), lipase increased (6.2%), serum amylase increased (6.2%), seizure (6.2%), lung infection (3.1%), and alanine aminotransferase increased (3.1%). The registry identifies these as serious-event terms; the record does not report the full clinical descriptions, timing, duration, severity grades, or outcomes for the events. The listed term percentages should not be added together: the record does not say that terms represent mutually exclusive participants or events.

As a general statistical point, safety counts depend on event definitions, observation time, and how events are collected and attributed. Those details are not reported in the registry record. Deaths are not reported in the registry record. These safety figures describe what the record lists and do not establish comparative safety or causation.

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

The study asks whether sorafenib plus protracted temozolomide has activity in recurrent glioblastoma multiforme, using 6-month PFS as the primary endpoint. The registry describes the endpoint definition, the treatment regimen, and the single-group design. However, it does not report the 6-month PFS percentage or its 95% confidence interval. The primary efficacy result therefore cannot be interpreted from the registry record.

Even if an outcome estimate were available, the study design would remain important. Because the trial is single-group and non-randomized, it does not offer a concurrent control comparison. Its outcome could describe the experience of participants receiving the combination, but it could not by itself separate treatment effects from other influences on prognosis or outcome. The absence of masking is another design feature relevant to how outcomes may be assessed, though further assessment procedures are not reported.

The safety record lists serious and other adverse event counts and several serious-event terms with percentages. These figures are descriptive. They do not show how safety compares with another regimen, and the registry does not provide sufficient detail to interpret event timing, duration, or clinical course. The pharmacokinetic outcomes are named, but their results are not reported in the registry record.

As a general statistical point, a treatment result is best understood by considering its estimate, uncertainty, analysis population, missing-data handling, and comparison design together. Here, the registry provides too little outcome analysis information to assess the magnitude or precision of the primary endpoint. It also does not report a statistical plan, multiplicity approach, or interim-analysis procedures. The completed status indicates that the study is recorded as completed; it does not substitute for outcome results. No conclusion that the regimen is effective or ineffective follows from the information recorded.

14. Why This Trial Matters Statistically

This trial matters statistically as an example of the distinction between an endpoint being defined and an endpoint result being available. The registry clearly specifies 6-month PFS and its clinical event definition, but does not report the estimate or confidence interval. Without those quantities, readers cannot assess the observed outcome or its precision, even though the study's objective and endpoint are identifiable.

The design also makes the scope of inference important. A single-group study can characterize outcomes and safety observations among participants treated with the combination. It cannot supply a randomized treatment contrast. This is not a flaw in describing the study's purpose; it is a limit on what its design can establish. Clear separation of within-group description from comparative effectiveness is central to sound statistical interpretation.

The record also illustrates why safety summaries need context. Event counts and listed percentages convey frequency information, but do not describe event timing, duration, or comparison with an alternative. Nor do they reveal how missing observations or analysis populations were handled. Those reporting details affect how confidently the results can be evaluated.

Finally, the record mentions planning illustrations based on an observed effect, but those should not be confused with original design justification or observed power. The trial's statistical plan and sample-size justification are not reported in the registry record. Keeping design assumptions, observed results, and post hoc planning calculations distinct helps prevent a planning exercise from being mistaken for evidence about treatment effect.

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 most important limitation for interpreting efficacy is that the registry record does not report the primary endpoint result. The 6-month PFS percentage and 95% confidence interval are not reported in the registry record. The record also lists no analyses, so the calculation and uncertainty assessment cannot be independently reviewed from the registry entry.

The single-group, non-randomized design provides no concurrent control comparison. Consequently, the record cannot establish a treatment contrast within the study. No masking was used, and the record does not describe independent endpoint assessment or other procedures that might address assessment bias. The eligibility criteria, characteristics of the enrolled population, and primary endpoint analysis population are not reported in the registry record.

Other statistical limitations include the absence of reported methods for handling missing outcome data, a multiplicity plan, interim analyses, or a detailed statistical analysis plan. The registry does not report a sample-size justification for the trial. Although it describes planning illustrations, these are not the same as a prespecified justification and are not observed power.

The safety information is also limited. Counts and selected serious-event terms are listed, but the registry record does not report event timing, duration, severity grading, participant-level overlap, or detailed follow-up. Deaths are not reported in the registry record. Pharmacokinetic outcomes are named, but their results are not reported in the registry record. The regimen description itself ends with an incomplete stopping criterion concerning an intercurrent non-cancer-related event. These limitations reflect what is and is not recorded; they do not establish that the underlying study did or did not collect additional information.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Ph. 2 Sorafenib + Protracted Temozolomide in Recurrent GBM — NCT00597493.
• Registry record last updated 2013-06-24; status last verified 2013-05.
• Results first posted 2013-06-24.
• 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 record describes NCT00597493, a completed Phase 2, single-group, non-randomized study of sorafenib plus protracted temozolomide for recurrent glioblastoma multiforme. Enrollment was 32. The listed regimen was 400mg of sorafenib twice daily and 50mg/m^2 of temozolomide once daily, with no masking.

The primary endpoint was 6-month PFS, defined using documented progression according to the Macdonald criteria or death from any cause. Its result and 95% confidence interval are not reported in the registry record. The registry lists safety and pharmacokinetic secondary outcomes, but does not report their results. It records 4 participants affected by serious adverse events and 28 affected in the other adverse event category, with 32 at risk for each. Because there is no concurrent control group, the recorded outcomes are descriptive rather than comparative.