Everolimus, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Everolimus, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma (NCT00553150), a na phase 1, phase 2 study. The primary outcome is Maximum Tolerated Dose (MTD) of Everolimus (RAD001) in Combination With Temozolomide (TMZ) and 3D-conformal Radiotherapy (RT) or Intensity-modulated Radiotherapy (IMRT) Followed by Adjuvant TMZ With or Without RAD001 (Phase I).

2. Clinical Question

The study also lists Phase II outcomes concerning response rate among patients receiving FLT-PET imaging, time to progression, progression-free survival at 6 months, and overall survival time. These are different questions from Phase I dose finding: they concern tumor response and time-to-event outcomes rather than the tolerability rule used to select a dose. The registry record does not report numerical results for those outcomes in the information available for this analysis.

3. Trial Design

NCT00553150 is a completed Phase I/II study sponsored by the Alliance for Clinical Trials in Oncology. The registry lists an enrollment of 122 and a study start of 2009-03, with primary completion in 2012-01. Its focus is newly diagnosed glioblastoma, within the broader condition category of brain and central nervous system tumors.

The design is single group, with allocation listed as NA and no masking. It is therefore not a randomized comparison of the treatment regimen against a separate control. The Phase I portion enrolled 18 patients to determine a maximum tolerated dose. The registry says RAD001 dosing was escalated in cohorts of 6 patients. The dose-limiting toxicity rule was used to guide dose selection during the radiation period.

The listed regimen combines oral everolimus and oral temozolomide with 3D-conformal radiotherapy or IMRT. The arm description then refers to a rest period before adjuvant everolimus and temozolomide. It describes adjuvant courses 3-8, with everolimus included with temozolomide. The registry's arm description is incomplete, so further details of the treatment schedule are not reported in the registry record.

The registry separates the primary Phase I dose-finding endpoint from Phase II outcomes. Those secondary outcomes include response rate in patients receiving FLT-PET imaging, time to progression, progression-free survival at 6 months, and overall survival time. Numerical results for these outcomes, and the Phase I DLT counts by dose level, are not reported in the registry record used for this account. Thus, the design and endpoint definitions can be described, but the primary dose-selection result cannot be recovered from these details.

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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Eighteen patients were enrolled in Phase I of the study to determine the maximum tolerated dose (MTD). The dosage of RAD001 was escalated in cohorts of 6 patients.

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 Maximum Tolerated Dose (MTD) of Everolimus (RAD001) in Combination With Temozolomide (TMZ) and 3D-conformal Radiotherapy (RT) or Intensity-modulated Radiotherapy (IMRT) Followed by Adjuvant TMZ With or Without RAD001 (Phase I), measured over Up to 49 days.

The primary endpoint counts participants who developed dose-limiting toxicities (DLTs), reported by dose level during the radiation period. The assessment timeframe is up to 49 days. This is a count outcome: it records how many participants meet the study's DLT definition, rather than measuring an average change on a continuous scale or the time until an event.

The registry defines DLTs using treatment delivery and specified toxicities. A DLT includes failure to deliver > 75% of planned TMZ or RAD001 doses during RT, interruption of RT for more than 5 days because of toxicity, or selected severe events. These include >= Grade 3 diarrhea or skin rash; >= Grade 4 neutropenia, leukopenia, or thrombocytopenia; specified metabolic events at >= Grade 4 despite optimal medical management; other >= 3 non-hematologic events; or >= Grade 4 radiation dermatitis.

The endpoint is used for dose finding because the number of DLTs at each dose level can inform whether that dose satisfies the protocol's stated tolerability rule. The maximum tolerated dose is defined a priori as the highest dose level at which 0 or 1 of 6 patients developed DLTs. That definition describes the decision rule; it does not itself identify which dose met the rule. The dose-level counts and the MTD result are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies a Phase I/II, single-group study and describes a Phase I dose-escalation component. The stated primary endpoint is the number of participants with DLTs at each dose level during RT, assessed up to 49 days. The endpoint is a count, and its interpretation depends on the trial's operational definition of a DLT. The registry says the MTD was defined in advance as the highest dose level at which 0 or 1 of 6 patients developed DLTs.

What does a count endpoint capture?

A count endpoint records how many participants meet an event definition within a specified assessment period. It can be useful in early-phase dose finding because the study question concerns whether a dose is associated with toxicities that meet predefined criteria. The count is meaningful only alongside the number assessed at that dose, the criteria used, and the follow-up period. Here, the registry provides the endpoint definition and the Phase I cohort description, but the dose-specific DLT counts are not reported in the registry record.

The DLT definition combines different kinds of events: treatment delivery, interruption of radiation, and specified clinical or laboratory toxicities. Such a composite rule can capture several ways a regimen may be difficult to deliver. At the same time, a single count does not show which criterion each participant met, how severe events were beyond the stated thresholds, or whether multiple criteria occurred in the same person. Those details are not reported in the registry record.

How does the dose-selection rule work?

The MTD rule is a decision threshold, not an estimate of comparative treatment effect. It specifies how many DLTs are compatible with a dose being selected under the stated design: the highest dose level at which 0 or 1 of 6 patients developed DLTs. A count below or at a threshold is still subject to uncertainty, particularly when a dose cohort is small. General statistical reasoning cautions that observed event counts can vary across samples even if the underlying event probability is unchanged. The registry's rule sets a practical criterion; it does not remove that sampling uncertainty.

Because the dose level is increased across cohorts, interpretation also depends on the sequence of doses and the observed DLT counts at each step. The registry says RAD001 was escalated in cohorts of 6 patients, but it does not report the dose levels, escalation sequence, stopping decisions, or DLT counts in the information used. Without those details, the dose-finding process cannot be reconstructed and no MTD can be identified.

What can confidence intervals add?

In general, a confidence interval expresses the range of values reasonably compatible with data under a specified statistical procedure. It helps distinguish a point estimate from its precision: estimates based on limited information are typically less precise than estimates based on more information. No confidence interval for the primary DLT outcome or the listed Phase II outcomes is reported in the registry record. It would not be appropriate to invent one from absent dose-level counts or outcome estimates.

For a count or proportion, uncertainty depends on both the number of events and the number of participants assessed. The registry gives Phase I and Phase II denominators for adverse-event reporting, but these safety figures are not the primary dose-level DLT results. They cannot be substituted for DLT counts because the outcome definitions differ. Likewise, the adverse-event denominators do not by themselves describe the number assessed for each efficacy outcome.

How should the study structure affect interpretation?

A single-group study can describe events and outcomes among participants receiving the regimen, but it does not provide a concurrent control group for estimating what would have happened under a different treatment. General statistical reasoning distinguishes within-group description from comparative inference: observing an outcome in a treated group does not isolate the contribution of each treatment component or establish a causal contrast. This limitation applies to any attempt to attribute an observed outcome to everolimus, temozolomide, or radiation individually.

The registry lists no masking. Lack of masking can matter for outcome assessment when judgments are involved, although the extent of that concern depends on the outcome and assessment procedures. The registry record does not report outcome-assessment procedures in enough detail to determine how this might affect particular outcomes. The statistical analysis plan, handling of missing observations, analysis populations, and adjustment for multiple outcomes are also not reported in the registry record. These omissions limit assessment of the precision, robustness, and potential sources of bias in the posted results.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary Phase I dose-finding endpoint and several secondary Phase II outcomes: response rate among patients receiving FLT-PET imaging, time to progression, progression-free survival at 6 months, and overall survival time. Considering multiple outcomes can raise a multiplicity question. In general, if many statistical tests are performed, the chance of at least one apparently unusual result can increase. Whether and how to adjust for multiple testing depends on the aims and analysis plan. Such an adjustment strategy is not reported in the registry record.

The record also does not report a statistical analysis plan, the populations included in each outcome analysis, or how missing outcome data were handled. Those details matter because the number of participants eligible for an endpoint may differ from the study enrollment, and because exclusions or incomplete follow-up can affect estimates. The listed enrollment of 122 should not be treated as the denominator for every endpoint. The record gives 18 patients enrolled in Phase I and safety denominators for the Phase I and Phase II adverse-event summaries, but does not state the analysis population for each efficacy outcome.

For time-to-event outcomes, general statistical interpretation depends on follow-up and censoring: participants who have not had an event by the end of observation may contribute information until their last known assessment. The registry names time to progression, progression-free survival at 6 months, and overall survival time, but does not report the analysis methods, event counts, follow-up details, or handling of censoring in the information. No assumptions about those procedures should be made.

These gaps do not show that a particular method was or was not used. They mean that the registry record does not support evaluating multiplicity control, missing-data assumptions, or analysis-population choices. Any interpretation of unreported efficacy estimates or their uncertainty would require details that are not reported in the registry record.

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: thrombosis (11.1%), neutrophil count decreased (9.9%), platelet count decreased (8.9%), hemoglobin decreased (5.6%), disease progression (5.6%).

The registry reports serious adverse events separately for Phase I and Phase II. It lists 5 of 18 Phase I participants and 32 of 101 Phase II participants as affected by serious adverse events. For other adverse events, it lists 18 of 18 in Phase I and 99 of 101 in Phase II. These are counts within the study's reported groups, not comparisons against a control group.

The record also lists serious-event terms with percentages: thrombosis, 11.1%; neutrophil count decreased, 9.9%; platelet count decreased, 8.9%; hemoglobin decreased, 5.6%; disease progression, 5.6%; and fatigue, 5.6%. These entries should be read as registry-reported event terms and percentages. The record does not give enough context to determine whether a participant could contribute more than one term, the observation period for each term, or the denominator underlying every percentage.

Serious adverse-event reporting is not interchangeable with the primary DLT endpoint. The DLT definition uses specified toxicity and treatment-delivery criteria during RT, whereas the safety figures are aggregate adverse-event summaries. The registry does not report whether each serious event met the DLT definition. These data describe reported safety events but cannot establish comparative risk, causation, or the full clinical course of an event.

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

The registry record identifies a dose-finding question: determine the maximum tolerated dose of everolimus when combined with temozolomide and radiation therapy, using a predefined DLT rule. It also lists Phase II outcomes for response, progression, and survival. This establishes what the study set out to assess, but the available information does not report the primary DLT counts by dose level, the selected MTD, or numerical Phase II outcome results.

Accordingly, the record does not support a conclusion about which everolimus dose met the trial's rule, the magnitude or precision of any response or survival outcome, or how outcomes compare with another treatment. No comparator group is listed, and the study is not a randomized comparison. Descriptive observations in a single group cannot separate the effects of the regimen's components or establish what would have occurred under an alternative approach.

The safety summaries do show reported counts of participants affected by serious and other adverse events in Phase I and Phase II. These counts offer a description of events recorded in those groups, but do not estimate a difference in safety between treatments. The list of serious-event terms and percentages likewise does not provide the details needed to judge event timing, attribution, overlap, or clinical course.

In general, a result is more informative when its definition, denominator, estimate, uncertainty, and analysis population are all available. Here, the endpoint definition and some safety denominators are stated, while key outcome estimates and analysis details are not reported in the registry record. The appropriate interpretation is therefore limited to the design, stated endpoint criteria, and reported safety counts. Missing efficacy and dose-finding values should remain unknown; they should not be inferred from the study title, outcome names, enrollment, or event summaries.

13. Why This Trial Matters Statistically

This study illustrates why early-phase dose finding and later outcome assessment should be kept conceptually separate. The Phase I endpoint is a count of participants who met a specified DLT definition, and the MTD decision rule uses that count at each dose level. A transparent rule helps readers understand how a dose was intended to be selected. Yet the rule alone is not a result: the actual counts and selected dose are necessary to assess its application.

It also illustrates the value of keeping outcome definitions distinct. Serious adverse-event summaries are not equivalent to DLT counts, even though both concern safety. The DLT endpoint includes treatment-delivery criteria and selected toxicity thresholds during RT; aggregate adverse-event summaries describe a broader set of reported events. Treating these measures as interchangeable could lead to incorrect interpretation.

Finally, the single-group structure sets a clear boundary on statistical inference. The study can describe outcomes among participants receiving the regimen, but there is no separate concurrent control group for a comparative estimate. The listed Phase II outcomes may address response and time-to-event questions, but their names do not establish results or comparative effects. Statistical interpretation requires the observed values, denominators, uncertainty, and analysis methods—not only a design label or endpoint title.

The record therefore demonstrates an important reporting principle: endpoint definitions and decision rules are useful, but they need to be accompanied by the results and analysis details required to evaluate them. Without the dose-level DLT counts and the Phase II outcome estimates, readers can identify the trial's questions and constraints but cannot assess the corresponding findings.

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 primary endpoint values are not reported in the registry record available for this analysis. The record describes DLTs by dose level and states an MTD rule, but does not provide the dose-specific counts or the selected MTD. This prevents an assessment of how the decision rule was applied.

Numerical results for the listed Phase II response, progression, and survival outcomes are also not reported in the registry record. Estimates of uncertainty, event counts, follow-up details, and analysis methods for those outcomes are not available in the information. Their inclusion as outcome names cannot substitute for results.

The single-group design, with allocation listed as NA and masking as none, has no separate randomized control group. It therefore cannot provide a like-for-like comparison against another treatment. Any observed outcomes would be descriptive for the study group rather than a controlled estimate of treatment differences. The combined regimen also does not isolate the contribution of each component.

The registry record does not report how missing data were handled, which analysis populations were used, whether multiple outcomes were adjusted for, or how outcome assessments were conducted. The safety summaries provide group counts and a list of serious-event terms, but do not give the full context needed to assess event timing, attribution, overlap, and follow-up. These are limits on what can be concluded from the registry information; they do not establish that a particular analysis or procedure was absent from the trial itself.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Everolimus, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma — NCT00553150.
• Registry record last updated 2020-02-13; status last verified 2020-02.
• Results first posted 2017-01-11.
• 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

NCT00553150 is a completed Phase I/II, single-group study of everolimus, temozolomide, and radiation therapy in patients with newly diagnosed glioblastoma. The registry lists enrollment of 122, a start of 2009-03, and primary completion in 2012-01. Allocation is listed as NA and masking as none.

The primary Phase I endpoint counts participants with DLTs by dose level during RT, up to 49 days. The stated MTD rule is the highest dose level at which 0 or 1 of 6 patients developed DLTs. The dose-level counts and selected MTD are not reported in the registry record. Phase II outcomes include response rate in patients receiving FLT-PET imaging, time to progression, progression-free survival at 6 months, and overall survival time; numerical results for these outcomes are not reported in the registry record.

Serious adverse events are listed for 5 of 18 Phase I participants and 32 of 101 Phase II participants. The study has no separate control group, so these safety summaries are descriptive rather than comparative.