Phase I-II Everolimus and Sorafenib in Recurrent High-Grade Gliomas: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase I-II Everolimus and Sorafenib in Recurrent High-Grade Gliomas (NCT01434602), a non-randomized phase 1, phase 2 study. The primary outcome is Maximum Tolerated Dose of Everolimus for Participants With Recurrent Malignant Gliomas.

2. Clinical Question

The study asked whether a tolerable dose and schedule of everolimus with sorafenib could be identified for patients with recurrent malignant glioma, and whether the combination could help control the disease. Its first phase focused on dose and schedule, while its second phase focused on disease control and continued safety assessment. The registry record describes a non-randomized, unmasked, sequential design, so the treatment groups are not randomized comparisons against a control group.

The registry record also lists secondary questions about progression-free survival, objective response, survival after therapy, symptom severity, and symptom interference with function. Those outcomes address different aspects of the study, but quantitative results for them are not reported in the registry record. The central statistical question that can be described from the record is therefore dose tolerability, rather than a randomized estimate of treatment benefit.

3. Trial Design

This was a Phase I-II, non-randomized, unmasked, sequential trial sponsored by the National Cancer Institute. Enrollment was 86. The study began on 2012-10-02, its primary completion date was 2020-10-19, and its status is completed. The registry record does not report the rationale used to select the planned enrollment.

Phase I used dose escalation to investigate the combination’s tolerability and schedule. One listed dose level paired everolimus 5mg daily with sorafenib 400mg twice daily. Another listed schedule used sorafenib 400mg twice daily for 7 days on and 7 days off, with everolimus 5mg daily. The Phase I arm descriptions also refer to a Phase I dosing table, but the registry record does not report the full escalation procedure or the decision rules used to move between dose levels.

Phase II used the dose level described as maximum tolerated dose -1, determined from Phase I dose escalation. The listed Phase II regimen was sorafenib 400mg twice daily for 7 days on and 7 days off, together with everolimus 5mg daily. The registry record identifies Phase II groups A, B, and C, but does not report enough detail in the posted results to establish how these groups differ or whether their outcomes are intended for direct comparison.

Because allocation was non-randomized and the phases were sequential, the groups should not be interpreted as like-for-like treatment arms. Changes in outcomes across groups could reflect differences in patient characteristics, treatment schedules, study phase, or other factors not reported in the registry record. The registry record describes safety assessment in both phases and frames Phase II as an assessment of disease control, but does not report the detailed statistical analysis plan.

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: This study started at MD Anderson under Dr. Gilbert in 2012 and transferred to the National Cancer Institute (NCI).

Phase I Dose Escalation

Reasons for not completing this period:

Phase II Recommended Phase 2 Dose

Reasons for not completing this period:

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 of Everolimus for Participants With Recurrent Malignant Gliomas, measured over First 28 days of treatment only (cycle 1).

The primary endpoint is the maximum tolerated dose of everolimus for participants with recurrent malignant gliomas. The registry record defines the assessment period as the first 28 days of treatment only, identified as cycle 1. It defines the maximum tolerated dose as the dose at which fewer than one-third of participants experience a dose-limiting toxicity to one of the study drugs.

A dose-limiting toxicity is defined in the record using specified blood-related and non-blood-related toxicities, as well as failure to recover sufficiently for re-treatment. The listed criteria include grade 3 thrombocytopenia, grade 4 anemia, grade 4 neutropenia, febrile neutropenia of any grade, and any non-hematologic grade 3 or grade 4 toxicity other than alopecia and/or hand/foot reaction. Failure to recover from toxicities to grade 1 or less, allowing re-treatment with everolimus within 14 days of the last dose of everolimus, is also included.

In a dose-escalation study, this endpoint helps identify a dose that meets the protocol’s tolerability rule during the specified assessment period. It is not, by itself, a measure of tumor response or longer-term safety. The registry record identifies the endpoint but does not report a numerical maximum tolerated dose or the number of participants experiencing dose-limiting toxicity at each dose level. The result for this primary endpoint is therefore not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does dose escalation estimate?

In general, dose escalation studies seek a dose that satisfies a prespecified tolerability rule, using observed toxicities during treatment. The registry defines the maximum tolerated dose using the frequency of dose-limiting toxicity and specifies the first 28 days of treatment as the primary assessment period. That definition makes the endpoint a decision rule about tolerability in the defined period, rather than an estimate of tumor response.

The interpretation depends on how participants are assigned to dose levels, how toxicity is assessed, and how escalation or de-escalation decisions are made. The registry describes dose escalation and names dose levels and schedules, but the detailed allocation procedure, cohort rules, and escalation algorithm are not reported in the registry record. A reader therefore cannot reconstruct the dose-finding process from the posted information alone.

Why define dose-limiting toxicity?

In general, a dose-limiting toxicity definition turns a range of clinical events into a consistent endpoint for dose-finding. The registry lists specific blood-related toxicities, febrile neutropenia, non-hematologic toxicities, and delayed recovery as criteria. It also excludes alopecia and/or hand/foot reaction from the stated non-hematologic criteria. Because the endpoint depends on these classifications, consistent grading and assessment are important. The record does not report how grading disagreements, incomplete assessments, or participants who stop treatment early were handled.

The stated threshold is fewer than one-third of participants experiencing a dose-limiting toxicity. That rule describes the target for selecting a dose; it does not mean every participant must be free of toxicity. Nor does a dose selected under this rule establish tolerability outside the defined treatment period or in populations not described by the trial.

What does sequential design imply?

In general, a sequential design means later study activity follows earlier activity rather than assigning all participants concurrently to randomized arms. Here, Phase I dose escalation informed the Phase II dose level, described as maximum tolerated dose -1. This structure is appropriate to describing the trial’s stated progression from dose finding to further assessment, but it does not create a randomized control comparison. Differences between Phase I and Phase II groups may reflect the phase, dose schedule, participant mix, or other features; the record does not provide analyses that separate these possibilities.

Masking is listed as none. In general, lack of masking can affect subjective assessments, such as symptom reporting or clinician judgments, while objective assessments may be less susceptible to that influence. The registry record does not report assessment procedures or steps used to reduce assessment bias.

How should the planning assumptions be read?

The registry describes a planning illustration 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 describes detecting a stated fraction of the observed effect. For time-to-event outcomes, the illustration uses the total number of events; for other outcomes, it uses participants per arm. These are planning assumptions, not descriptions of the trial’s non-randomized sequential allocation, and the record does not report that they were the trial’s original design assumptions.

In general, sample-size planning asks how much information a proposed study might need under specified assumptions. Its result is sensitive to the assumed effect, outcome variability, event rate, allocation, and statistical model. Planning estimates do not measure the power actually achieved by a completed study. The registry record does not report numerical planning estimates in the posted results, and they should not be read as observed power.

What do statistical uncertainty and multiplicity mean?

In general, an estimate summarizes the data, while a confidence interval communicates its precision under the model and sampling assumptions. A wide interval indicates greater uncertainty; a narrow interval indicates less uncertainty, but neither alone establishes clinical importance. A p-value, when used, summarizes how unusual the data would be under a specified null hypothesis and analysis. It does not measure the probability that a treatment works.

When several outcomes or comparisons are assessed, multiplicity can increase the chance of at least one apparently notable finding by chance. General approaches include prespecifying a primary analysis, adjusting inference across tests, or treating secondary analyses as exploratory. The registry lists 12 outcome measures and no analyses. Its approach to multiplicity, the handling of missing observations, and the analysis populations are not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 12 outcome measures, including the maximum tolerated dose endpoint and secondary outcomes covering progression-free survival, objective response, survival after therapy, symptom severity, and symptom interference with function. It reports 0 analyses. The registry record does not report a multiplicity strategy, such as a hierarchy of tests, an adjustment for multiple comparisons, or a distinction between confirmatory and exploratory analyses. Without this information and the outcome estimates, the statistical evidence across the listed outcomes cannot be evaluated.

Missing data procedures are not reported in the registry record. This includes how participants who withdrew, did not complete an assessment, or lacked follow-up information were treated in analyses. The record does not report whether outcome-specific denominators were used, how censoring was handled for time-to-event outcomes, or whether sensitivity analyses were performed. These details matter because the way incomplete follow-up is handled can affect both estimates and their uncertainty.

Analysis populations are also not reported in the registry record. The posted information does not specify which participants were included in each outcome analysis, whether the analysis set differed by phase or group, or how participants who received different amounts of treatment were accounted for. Enrollment was 86, but that number alone does not establish how many participants contributed to any particular endpoint.

In general, multiplicity, missing data, and analysis-population choices can influence how estimates should be interpreted. Their absence from the posted record limits assessment of the planned statistical safeguards and prevents a full appraisal of how the reported safety counts or any unposted outcome analyses were generated.

11. Safety Results

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

Deaths

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: facial nerve disorder (16.7%), hypertriglyceridemia (16.7%), intracranial hemorrhage (16.7%), neoplasms benign, malignant and unspecified (incl cysts and polyps) - other, specify (16.7%), seizure (16.7%).

The registry reports serious adverse event counts for five group descriptions. In the Phase I Dose Level I group, 3 participants were affected among 6 at risk. In the Phase I Dose Level -1 group, 2 were affected among 7 at risk. The Phase II Group A listing reports 3 among 12, Group B reports 12 among 40, and Group C reports 2 among 21. These figures describe the counts recorded for each group; they are not comparative estimates from a randomized safety analysis.

The record also lists deaths by group: 5, 6, 9, 19, and 11, respectively, in the order of the group descriptions above. The registry does not report whether these deaths were considered related to treatment or the period over which they were counted. The listed counts should therefore not be interpreted as treatment-attributable deaths.

Serious adverse event terms include facial nerve disorder, hypertriglyceridemia, intracranial hemorrhage, neoplasms benign, malignant and unspecified (including cysts and polyps) - Other, Specify, and seizure, each listed at 16.7%; confusion is listed at 14.3%. The record does not report the term-specific denominators, event counts, or whether participants could contribute more than one term. Percentages for different terms should not be added or treated as mutually exclusive categories.

Serious adverse events are not necessarily the same as all adverse events. The registry also reports other adverse event counts, but does not provide enough information to establish the event collection period or attribution rules. These safety summaries are descriptive and do not establish a causal relationship with either drug.

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

The record documents a completed Phase I-II study with enrollment of 86 and a primary focus on identifying the maximum tolerated dose of everolimus in combination with sorafenib. It describes the dose-limiting toxicity criteria and the transition from Phase I dose escalation to Phase II treatment at a dose level derived from that process. It also posts group-level safety counts and names secondary outcomes of interest.

However, the numerical result for the primary endpoint is not reported in the registry record. Quantitative results for the listed secondary outcomes are also not reported there, and the record reports 0 analyses. As a result, the posted information does not establish a maximum tolerated dose, quantify disease response, or estimate effects on progression-free survival, survival after therapy, or symptoms.

The safety figures can be read as descriptive counts of participants affected among those listed as at risk, along with group death counts and selected event terms. They do not, without additional information, show that an event was caused by treatment or permit a fair comparison among groups. The study’s non-randomized, sequential design further limits the interpretation of differences between groups as treatment effects.

In general, absence of a result in the registry is not itself evidence that an outcome did or did not occur. It means that the posted record does not supply the information needed to estimate that outcome or its precision. The record can therefore support a description of the study’s aims, design, endpoint definitions, and selected safety summaries, but not a conclusion about clinical efficacy or comparative safety.

13. Why This Trial Matters Statistically

This study is statistically notable for the way its questions change across phases. Phase I addresses dose and schedule through dose escalation, while Phase II is described as assessing whether the combination can help control malignant glioma. The primary endpoint is accordingly a tolerability-based dose-finding measure, not a direct efficacy endpoint. Keeping those questions distinct is essential when interpreting the design.

The sequential structure also illustrates why dose-finding groups should not automatically be treated as comparison arms. A later phase uses a dose informed by earlier escalation, and the registry identifies no randomized allocation. Group-level differences may therefore reflect design and participant differences as well as treatment exposure. The record itself cautions that the arms are not a like-for-like control comparison.

Another important statistical lesson is the difference between a defined outcome and a reported result. The registry gives a detailed definition of dose-limiting toxicity and names several secondary outcomes, but does not report the numerical result for the primary endpoint or quantitative analyses of the secondary outcomes. A clear endpoint definition is useful, but it cannot substitute for estimates and information about their precision.

The safety summaries demonstrate a similar distinction. Counts and percentages can describe what was recorded in groups, but interpretation depends on denominators, follow-up periods, event attribution, and analysis rules. Those details are not fully reported in the registry record. This makes the trial a useful example of how design, outcome definition, and completeness of results reporting jointly determine what statistical conclusions are supportable.

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 main limitation for statistical interpretation is that the registry record does not report a numerical result for the primary maximum tolerated dose endpoint. It also does not report quantitative results or analyses for the listed secondary outcomes. Consequently, the record does not permit assessment of outcome estimates, uncertainty, or how closely the results address the study’s stated aims.

The design is non-randomized and sequential. The registry explicitly notes that the arms are not a like-for-like control comparison. This limits causal interpretation of differences across groups, particularly because Phase I and Phase II have different roles and the Phase II dose was determined through Phase I escalation. The record does not report sufficient group-level clinical or analysis details to assess comparability.

The full dose-escalation procedure is not reported in the registry record. The endpoint definition is available, but the record does not describe the operational escalation rules, how participants were assigned to dose levels, how incomplete toxicity assessments were handled, or how the dose decision was reached. These omissions prevent independent reconstruction of the primary endpoint analysis.

For safety, the record lists counts, percentages, and deaths by group, but does not report the event collection period, term-specific denominators, attribution to treatment, or enough detail to determine whether categories overlap. These summaries should not be treated as comparative risks or causal evidence.

Finally, multiplicity handling, missing-data procedures, analysis populations, and detailed statistical methods are not reported in the registry record. Enrollment of 86 does not reveal the number analyzed for each endpoint. Together, these reporting gaps constrain assessment of precision, bias, and the robustness of any outcome interpretation.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Phase I-II Everolimus and Sorafenib in Recurrent High-Grade Gliomas — NCT01434602.
• Registry record last updated 2022-06-01; status last verified 2022-05.
• Results first posted 2022-02-01.
• 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

NCT01434602 is a completed, non-randomized, unmasked, sequential Phase I-II study sponsored by the National Cancer Institute. It enrolled 86 participants with recurrent high-grade or malignant gliomas and evaluated everolimus with sorafenib. The study began on 2012-10-02, with primary completion on 2020-10-19.

Phase I aimed to identify a tolerable dose and schedule through dose escalation. Phase II used a dose level determined from Phase I and assessed disease control and safety. The primary endpoint was maximum tolerated dose of everolimus during the first 28 days of treatment, defined using dose-limiting toxicity criteria.

The registry lists 12 outcome measures, including progression-free survival, objective response, survival after therapy, and symptom outcomes. It reports 0 analyses. The primary endpoint result and quantitative results for the listed secondary outcomes are not reported in the registry record. Group-level serious adverse event counts and selected event terms are posted, but the record does not provide enough detail to support causal or randomized comparative interpretations.