Phase 1-2 of Temozolomide and Hypofractionated Radiotherapy in Tx of Supratentorial Glioblastoma Multiform: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase 1-2 of Temozolomide and Hypofractionated Radiotherapy in Tx of Supratentorial Glioblastoma Multiform (NCT01120639), a non-randomized phase 1, phase 2 study. The primary outcome is Number of Dose-limiting Toxicities (DLTs).

2. Clinical Question

This is a safety-oriented early-phase question, not a randomized test of whether the combination is superior to another treatment. The protocol description links dose selection to treatment-related Grade 3 to 5 central nervous system toxicity within 30 days. The registry also lists outcomes concerning acute and long-term toxicity, radiographic response, progression-free survival, overall survival, and quality of life. Those outcomes broaden the study’s descriptive scope, but they do not replace the stated primary endpoint or establish a causal comparison between doses.

3. Trial Design

The registry record identifies this as a phase 1–2, non-randomized, unmasked study with a sequential model. Enrollment was 30. The listed study dates are a start in 2010-04 and primary completion in 2016-11; the overall status is completed. Stanford University is listed as the sponsor. The study concerned glioblastoma and combined temozolomide with hypofractionated stereotactic radiosurgery.

The treatment groups were defined by radiation dose: 25 Gray x 5 fractions, 30 Gray x 5 fractions, 35 Gray x 5 fractions, and 40 Gray x 5 fractions, each combined with temozolomide. The descriptions say participants were stratified according to PTV, less than 60 cm³ versus 60 to 150 cm³. The record does not report how the sequential dose assignment operated, whether the sequence had prespecified decision rules beyond the endpoint definition, or how participants were distributed across the dose and volume strata.

Because allocation was not randomized, dose groups should not be read as exchangeable treatment arms. Sequential assignment can be useful in early-phase research when the focus is tolerability across dose levels. In general, however, differences between groups can reflect participant characteristics, treatment sequence, or other factors as well as dose. The registry record does not describe adjustment for such differences. There is no masking, so treatment assignment was not concealed from participants or study personnel according to the recorded design.

The listed primary endpoint is the number of DLTs observed within 30 days, reported by radiation dose and PTV stratum. Secondary outcomes include toxicity beyond the acute period, radiographic response, survival outcomes, and quality-of-life surveys. The registry record lists 10 outcome measures, but the posted results do not include analyses for these outcomes; the number of analyses is recorded as 0. The record does not report a randomized comparator, a statistical analysis plan, or an explanation of the study’s sample-size rationale.

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: Participants receiving each radiotherapy level were stratified by tumor size.

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 Number of Dose-limiting Toxicities (DLTs), measured over 30 days.

The primary endpoint is the number of dose-limiting toxicities observed within 30 days after stereotactic radiosurgery. A DLT was defined as treatment-related Grade 3 to 5 central nervous system toxicity, with possible, probable, or definite attribution, assessed using CTCAE v4. The record says the outcome was to be reported by radiation dose and by PTV stratum.

The protocol’s maximum-tolerated-dose definition uses the observed DLT count at each dose level. It defines the MTD as either the highest radiation dose per protocol or a dose level at which DLTs occurred in at least 2 of 3 participants and/or at least 2 of 6 participants. The registry record does not explain the operational decision process for applying these alternatives, nor does it report the DLT counts or the selected MTD.

In general, a dose-limiting toxicity endpoint is used in early-phase research to describe short-term tolerability at increasing treatment doses and to guide dose selection. Its specified observation window makes the scope clear: it captures the defined acute toxicities during the period stated, not every possible later harm. The registry separately lists acute and long-term toxicity outcomes, but results for these outcomes are not reported in the registry record. The primary endpoint alone cannot establish comparative effectiveness or characterize all longer-term risks.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record labels the design phase 1–2, non-randomized, unmasked, and sequential. Those labels describe broad features of the design, but they do not give a complete statistical analysis plan. The planned analysis methods, methods for handling incomplete observations, and the rationale for enrollment are not reported in the registry record.

What does a sequential design mean?

In general, a sequential dose study evaluates treatment at successive dose levels rather than assigning all participants concurrently to randomized groups. Such a structure can support dose-finding because observed tolerability may inform which doses are considered. The registry record identifies a sequential model and describes four dose levels, but does not report the specific sequence of enrollment, escalation or stopping rules, or any interim decision procedures. These features should not be inferred from the design label alone.

Non-randomized allocation matters for interpretation. Randomization is a method for balancing, on average, both measured and unmeasured baseline characteristics across treatment groups. Without it, groups may differ for reasons other than dose. In general, statistical adjustment can address some measured differences, but it cannot guarantee removal of all confounding. The registry record does not report adjusted analyses, covariate methods, or a comparison plan. Thus, the dose groups should not be interpreted as a controlled treatment-effect comparison.

How is the primary endpoint defined?

The primary outcome is a count of DLTs within 30 days of stereotactic radiosurgery. The qualifying event is treatment-related Grade 3 to 5 central nervous system toxicity under CTCAE v4, with possible, probable, or definite attribution. A count is a discrete outcome: it records how many qualifying events were observed, rather than a continuous measurement such as a score. The registry says the count was to be reported by radiation dose and PTV stratum, but does not report the counts.

For count outcomes, the denominator and observation process matter. A group with different numbers of participants or different follow-up completeness may have different opportunities to accrue events. The record gives group sizes in the serious-adverse-event listing, but does not provide the primary endpoint denominators by dose and PTV stratum, details of evaluability, or a missing-data approach. General count-data methods may also need to account for over-dispersion, which occurs when variability exceeds what a simple count model expects. The registry does not report a model choice or indicate whether over-dispersion was assessed.

What does the MTD rule contribute?

The registry’s definition uses DLT counts at a dose level and describes thresholds involving at least 2 of 3 participants and/or at least 2 of 6 participants. It also gives the highest radiation dose per protocol as an alternative part of the definition. This is a protocol rule for interpreting safety observations, not a statistical estimate with reported uncertainty. The registry record does not report how the alternatives were applied to the enrolled participants, what dose was selected, or whether any dose-level decision was made using additional criteria.

In general, a threshold-based dose rule is a decision framework. It can help make an early-phase dose selection process explicit, but the result depends on observed counts and on the rule’s exact operation. The rule itself does not quantify the precision of a toxicity rate or establish comparative benefit. No DLT counts or uncertainty intervals are reported in the registry record.

What do the listed secondary outcomes imply?

The registry lists acute toxicity within 30 days, long-term toxicity after more than 30 days, radiographic response, progression-free survival, overall survival, and quality of life measured with EORTC-QLQ C30, Brain-20, and MDASI-BT surveys. These outcomes involve different data types and time structures. In general, survival outcomes often require methods that account for censoring and follow-up time, while quality-of-life scores may require rules for scoring and missing questionnaire items. The registry record does not report these analysis details or results.

Sample-size illustrations are planning aids, not observed power. The stated illustration assumptions use a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect to detect expressed as a fraction of the observed effect. Time-to-event illustrations use the total number of events; other illustrations refer to participants per arm. These are not the trial’s own design justification, which is not reported in the registry record, and they should not be read as observed power. No analysis estimates are reported in the registry record from which to evaluate how such illustrations relate to trial findings.

The registry records 0 analyses. It does not report p-values, confidence intervals, model estimates, or a statistical plan specifying tests, adjustment, or analysis populations. General statistical principles can explain what such methods would address, but they cannot fill the gap in the posted results. Any interpretation of treatment differences, precision, or robustness would require results and methods not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists several secondary outcomes, including toxicity at different time periods, radiographic response, progression-free survival, overall survival, and quality of life measured by three surveys. Considering multiple outcomes can create multiplicity: in general, the more statistical tests conducted, the greater the chance that at least one result appears notable by chance if no adjustment or interpretation plan is used. Whether and how to address multiplicity depends on which outcomes are confirmatory, how tests are organized, and what conclusions are intended.

The registry record does not report a multiplicity strategy, a hierarchy of secondary endpoints, or which analyses were prespecified. It records 10 outcome measures and 0 analyses. Results, p-values, and confidence intervals for the listed secondary outcomes are not reported in the registry record. Therefore, the posted information cannot establish whether multiplicity adjustments were applied or how any analyses should be interpreted as confirmatory versus exploratory.

Missing-data methods and analysis populations are also not reported in the registry record. The record does not describe how participants with incomplete toxicity follow-up, unavailable imaging, censored survival information, or missing quality-of-life responses were handled. In general, missingness can affect the number of observations contributing to an estimate and can bias results when the reasons for missing data are related to outcomes or treatment. No assumptions or sensitivity analyses are reported.

The record’s enrollment figure does not establish that every enrolled participant contributed to every endpoint. The analysis population for the primary endpoint and the secondary outcomes is not reported in the registry record. Without participant flow, endpoint-specific denominators, and missing-data procedures, the completeness and representativeness of any outcome estimates cannot be assessed from the posted results.

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: neoplasms benign, malignant and unspecified (incl cysts and polyps) - other, death (66.7%), nervous system disorders-other, altered mental state (33.3%), seizure (25.0%), pneumonia (16.7%), surgical and medical procedures - other, ressection of recurrent tumor (16.7%).

The registry’s serious-adverse-event listing gives groups of 6 participants for the 25 Gray, 30 Gray, and 35 Gray dose levels, and 12 for the 40 Gray dose level. Serious events were recorded as affecting 6 of 6, 6 of 6, 6 of 6, and 9 of 12, respectively. Other adverse events were recorded as affecting 6 of 6, 5 of 6, 6 of 6, and 12 of 12, respectively. These are the registry’s group counts; they are not the primary DLT outcome.

The deaths column lists 6, 5, 4, and 10 across those dose groups, respectively. The record does not report cause-specific interpretation for those group counts in this listing. Serious events listed include “death” under neoplasms, altered mental state, seizure, pneumonia, resection of recurrent tumor, and generalized muscle weakness. The listed percentages for serious-event terms are 66.7%, 33.3%, 25.0%, 16.7%, 16.7%, and 8.3%, respectively.

These figures should be read as descriptive safety listings, not as a randomized comparison or as proof that a particular dose caused an event. The study was non-randomized, and the listing does not establish treatment attribution for every event. Serious adverse events also differ from DLTs, which have a specific definition, attribution requirement, grade range, organ system, and 30-day window. Primary DLT results are not reported in the registry record.

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

The registry record establishes that a phase 1–2, non-randomized, unmasked study evaluated temozolomide with hypofractionated stereotactic radiosurgery at four radiation dose levels. It defines the primary question as the number of treatment-related Grade 3 to 5 central nervous system DLTs within 30 days and describes a threshold-based maximum-tolerated-dose definition. Those details clarify the intended safety assessment.

The record does not report the primary DLT counts, the selected maximum-tolerated dose, or statistical analyses. Accordingly, the posted results do not establish the frequency of qualifying DLTs by dose or PTV stratum, nor do they indicate how precisely any toxicity estimate was measured. The registry lists serious adverse events and other outcomes, but those listings are not substitutes for the missing primary endpoint findings.

The design also does not support a randomized efficacy comparison. Non-randomized dose groups can differ in participant characteristics or other factors, and no adjustment strategy is reported. The listed response, progression-free survival, overall survival, and quality-of-life outcomes indicate that these areas were of interest, but their results are not reported in the registry record. The study description alone therefore cannot establish the magnitude or precision of those outcomes.

In general, statistical evidence depends on both the observed estimates and their uncertainty, as well as the design and analysis assumptions. A protocol endpoint definition, enrollment figure, or planning illustration cannot replace outcome data. The record’s completion status indicates that the study is marked completed, but does not by itself show which outcomes were observed or analyzed. The main defensible reading is descriptive: the registry documents a dose-focused early-phase study and its intended endpoint, while leaving the primary result and analysis methods unreported.

This distinction matters because absence of posted results is not evidence of either a favorable or unfavorable finding. It means the registry record does not give enough outcome information to determine what the study observed. No conclusion about treatment benefit, comparative effectiveness, or the overall balance of benefits and harms follows from the design description alone.

13. Why This Trial Matters Statistically

This study is statistically notable because it addresses dose selection rather than a randomized comparison of treatment strategies. Early-phase studies commonly focus on tolerability and on describing outcomes across dose levels. Here, the registry specifies a short-window DLT endpoint and a dose-level rule for defining the maximum tolerated dose. That makes the endpoint’s definition and observation period central to interpretation.

The record also illustrates why a design label is not a complete methods description. “Sequential” and “non-randomized” convey important structural features, but they do not reveal the assignment algorithm, escalation decisions, interim procedures, or statistical model. The exact dose-decision process is not reported in the registry record. Those omissions limit independent assessment of how observations would have informed dose selection.

Separating DLTs from serious adverse events is another important statistical distinction. A broad safety listing and a narrowly defined primary endpoint answer different questions. The serious-event counts can describe the posted safety categories, but they do not yield the primary DLT result without the required attribution, grade, organ-system, and time-window information.

Finally, the registry lists a broad range of secondary outcomes but reports 0 analyses. This highlights the difference between outcomes named in a record and outcomes with posted estimates. Without results, methods, and uncertainty measures, readers cannot assess the size, precision, or consistency of findings. The trial’s statistical contribution can be understood from its design and endpoint definition, but the registry record does not permit an evaluation of its observed primary result.

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 of the registry information is that the primary endpoint results are not reported. Although the record defines DLT and gives a maximum-tolerated-dose rule, it does not provide observed DLT counts by dose or PTV stratum, or report a selected dose. This prevents assessment of the primary safety question as stated.

The non-randomized, sequential design limits dose-group comparisons. The groups are not described as concurrent randomized controls, and the registry record does not report participant characteristics by dose, adjustment methods, or an analysis designed to separate dose effects from other differences. The record also does not explain the sequence of enrollment or the application of dose-level decision rules.

Enrollment was 30, but endpoint-specific analysis populations and denominators are not reported. The registry does not describe missing-data handling, follow-up completeness, censoring, or quality-of-life questionnaire completion. It also does not report estimates or uncertainty intervals for the listed primary and secondary outcomes. These gaps make it impossible to evaluate precision or determine how much information contributed to each outcome.

The registry lists serious-adverse-event counts, but the listing does not supply the primary DLT classification. Serious events and DLTs have different definitions, and the record does not provide enough detail to reconcile the two. The statistical analysis plan, sample-size justification, multiplicity handling, and interim analysis procedures are not reported in the registry record. Finally, while the record lists several secondary outcomes, the number of analyses is recorded as 0; outcome names alone do not establish that findings were analyzed or posted.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Phase 1-2 of Temozolomide and Hypofractionated Radiotherapy in Tx of Supratentorial Glioblastoma Multiform — NCT01120639.
• Registry record last updated 2021-08-06; status last verified 2021-08.
• Results first posted 2019-07-31.
• 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

The registry record describes a completed phase 1–2, non-randomized, unmasked, sequential study sponsored by Stanford University, with enrollment of 30. It evaluated temozolomide with stereotactic radiosurgery at 25 Gray x 5 fractions, 30 Gray x 5 fractions, 35 Gray x 5 fractions, and 40 Gray x 5 fractions. Participants were stratified by PTV, less than 60 cm³ versus 60 to 150 cm³.

The primary endpoint was the number of treatment-related Grade 3 to 5 central nervous system DLTs within 30 days. The record defines a maximum-tolerated-dose rule but does not report DLT counts or a selected dose. It lists secondary outcomes including toxicity, response, survival, and quality of life, while recording 0 analyses. Statistical methods, analysis populations, missing-data procedures, and the study’s own sample-size justification are not reported in the registry record.