Microtubule-Targeted Agent BAL101553 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 Microtubule-Targeted Agent BAL101553 and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma (NCT03250299), a na phase 1 study. The primary outcome is Number of Patients With Dose-Limiting Toxicities (DLTs) for Each Maximal Tolerated Dose (MTD)-Determining Dose Cohort.

2. Clinical Question

3. Trial Design

This was a phase I study of BAL101553 combined with radiation therapy in patients with newly diagnosed MGMT promoter unmethylated glioblastoma. The registry lists an enrollment of 26 and describes the design as sequential, with a fixed 3+3 dose-escalation approach. Allocation is listed as not applicable and masking as none. The study therefore does not provide a randomized comparison between the dose cohorts or against a separate control group.

The dose-finding description specifies BAL101553 7 days per week, combined with radiation on days 1-5 for 6 weeks, followed by 4 weeks of rest. The registry lists BAL101553 cohorts at 4 mg, 6 mg, 8 mg, 12 mg and 15 mg. These are dose cohorts within an escalation study, not treatment arms allocated to make a controlled comparison. Differences between cohort counts should not be read as comparative treatment effects.

The listed start date is 2017-12-15, and the primary completion date is 2022-06-03. The study status is terminated. The reason for termination is not reported in the registry record, so the status alone does not explain why the study ended or whether it ended for safety, operational, or other reasons. Basilea Pharmaceutica is listed as the sponsor.

The primary endpoint was the number of patients with dose-limiting toxicities for each MTD-determining dose cohort, assessed up to 10 weeks. Secondary outcomes listed are grade 3 to grade 5 adverse events, overall survival, and progression-free survival. Results for those outcomes are not reported in the registry record. No statistical analysis entries are listed, and details of the planned analysis beyond the design description are not reported.

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.

BAL101553 4 mg Cohort

BAL101553 6 mg Cohort

Reasons for not completing this period:

BAL101553 8 mg Cohort

Reasons for not completing this period:

BAL101553 12 mg Cohort

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: MTD-determining population: All patients who met any of the following criteria: * Received at least one dose of BAL101553 and has experienced a DLT; * Received ≥80% of their expected dose of BAL101553 and completed 6 weeks of combined treatment and 4 weeks of rest.

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 Patients With Dose-Limiting Toxicities (DLTs) for Each Maximal Tolerated Dose (MTD)-Determining Dose Cohort, measured over Up to 10 weeks.

The primary endpoint counts participants with dose-limiting toxicities in each dose cohort used to determine the maximum tolerated dose. The registry defines a dose-limiting toxicity as a clinically significant adverse event or abnormal laboratory value judged unrelated to disease progression, intercurrent illness, or concomitant medications. The event had to be considered at least possibly related to BAL101553 or to the combination of BAL101553 and radiation.

The endpoint is assessed over a timeframe of up to 10 weeks. The registry also defines the MTD-determining population: patients who received at least one dose of BAL101553 and experienced a dose-limiting toxicity, or patients who received at least 80% of their expected BAL101553 dose and completed 6 weeks of combined treatment and 4 weeks of rest. These criteria describe which patients could contribute to dose determination; they do not establish how many patients met the criteria.

General statistical context: in early dose-finding research, counting dose-limiting toxicities helps describe tolerability at the tested doses and informs dose escalation decisions. It is not a direct measure of whether treatment improves survival or controls disease. The registry record does not report the cohort-specific primary endpoint counts, the dose selected as the maximum tolerated dose, or an estimate of uncertainty around those results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical context below is general unless it specifically describes the registered design or endpoint. The registry record describes a sequential fixed 3+3 dose-escalation study and a count-based primary endpoint. It does not report the full statistical analysis plan, the escalation decision rules in detail, or results for the primary endpoint.

What does a dose-finding count represent?

A count of participants with dose-limiting toxicities is a direct summary of how many people in a cohort met the protocol’s toxicity definition during the assessment window. The count is interpreted in relation to the number of participants assessed, the definition of a qualifying event, and the observation period. Here, the registered timeframe is up to 10 weeks. The record’s definition requires the event to be clinically significant, not attributed to specified alternative causes, and considered at least possibly related to BAL101553 or the combination with radiation.

General statistical context: counts are useful for describing events in small dose cohorts, but they provide limited precision about the underlying event frequency. A count alone also does not show how severe each event was, when it occurred, whether treatment was interrupted, or how clinicians applied the attribution criteria. Those details are not reported in the registry record for the primary endpoint.

How should a sequential dose-escalation design be read?

In a sequential design, enrollment and dose assignment follow the dose-finding process rather than random allocation between concurrent treatment groups. The registry describes a fixed 3+3 dose-escalation approach, and allocation is listed as not applicable. Cohorts therefore serve the study’s dose-finding purpose; they are not designed as exchangeable groups for estimating comparative treatment effects. Differences in event counts between cohorts can reflect cohort size and participant differences as well as dose. Without randomization or an appropriate adjusted analysis, the counts should not be treated as evidence that one dose caused more or fewer events than another.

General statistical context: a 3+3 design is a rule-based approach used in some phase I studies to guide dose escalation based on observed toxicities. The registry gives the design label but does not report the detailed decision rules, cohort-by-cohort escalation decisions, or the rationale for each dose level. These elements should not be inferred from the label alone.

What do uncertainty estimates add?

General statistical context: a confidence interval gives a range of values compatible with the data under a specified statistical method. It conveys uncertainty in an estimate, rather than guaranteeing that the true value lies within the interval. For event counts in small cohorts, uncertainty can be substantial; counts without intervals do not communicate that uncertainty fully. The registry record does not report confidence intervals for the primary endpoint or the posted adverse-event counts.

General statistical context: a p-value addresses how compatible data are with a specified null model, under the assumptions of the analysis. It is not the probability that a treatment works, nor does it measure clinical importance. No p-values or analysis entries are listed for this study. Since the design is sequential and has no randomized comparator, a test of between-treatment efficacy is not established by the posted record.

What is the role of the planning illustrations?

The registry context describes planning illustrations based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It states that the effect to detect is a stated fraction of the observed effect. For time-to-event outcomes, the illustration concerns total events; for other outcomes, it concerns participants per arm. Such illustrations are hypothetical planning calculations, not observed trial findings or evidence that the study had a particular probability of detecting an effect. No specific illustration results are reported in the registry record.

General statistical context: sample-size planning depends on assumptions about the target effect, variability or event rate, allocation, significance threshold, and analysis method. Changing those assumptions changes the planned sample size. Planning calculations cannot replace an analysis of observed outcomes, and they do not show whether an observed treatment effect is real. The record does not report the trial’s own sample-size justification, so the planning illustration should not be attributed to the original study design.

For survival outcomes, methods generally use information about event occurrence and follow-up, rather than relying only on the number enrolled. The registry lists overall survival and progression-free survival as secondary outcomes, but does not report their results, follow-up summaries, or analysis methods. No survival effect or precision estimate can be interpreted from the available 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("BAL101553 4 mg MTD-determining Cohort", "BAL101553 6 mg MTD-determining Cohort", "BAL101553 8 mg MTD-determining Cohort", "BAL101553 12 mg MTD-determining Cohort", "BAL101553 15 mg MTD-determining Cohort")
n      <- c(5, 5, 6, 4, 4)
events <- c(0, 0, 1, 1, 0)
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  BAL101553 4 mg MTD-determining Cohort  5  0  0.0  0.0  52.2  0.0  43.4  0.4  45.9
ARM  BAL101553 6 mg MTD-determining Cohort  5  0  0.0  0.0  52.2  0.0  43.4  0.4  45.9
ARM  BAL101553 8 mg MTD-determining Cohort  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  BAL101553 12 mg MTD-determining Cohort  4  1  25.0  0.6  80.6  4.6  69.9  5.3  71.6
ARM  BAL101553 15 mg MTD-determining Cohort  4  0  0.0  0.0  60.2  0.0  49.0  0.5  52.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary endpoint and secondary outcomes covering grade 3 to grade 5 adverse events, overall survival, and progression-free survival. The statistical approach for testing or estimating these outcomes is not reported in the registry record. It is also not reported whether any adjustment for multiple outcomes or repeated analyses was planned. Without that information, the possibility of multiplicity and its effect on interpretation cannot be assessed.

Missing-data handling is not reported in the registry record. The primary endpoint population is defined by criteria involving receipt of BAL101553, occurrence of a dose-limiting toxicity, expected dose received, and completion of treatment and rest. The record does not describe how patients with incomplete observation, early discontinuation without a recorded dose-limiting toxicity, or missing toxicity assessments were handled in the primary endpoint analysis. Nor does it report how missing survival follow-up or censoring was handled.

The record lists zero analysis entries. It does not report an analysis population for the secondary outcomes, a method for determining whether an event was treatment-related beyond the primary endpoint definition, or estimates with uncertainty for the primary endpoint. The listed MTD-determining population criteria are not themselves a report of who was included in an analysis or how many participants met the criteria. These omissions limit evaluation of the completeness and reproducibility of the analyses.

12. 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: constipation (25.0%), sepsis (25.0%), urinary tract infection (25.0%), aphasia (20.0%), brain oedema (20.0%).

The safety record lists serious adverse events by dose cohort. For BAL101553 4 mg, 2 of 5 participants at risk are recorded as affected; for 6 mg, 3 of 5; for 8 mg, 2 of 7; for 12 mg, 2 of 5; and for 15 mg, 1 of 4. The corresponding counts listed for other adverse events are 5 of 5, 5 of 5, 7 of 7, 5 of 5, and 4 of 4. These are participant counts, not measures of event frequency per unit of follow-up.

Among the listed serious adverse event terms, constipation, sepsis, and urinary tract infection are each reported as 25.0%; aphasia, brain oedema, and cognitive disorder are each reported as 20.0%. The registry does not report the denominators or calculation details for these term percentages. A term percentage should not be assumed to represent the proportion of participants in a specific dose cohort.

The death counts listed for the 4 mg, 6 mg, 8 mg, 12 mg, and 15 mg cohorts are 5, 5, 4, 4, and 0. The registry does not report the relationship of these deaths to treatment or their timing. Serious adverse events, other adverse events, and deaths are distinct summaries; none should be treated as a count of dose-limiting toxicities without the endpoint criteria and analysis results.

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

The posted record establishes that this was a phase I, sequential dose-finding study of BAL101553 combined with radiation in newly diagnosed MGMT promoter unmethylated glioblastoma. It specifies the dose cohorts, treatment schedule, primary toxicity endpoint, and definition of a dose-limiting toxicity. It also includes cohort-level safety counts and lists secondary outcomes of overall survival and progression-free survival.

It does not report the primary endpoint results, the maximum tolerated dose selected, or results for overall survival or progression-free survival. Thus, the record does not allow readers to determine how many patients met the registered dose-limiting toxicity definition in each cohort, or to assess the precision of those counts. The posted safety counts describe events recorded in the listed cohorts, but they do not by themselves establish causation or a comparative safety effect.

The study is not described as randomized and has no concurrent comparator. Its dose cohorts are not suitable as if they were control groups in a randomized trial. Apparent differences in counts across cohorts cannot be separated from differences in cohort size, sequential enrollment, and other participant or study factors using the information reported.

General statistical context: a trial’s status and outcome summaries answer different questions. Terminated status indicates that the study ended in that status, but the reason for termination is not reported in the registry record. It does not establish that a treatment was effective, ineffective, unsafe, or safe. Similarly, an enrolled sample and listed adverse-event counts do not substitute for outcome estimates and uncertainty intervals.

The evidence available in the registry record is therefore descriptive and incomplete for assessing the primary dose-finding result or any clinical outcome benefit. It supports describing the study design and the recorded safety counts, while leaving the principal endpoint and survival outcomes unresolved.

14. Why This Trial Matters Statistically

This study is statistically informative as an example of how a phase I dose-finding question differs from an efficacy comparison. Its registered primary endpoint counts dose-limiting toxicities in MTD-determining cohorts, and its sequential fixed 3+3 design is intended to support dose escalation decisions. Those aims differ from estimating whether one treatment improves an outcome relative to a control.

The distinction matters because the cohort counts are easy to overinterpret. The dose cohorts have different numbers of participants at risk, and they were not formed by randomized allocation. Counts may help describe what was recorded at each dose, but they do not establish a causal dose-response pattern or a comparative treatment effect. The endpoint definition and assessment window also matter: a serious adverse event is not automatically a dose-limiting toxicity, since the registered DLT definition includes criteria for clinical significance and attribution.

The record also illustrates the importance of reporting complete outcome analyses. Although overall survival and progression-free survival are listed, their results are not reported in the registry record. The primary endpoint results are likewise absent. Without those results, readers cannot evaluate the dose-finding conclusion, uncertainty, or survival outcomes.

Finally, the planning assumptions described for sample-size illustrations should be kept separate from the trial’s own design and findings. General planning calculations are not observed power and do not fill the gap left by absent outcome results. The record is most useful for understanding the intended safety question and the limits of what can be concluded from the posted counts.

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 main limitation for interpretation is that the registry record does not report the primary endpoint results. Although the dose-limiting toxicity definition, assessment timeframe, and MTD-determining population criteria are specified, cohort-specific DLT counts and the dose selected are absent. The record also does not report estimates of uncertainty for those outcomes.

The study was sequential, with a fixed 3+3 dose-escalation design, and allocation is listed as not applicable. There is no randomized comparator, so the cohort data do not provide a controlled estimate of differences between doses or against another treatment. The cohort sizes listed in the safety summaries vary, and no adjustment or comparative analysis is reported.

The registry lists the study as terminated but does not report the reason. The timing and treatment relationship of the listed deaths are also not reported. For the serious adverse event term percentages, denominators and calculation details are not stated. These gaps make it difficult to interpret the safety summaries beyond their recorded counts and labels.

Overall survival and progression-free survival are listed as secondary outcomes, but their results, follow-up details, and analysis methods are not reported in the registry record. Missing-data procedures, censoring methods, multiplicity handling, and details of the analysis populations are also not reported. The registry description of the dose-finding design does not include detailed escalation decisions or the trial’s own sample-size justification. These limitations constrain both reproducibility and assessment of the findings.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Microtubule-Targeted Agent BAL101553 and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma — NCT03250299.
• Registry record last updated 2024-06-24; status last verified 2024-02.
• Results first posted 2024-06-24.
• 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

NCT03250299 is a phase I, sequential dose-finding study sponsored by Basilea Pharmaceutica. It examined oral BAL101553 combined with radiation therapy in patients with newly diagnosed MGMT promoter unmethylated glioblastoma. The record lists enrollment of 26, a fixed 3+3 dose-escalation design, no masking, and terminated status.

The primary endpoint was the number of patients with dose-limiting toxicities in each MTD-determining dose cohort, assessed up to 10 weeks. Secondary outcomes listed were grade 3 to grade 5 adverse events, overall survival, and progression-free survival. The record includes dose-cohort safety counts, but does not report primary endpoint or survival results, the reason for termination, or analysis entries. No randomized comparator is described.