Phase 1/2a Study of BAL101553 as 48-hour Infusions in Patients With Advanced Solid Tumors or Recurrent Glioblastoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase 1/2a Study of BAL101553 as 48-hour Infusions in Patients With Advanced Solid Tumors or Recurrent Glioblastoma (NCT02895360), a non-randomized phase 1, phase 2 study. The primary outcome is Maximum Tolerated Dose (MTD) of BAL101553.

2. Clinical Question

3. Trial Design

This was a completed, open-label Phase 1/2a study of BAL101553, with sequential dose escalation and expansion. It was non-randomized and had no masking. The intervention was single-agent BAL101553 administered by intravenous infusion over 48 hours to adults with advanced or recurrent solid tumors or recurrent glioblastoma. The registry lists an enrollment of 43.

Phase 1 used a fixed 3+3 dose-escalation design in patients with advanced solid tumors. The listed Phase 1 cohorts were 30 mg/m², 45 mg/m², 70 mg/m² and 90 mg/m². The primary endpoint focused on dose-limiting toxicities during the first 28-day treatment cycle and on using those findings to determine the MTD. The record describes the MTD-determining population as patients meeting minimum criteria involving receipt of BAL101553 during Cycle 1 and either experiencing a DLT or receiving all three doses without a DLT. The wording of the population description is incomplete in the registry record.

Phase 2a evaluated BAL101553 at the MTD in patients with platinum-resistant or refractory ovarian cancer or recurrent glioblastoma. The registry lists separate ovarian cancer and recurrent glioblastoma cohorts. Because the study was not randomized and did not include a like-for-like control group, comparisons between these cohorts or between Phase 1 dose levels are descriptive rather than controlled estimates of treatment effects.

Secondary outcomes included safety and tolerability based on related treatment-emergent adverse events, pharmacokinetic measures for BAL101553 and BAL27862, oral bioavailability measured by BAL27862 in Phase 1, and antitumor activity by best response using RECIST or RANO criteria. The registry record gives a start date of 2016-08-24 and a primary completion date of 2020-08-07, and lists the study as completed.

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.

Phase 1 - 30 mg/m² Cohort

Reasons for not completing this period:

Phase 1 - 45 mg/m² Cohort

Reasons for not completing this period:

Phase 1 - 70 mg/m² Cohort

Reasons for not completing this period:

Phase 1 - 90 mg/m² Cohort

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: MTD-determining population in Phase 1: All patients who meet the following minimum criteria during the first 28-day treatment cycle (Cycle 1) * received at least one partial or complete dose of BAL101553 and has experienced a DLT; * received all three doses of BAL101553 without experiencing a DLT (including the ability to initiate treatment Cycle 2), have been observed for ≥ 28 days following the first dose, and have been evaluated for safety.

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.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Maximum Tolerated Dose (MTD) of BAL101553, measured over 28 day cycle.

The primary endpoint was the maximum tolerated dose of BAL101553, expressed in mg/m². It was assessed in the Phase 1 MTD-determining population using dose-limiting toxicities recorded during the first 28-day treatment cycle. Toxicities were graded according to CTCAE, and the endpoint description identifies the number of participants with adverse effects as the basis for assessing tolerability at various dose levels.

An MTD endpoint is used in early-phase dose-escalation research to characterize tolerability across doses and guide selection of a dose for further study. In general, this endpoint is not a direct measure of whether a treatment improves a clinical outcome. It describes a dose-selection question: how observed toxicity during a defined treatment period informs a tolerable dose under the study’s rules. The fixed 3+3 escalation design is the stated Phase 1 approach, but the registry record does not report the detailed dose-escalation decisions or a numerical MTD result.

The primary endpoint’s timeframe was the first 28-day treatment cycle. The record’s primary outcome entry does not give a numerical result, a confidence interval, or a detailed analysis of dose-limiting toxicities by dose. The MTD value and the full participant-level basis for its determination are not reported in the registry record. Consequently, the endpoint can be described from its definition, but the posted record does not allow readers to verify the MTD selection from the primary outcome result.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The study used a sequential early-phase design, with dose escalation in Phase 1 and expansion in Phase 2a. Phase 1 is described as a fixed 3+3 design. In general, dose-escalation designs use toxicity observations at successive dose levels to guide whether escalation, continuation or stopping is appropriate. The 3+3 label identifies the stated design family, but the registry record does not give the detailed escalation rules, decision history, or the number of participants evaluated for dose-limiting toxicity at each decision point. It also does not report the selected MTD.

What does the primary endpoint measure?

The endpoint was the MTD of BAL101553, with dose-limiting toxicities assessed during the first 28-day treatment cycle in the Phase 1 MTD-determining population. Toxicities were graded according to CTCAE. The endpoint description frames tolerability in terms of the number of participants with adverse effects at various dose levels. In general, a count endpoint records how many people meet a defined event criterion; it does not, on its own, convey the severity distribution, timing, duration, or causal certainty of each event. Those additional details depend on the trial’s definitions and reporting.

The registry population description refers to patients who received at least one partial or complete dose and experienced a DLT, or who received all three doses without experiencing a DLT. The text ends after describing these criteria, so the full population definition is not reported in the registry record. That matters because the exact analysis population determines which participants contribute to an MTD decision. The registry also does not report participant-level toxicity records or the specific DLT counts by dose.

How should the design shape interpretation?

In general, a sequential dose-escalation study is designed to inform dose selection rather than to provide a randomized comparison of treatment outcomes. Participants enter dose cohorts in sequence, and the observed tolerability experience can influence subsequent dosing. That makes each cohort’s context important. In this study, the record lists Phase 1 dose cohorts and separate Phase 2a disease cohorts. Differences among those groups cannot be read as if they were randomized treatment effects, because allocation was non-randomized and there was no like-for-like control comparison.

The trial was open-label, with no masking. In general, knowledge of treatment can affect the observation, attribution or reporting of subjective events, though the registry record does not say whether or how that influenced assessments in this study. CTCAE grading provides a structured approach to toxicity classification, but grading alone does not establish that BAL101553 caused an event.

What can event counts and uncertainty tell readers?

In general, counts are most interpretable when their event definition, denominator, follow-up period and analysis population are clear. The registry reports cohort-specific numbers at risk and affected for serious and other events, plus deaths. Those counts describe the posted record by cohort. They do not replace the primary MTD analysis, and they should not be converted into causal comparisons across cohorts. The primary endpoint result does not include a confidence interval or another uncertainty measure in the registry record.

A confidence interval, in general, expresses the uncertainty associated with an estimated quantity under a specified statistical model and analysis. It does not guarantee that the estimate is unbiased, nor does it account automatically for design limitations or incomplete reporting. No interval for the MTD is reported in the registry record. The registry also does not provide a detailed statistical analysis plan, a sample-size justification, or information about interim analyses.

What do the secondary outcomes add?

The listed secondary outcomes cover related treatment-emergent adverse events, pharmacokinetic measures, oral bioavailability in Phase 1, and antitumor activity assessed by best response under RECIST or RANO criteria. In general, pharmacokinetic summaries describe drug exposure or concentration-related characteristics; response criteria provide structured rules for classifying tumor response. The registry record lists these outcome domains, but the detailed numerical results and analysis methods are not reported in the outcome information summarized in the record.

The sample-size material associated with the record is described as a planning illustration based on an observed effect, with two-sided significance level 0.05, equal allocation, and a normal approximation. It is not the study’s own design and should not be read as observed power or as the sample-size justification for this trial. The record does not provide the numerical planning scenarios in the registry record for this analysis, so no planning estimate can be interpreted.

In general, over-dispersion occurs when count outcomes vary more than a chosen statistical model expects. Accounting for it can be important when modeling event counts because a model that understates variability may produce overly narrow uncertainty estimates. The registry record does not report a count-model analysis for the primary endpoint, and the endpoint is described as a dose-selection outcome rather than as a modeled comparative count. No claim about over-dispersion adjustment can therefore be made for this study.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists seven outcome measures, including the primary MTD endpoint and secondary safety, pharmacokinetic, bioavailability and antitumor activity outcomes. It lists zero analyses. The registry record does not report a multiplicity adjustment, a hierarchy for interpreting multiple outcomes, or a prespecified statistical analysis plan. Without those details, it is not possible to determine how the investigators intended to control the chance of false-positive findings across multiple analyses. This is particularly relevant when a study reports numerous outcomes or examines results across dose levels and indications. In general, multiplicity methods can address the increased risk of chance findings when several hypotheses are tested, but the choice and use of such methods must be documented to evaluate their role.

The record does not report how missing outcome data were handled, the amount of missingness for each endpoint, or whether participants who did not complete the first 28-day cycle were included in a particular analysis. The primary endpoint is defined in a specific MTD-determining population, but the full criteria are not completely available in the registry text. The record also does not provide a flow of participants through the dose-escalation and expansion cohorts or a detailed accounting of evaluability for the primary endpoint.

These omissions limit assessment of the analysis population, the impact of incomplete follow-up, and the robustness of endpoint results. In general, missing-data methods depend on why observations are missing and on the estimand being addressed; a method cannot be evaluated without clear information about what was missing and how it was handled. The registry record does not report a sample-size justification, interim-analysis plan, or other details that would clarify these aspects of the statistical plan.

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: bladder neoplasm surgery (33.3%), nausea (25.0%), vomiting (25.0%), pyrexia (25.0%), fall (16.7%).

The registry reports serious-event and other-event counts separately for each listed cohort, along with deaths. For example, in the Phase 1 30 mg/m² cohort, the serious-event figures list 1 affected among 4 at risk, and the other-event figures list 4 affected among 4 at risk. In the Phase 1 70 mg/m² cohort, the corresponding figures are 7 affected among 9 at risk for serious events and 9 affected among 9 at risk for other events; the registry also lists 3 deaths for that cohort. These cohort counts are descriptive, not randomized comparisons.

The record lists the following serious-event terms with percentages: Bladder neoplasm surgery, 33.3%; Nausea, 25.0%; Vomiting, 25.0%; Pyrexia, 25.0%; Fall, 16.7%; and Neuropathy peripheral, 11.1%. The denominator and method used for these percentages are not reported in the registry record. The percentages should therefore be read as the posted term frequencies, not as precise risks that can be compared across cohorts from the information available.

Serious-event counts do not establish that treatment caused the events. The study’s safety outcome refers to related treatment-emergent adverse events, but attribution requires the relevant definitions and assessment process. The record does not provide enough detail to infer causality from these counts alone.

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

The registry record establishes that BAL101553 was studied in an open-label, non-randomized Phase 1/2a trial using sequential dose escalation and expansion. It describes the Phase 1 primary endpoint as the MTD, assessed through dose-limiting toxicities in the first 28-day treatment cycle. It also identifies the Phase 1 dose cohorts, the Phase 2a disease cohorts, and cohort-level safety counts. These registry entries characterize the study and the kinds of observations it collected.

The record does not report the numerical MTD result. It therefore does not show which dose was selected or how the dose-limiting-toxicity findings supported that selection. The absence of that endpoint result also means that readers cannot assess the estimate’s precision or independently reconstruct the MTD decision from the posted outcome information. The registry’s listed secondary outcome domains likewise do not establish specific pharmacokinetic or antitumor results without their numerical estimates and analysis details.

This was not a randomized treatment comparison. In general, differences between groups in a non-randomized study can reflect differences in who entered each group, dose, disease indication, follow-up, or other factors, as well as treatment. The cohort counts should not be interpreted as evidence that one dose or indication is safer or more effective than another. Nor do safety event counts establish that BAL101553 caused an event.

The study’s early-phase dose-selection objective is distinct from demonstrating clinical benefit. An MTD is a tolerability-related dose-selection outcome under a specified design; it is not itself proof that a treatment improves survival, tumor response or quality of life. The registry lists antitumor activity among the secondary outcomes, but the relevant numerical results are not reported in the record. No conclusion about treatment benefit or lack of benefit follows from the MTD endpoint definition or the posted safety counts alone.

13. Why This Trial Matters Statistically

This trial illustrates an important distinction in early-phase clinical research: a study can be structured to identify a dose for further investigation without being designed to estimate a controlled treatment effect. The stated Phase 1 fixed 3+3 dose escalation and the MTD endpoint make dose tolerability the central statistical question. Phase 2a then expanded evaluation at the MTD in specified disease cohorts. Understanding that sequence helps prevent a dose-finding study from being read as if it were a randomized efficacy trial.

The design also shows why analysis populations and endpoint rules matter. The primary outcome depends on dose-limiting toxicities during a defined first treatment cycle and on a specified MTD-determining population. If the full population definition, dose-level results and MTD decision are absent, readers cannot fully evaluate how the endpoint was operationalized or how the final dose choice followed from the observations. A clear report of these elements is central to interpreting dose-escalation evidence.

The registry also makes visible the distinction between event reporting and causal inference. Cohort-specific adverse-event figures can describe what was recorded, while the non-randomized design and lack of a control group constrain comparisons. The record’s open-label status and incomplete reporting of analysis details further underscore the importance of reading numerical safety descriptions alongside their definitions, denominators and assessment methods.

For biostatisticians and clinical researchers, the case highlights a general reporting principle: a defined endpoint is not a substitute for a reported estimate. Numerical results, uncertainty, analysis populations and the decision process are needed to assess both the statistical and clinical meaning of a dose-selection outcome. Here, the registry describes the framework but does not report the primary MTD value or its supporting analysis.

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.

Several limitations are specific to the information recorded for this study. The most consequential is that the registry defines the primary MTD endpoint but does not report its numerical result. The dose-limiting-toxicity findings by dose level and the decision process leading to an MTD are also not reported in the registry record. This prevents verification of the primary dose-selection conclusion from the posted endpoint information.

The design was non-randomized and open-label, with no like-for-like control group. The study included sequential Phase 1 dose cohorts and Phase 2a cohorts defined by disease indication. As a result, comparisons across these groups cannot isolate treatment effects from differences in dose or patient population. Cohort safety counts are descriptive, and event attribution cannot be established from counts alone.

The registry’s MTD-determining population description is incomplete, and the record does not provide participant flow or detailed endpoint evaluability. It also does not report the statistical analysis plan, sample-size justification, handling of missing data, multiplicity strategy, or interim-analysis details. The serious-event term percentages are listed without a reported denominator or calculation method. These omissions limit evaluation of the precision and completeness of the safety and endpoint summaries.

Finally, the registry lists secondary pharmacokinetic and antitumor outcomes but does not report their detailed numerical findings in the record summarized for this analysis. The record therefore supports description of the trial’s design and outcome framework, but only limited statistical assessment of its results.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Phase 1/2a Study of BAL101553 as 48-hour Infusions in Patients With Advanced Solid Tumors or Recurrent Glioblastoma — NCT02895360.
• Registry record last updated 2023-05-10; status last verified 2023-05.
• Results first posted 2021-10-11.
• 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

The registry record describes a completed, open-label, non-randomized Phase 1/2a study of intravenous BAL101553 administered as a 48-hour infusion. Phase 1 used fixed 3+3 dose escalation in patients with advanced solid tumors; Phase 2a evaluated BAL101553 at the MTD in patients with platinum-resistant or refractory ovarian cancer or recurrent glioblastoma. The record lists enrollment of 43 and a primary endpoint of MTD based on dose-limiting toxicities during the first 28-day treatment cycle.

Secondary outcomes included treatment-emergent adverse events, pharmacokinetic measures, oral bioavailability and antitumor activity. Cohort-level safety counts and selected serious-event terms are listed. The numerical MTD result, detailed endpoint analyses, and several elements of the statistical plan are not reported in the registry record. The non-randomized design does not support like-for-like causal comparisons across dose or disease cohorts.