This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for A Study to Find the Best Dose of BI 836880 Alone and in Combination With BI 754091 in Japanese Patients With Different Types of Advanced Cancer (NCT03972150), a non-randomized phase 1 study. The primary outcome is Maximum Tolerated Dose (MTD) of BI 836880 Monotherapy and Combination Therapy of BI 836880 and BI754091.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT03972150 |
| Phase | Phase 1 |
| Condition | Neoplasms |
| Allocation | Non-Randomized |
| Design model | Sequential |
| Masking | None (open label) |
| Enrollment | 21 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Boehringer Ingelheim |
| Results posted | Yes |
2. Clinical Question
Population
Japanese patients with advanced solid tumours were eligible for the dose-escalation study. The registry describes a treated dose-escalation population for the primary dose-finding assessment: patients enrolled in the relevant cohort, administered at least one dose of study medication, and evaluable for the MTD determination.
Intervention
Part 1 assessed BI 836880 as monotherapy at 360 mg and 720 mg. Part 2 assessed BI 836880 with 240 mg of ezabenlimab, also identified as BI 754091, at BI 836880 doses of 120 mg, 360 mg, and 720 mg. Treatment was administered intravenously on Day 1 of each 3-week cycle.
Comparator
There was no randomized control group. The study was non-randomized and used sequential dose escalation. Its dose groups are different treatment regimens and dose levels, not like-for-like randomized comparison arms.
Primary question
What maximum tolerated dose, or recommended Phase 2 dose, could be identified for BI 836880 alone and for BI 836880 combined with BI 754091? The primary endpoint was the dose-finding assessment during the first treatment cycle, defined as the first 21 days following the start of trial medication.
This is a dose-finding question rather than a randomized comparison of clinical benefit. The registry lists safety and tolerability, pharmacokinetic characterization, and dose selection as the study objectives. The primary endpoint was based on dose-limiting toxicity risk during the specified evaluation period. The registry record does not report an actual MTD or RP2D result, so it does not establish which dose was selected for either treatment approach.
3. Trial Design
This was an open-label, Phase I study with non-randomized, sequential allocation. It enrolled 21 participants overall. The registry gives the study title and population as Japanese patients with advanced solid tumours, and describes the condition broadly as neoplasms. Treatment was divided into a monotherapy part and a combination-therapy part; there was no randomized control arm and no masking.
In Part 1, participants received BI 836880 monotherapy at 360 mg or 720 mg. In Part 2, participants received BI 836880 with 240 mg of ezabenlimab (BI 754091), at BI 836880 doses of 120 mg, 360 mg, or 720 mg. The regimens were given by intravenous infusion on Day 1 of each 3-week cycle. The treatment descriptions state that therapy continued until progressive disease, unacceptable toxicity, or another withdrawal criterion was met.
The primary objective was to determine the MTD and/or RP2D for monotherapy and combination therapy. Secondary objectives were to document safety and tolerability and characterize pharmacokinetics. The listed pharmacokinetic outcomes include maximum measured plasma concentration (Cmax) and area under the concentration-time curve from 0 to 504 hours (AUC0-504h) for BI 836880, and corresponding measures for ezabenlimab in the combination part. The record identifies measures at specified treatment cycles.
The study started on 2019-06-12, reached primary completion on 2020-10-27, and is listed as completed. The registry record does not report the detailed sequence of dose decisions or the criteria used to move between dose levels beyond the stated model-based MTD procedure. Because allocation was not randomized, outcomes across regimens should not be interpreted as controlled treatment contrasts.
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: All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.
Overall Study
| Stage | Part 1: 360 mg BI 836880 | Part 1: 720 mg BI 836880 | Part 2: 120 mg of BI 836880/ 240 mg Ezabenlimab | Part 2: 360 mg BI 836880/ 240 mg Ezabenlimab | Part 2: 720 mg BI 836880 / 240 mg Ezabenlimab |
|---|---|---|---|---|---|
| STARTED | 3 | 6 | 3 | 3 | 6 |
| COMPLETED | 0 | 0 | 0 | 1 | 3 |
| NOT COMPLETED | 3 | 6 | 3 | 2 | 3 |
Reasons for not completing this period:
| Reason | Part 1: 360 mg BI 836880 | Part 1: 720 mg BI 836880 | Part 2: 120 mg of BI 836880/ 240 mg Ezabenlimab | Part 2: 360 mg BI 836880/ 240 mg Ezabenlimab | Part 2: 720 mg BI 836880 / 240 mg Ezabenlimab |
|---|---|---|---|---|---|
| Adverse Event | 0 | 1 | 1 | 0 | 0 |
| Progressive disease | 3 | 5 | 2 | 2 | 3 |
Analysis population for the primary outcome, as defined in the registry: Dose escalation cohort treated set in monotherapy/combination therapy: This patients sets included all patients enrolled in dose escalation cohort of monotherapy/combination therapy who were documented to have administrated at least one dose of study medication and were evaluable for the MTD determination. This set is used for dose finding and MTD determination in Part I/Part II.
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.
Population: Treated set (TS) in monotherapy: This patient set included all patients enrolled in the trial who were documented to have administrated at least one dose of BI 836880 monotherapy. Treated set (TS) in combination therapy: This patient set included all patients enrolled in the trial who were documented to have administrated at least one dose of BI 836880 and ezabenlimab combination therapy.
| Characteristic | Unit | Part 1: 360 mg BI 836880 | Part 1: 720 mg BI 836880 | Part 2: 120 mg of BI 836880/ 240 mg Ezabenlimab | Part 2: 360 mg BI 836880/ 240 mg Ezabenlimab | Part 2: 720 mg BI 836880 / 240 mg Ezabenlimab | Total |
|---|---|---|---|---|---|---|---|
| Participants analysed | 3 | 6 | 3 | 3 | 6 | 21 | |
| Age, Continuous | Years | 62.7 (SD 15.7) | 54.8 (SD 14.7) | 51.7 (SD 12.0) | 57.3 (SD 15.5) | 62.0 (SD 8.8) | 57.9 (SD 12.4) |
| Sex: Female, Male: Female | Participants | 2 | 4 | 2 | 1 | 4 | 13 |
| Sex: Female, Male: Male | Participants | 1 | 2 | 1 | 2 | 2 | 8 |
| Ethnicity (NIH/OMB): Hispanic or Latino | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
| Ethnicity (NIH/OMB): Not Hispanic or Latino | Participants | 3 | 6 | 3 | 3 | 6 | 21 |
| Ethnicity (NIH/OMB): Unknown or Not Reported | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): Asian | Participants | 3 | 6 | 3 | 3 | 6 | 21 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): Black or African American | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): White | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): More than one race | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
6. Primary Endpoint
The registry lists the primary outcome as Maximum Tolerated Dose (MTD) of BI 836880 Monotherapy and Combination Therapy of BI 836880 and BI754091, measured over First treatment cycle, the first 21 days following the start of trial medication..
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | milligram |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint was the maximum tolerated dose of BI 836880 monotherapy and of the BI 836880 plus BI 754091 combination. MTD is a dose-finding endpoint: it uses dose-limiting toxicities observed during a defined evaluation period to assess the toxicity risk associated with dose levels. In this trial, the evaluation period was the first treatment cycle, the first 21 days following the start of trial medication.
The registry defines MTD using a Bayesian logistic regression model guided by escalation with overdose control. Its stated criterion was the highest dose with less than 25% risk that the true dose-limiting toxicity rate is equal to or above 0.33. The registry also specifies probability bands for model-estimated DLT risk: underdosing, [0.00, 0.16); targeted toxicity, [0.16, 0.33); and over toxicity, [0.33, 1.00]. These are categories for interpreting estimated toxicity risk, not reported event rates for the trial’s dose groups.
The endpoint is used to support dose selection in early-phase research, where identifying a dose with an acceptable toxicity profile is a central objective. It does not by itself measure whether treatment improves a cancer outcome. Although the registry states that determining an MTD and/or RP2D was a primary objective, it does not report the resulting dose determination or the model estimates. The endpoint’s definition is therefore available, but its trial result is not reported in the registry record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record describes a small, early-phase dose-escalation study, not a trial designed around a randomized comparison of treatment effects. Its main statistical purpose was to estimate dose-related toxicity risk for BI 836880 alone and when combined with BI 754091, then use that information for dose selection. The record identifies a Bayesian logistic regression model and an escalation-with-overdose-control approach, but does not report the model output or a selected MTD or RP2D.
The posted safety counts show serious adverse events in some combination-dose groups and none in the two monotherapy groups. In the 120 mg BI 836880 plus 240 mg ezabenlimab group, 1 participant was reported with a serious adverse event; in the 360 mg plus 240 mg group, 1 was reported; and in the 720 mg plus 240 mg group, 3 were reported. The corresponding counts at risk were 3, 3, and 6. No deaths were reported in any listed group. These descriptive counts do not establish that the combination caused the events, nor do they permit a reliable comparative estimate between regimens.
Other adverse events were reported for all participants listed as at risk in each group. Such broad counts convey that events were recorded, but do not describe their severity, timing, duration, or relationship to study treatment. The registry separately lists serious adverse event terms and percentages, including hepatic function abnormal, alanine aminotransferase increased, aspartate aminotransferase increased, and cerebral infarction at 33.3% each. The registry record does not provide enough detail in the registry record to interpret the percentages as comparative risks or to determine whether these terms occurred in the same participants.
The study’s non-randomized sequential structure is important. Dose groups are not exchangeable by design, and differences in their counts can reflect the small groups, differing dose levels, treatment regimen, or other factors. The figures do not support a causal claim that one regimen is safer or more hazardous than another. Nor do they answer whether either treatment improves tumour outcomes: no efficacy result is reported in the registry record described for this analysis.
The distinction between an endpoint definition and an endpoint result is central to interpretation. The registry explains how the dose-finding decision was intended to be made, including its risk criterion and probability categories. It does not report the estimated probabilities, the dose-limiting toxicity observations used for the analysis, or the dose ultimately identified. Accordingly, the record permits a description of the planned statistical framework and posted safety counts, but not a conclusion about the dose selected or the precision of that selection.
9. Statistical Methods Explained
What does the dose-finding model do?
The registry says the MTD analysis used a Bayesian logistic regression model (BLRM) guided by the escalation with overdose control (EWOC) principle. In general, logistic regression models relate an outcome that has two possible states to explanatory information. For dose-finding, the outcome of interest is whether a dose-limiting toxicity occurs during the evaluation period, while dose level is used to model toxicity risk. A fitted model can estimate risk across dose levels, including levels where only limited direct observations are available. The registry record does not report the model’s fitted estimates or its detailed specification.
In general, a Bayesian analysis represents uncertainty about model quantities with probability distributions and updates that uncertainty using observed data. The resulting dose-specific probabilities are not simply the observed fraction of participants with a toxicity. They are model-based estimates, and their interpretation depends on both the observed data and the model assumptions. The registry states that the dose probabilities were summarized in underdosing, targeted-toxicity, and over-toxicity intervals. It does not report the underlying probability estimates for individual doses.
How does overdose control guide escalation?
In general, escalation with overdose control is a way of using model-estimated toxicity risk to restrict movement toward doses considered too risky. The registry’s MTD criterion was the highest dose for which there was less than 25% risk that the true DLT rate was equal to or above 0.33. This is a probability-based decision rule; it is not the same as observing a toxicity rate below a threshold in the participants treated at that dose. The registry record does not report how the rule was applied at each decision point or which dose met the criterion.
The specified categories label estimated dose risk as underdosing, targeted toxicity, or over toxicity. In general, such bands provide a consistent way to describe model estimates in relation to a target range. They do not themselves prove that a dose is safe, effective, or appropriate for later study. The categories are part of the dose-selection framework, and their interpretation depends on the model output, which is not reported in the registry record.
What does the endpoint timeframe mean?
The MTD evaluation period was the first treatment cycle, described as the first 21 days following the start of trial medication. In general, a fixed toxicity window defines which observations count toward a dose-finding endpoint. Events outside that period may still matter for broader safety assessment, but they are not necessarily part of the specific primary MTD evaluation. The registry record does not report how later-onset events were incorporated into dose selection, if at all.
How should the safety counts be read?
Safety counts are descriptive. For each treatment group, the registry gives the number at risk and the number affected by serious adverse events, other adverse events, and death. In general, counts show how many participants had a recorded event within the registry’s reporting framework; they do not by themselves establish causation. Counts from small, non-randomized groups are especially limited for comparisons because a small change in the number of events can substantially alter the apparent pattern. No new comparative estimate should be inferred from the group counts.
The serious adverse event terms are reported with percentages, but the registry entries in this record do not fully specify the denominator or event-level overlap for those terms. A participant may have more than one event term, and an event term is not necessarily equivalent to a participant-level outcome. Without the underlying event data and a clear denominator, the listed terms should be treated as descriptive reporting rather than as a basis for comparing dose groups.
What is not available for assessing statistical precision?
The record gives no model estimates, uncertainty intervals for the estimated DLT risks, or MTD result. It also does not report the detailed dose-escalation decisions or a statistical analysis plan beyond the stated BLRM and EWOC description. In general, uncertainty intervals communicate how imprecisely a model-based estimate is determined; without reported estimates and intervals, the precision of the dose-selection analysis cannot be assessed from the registry record. The distinction matters: a named method explains the intended analysis, but does not substitute for its numerical results.
The study also lists pharmacokinetic endpoints, including Cmax and AUC0-504h for BI 836880 and ezabenlimab at specified cycles. Those are concentration-based measures, not the primary toxicity endpoint. The registry record described for this analysis does not report numerical pharmacokinetic results. Therefore, the statistical interpretation can characterize the endpoint definitions and general methods, but cannot quantify drug exposure or relate it to the observed safety counts.
10. Multiplicity, Missing Data and Analysis Populations
The registry record does not report a strategy for controlling multiplicity across the primary dose-finding assessments, the monotherapy and combination parts, or the listed pharmacokinetic outcomes. In general, multiplicity concerns arise when several hypotheses or outcomes are assessed; repeated assessment can affect the interpretation of nominal statistical evidence. This trial’s primary objective was dose selection using a model-based framework, rather than a set of reported confirmatory tests. No adjustment method or formal testing hierarchy is reported in the registry record.
Handling of missing data is not reported in the registry record. The primary population description refers to patients enrolled in a dose-escalation cohort who received at least one dose and were evaluable for the MTD determination. The available description does not specify how participants without a complete DLT evaluation were classified, how withdrawals during the evaluation period were handled, or whether any imputation was used. Those details matter because dose-finding depends on classifying toxicity observations within a defined period.
The registry record does not report interim analyses, a sample-size justification, or further details of the statistical analysis plan. The listed enrollment is 21, but the record does not describe a target sample size for each treatment group or explain how enrollment was determined. It also does not provide a flow of participants through the dose-evaluation population. These omissions limit assessment of analysis populations and the completeness of toxicity follow-up.
For the same reason, the posted information does not allow evaluation of missing pharmacokinetic measurements or the handling of measurements below quantification limits. No numerical pharmacokinetic results or missingness rules are reported. The absence of these details should not be interpreted as evidence that data were complete or that a particular method was used.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Part 1: 360 mg BI 836880 | 0 | 3 | 0.0% |
| Part 1: 720 mg BI 836880 | 0 | 6 | 0.0% |
| Part 2: 120 mg of BI 836880/ 240 mg Ezabenlimab | 1 | 3 | 33.3% |
| Part 2: 360 mg BI 836880/ 240 mg Ezabenlimab | 1 | 3 | 33.3% |
| Part 2: 720 mg BI 836880 / 240 mg Ezabenlimab | 3 | 6 | 50.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Part 1: 360 mg BI 836880 | 0 of 3 |
| Part 1: 720 mg BI 836880 | 0 of 6 |
| Part 2: 120 mg of BI 836880/ 240 mg Ezabenlimab | 0 of 3 |
| Part 2: 360 mg BI 836880/ 240 mg Ezabenlimab | 0 of 3 |
| Part 2: 720 mg BI 836880 / 240 mg Ezabenlimab | 0 of 6 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Part 1: 360 mg BI 836880 | 3 of 3 |
| Part 1: 720 mg BI 836880 | 6 of 6 |
| Part 2: 120 mg of BI 836880/ 240 mg Ezabenlimab | 3 of 3 |
| Part 2: 360 mg BI 836880/ 240 mg Ezabenlimab | 3 of 3 |
| Part 2: 720 mg BI 836880 / 240 mg Ezabenlimab | 6 of 6 |
Most frequent serious adverse event terms
| Event term | Organ system | Part 1: 360 mg BI 836880 | Part 1: 720 mg BI 836880 | Part 2: 120 mg of BI 836880/ 240 mg Ezabenlimab | Part 2: 360 mg BI 836880/ 240 mg Ezabenlimab | Part 2: 720 mg BI 836880 / 240 mg Ezabenlimab |
|---|---|---|---|---|---|---|
| Hepatic function abnormal | Hepatobiliary disorders | 0 of 3 | 0 of 6 | 1 of 3 | 1 of 3 | 0 of 6 |
| General physical health deterioration | General disorders | 0 of 3 | 0 of 6 | 0 of 3 | 0 of 3 | 1 of 6 |
| Alanine aminotransferase increased | Investigations | 0 of 3 | 0 of 6 | 1 of 3 | 0 of 3 | 0 of 6 |
| Aspartate aminotransferase increased | Investigations | 0 of 3 | 0 of 6 | 1 of 3 | 0 of 3 | 0 of 6 |
| Central nervous system neoplasm | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 0 of 3 | 0 of 6 | 0 of 3 | 0 of 3 | 1 of 6 |
| Malignant neoplasm progression | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 0 of 3 | 0 of 6 | 0 of 3 | 0 of 3 | 1 of 6 |
| Metastases to central nervous system | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 0 of 3 | 0 of 6 | 0 of 3 | 0 of 3 | 1 of 6 |
| Cerebral infarction | Nervous system disorders | 0 of 3 | 0 of 6 | 0 of 3 | 1 of 3 | 0 of 6 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Part 1: 360 mg BI 836880 | Part 1: 720 mg BI 836880 | Part 2: 120 mg of BI 836880/ 240 mg Ezabenlimab | Part 2: 360 mg BI 836880/ 240 mg Ezabenlimab | Part 2: 720 mg BI 836880 / 240 mg Ezabenlimab |
|---|---|---|---|---|---|---|
| Hypertension | Vascular disorders | 1 of 3 | 2 of 6 | 3 of 3 | 0 of 3 | 1 of 6 |
| Diarrhoea | Gastrointestinal disorders | 1 of 3 | 0 of 6 | 2 of 3 | 0 of 3 | 3 of 6 |
| Pyrexia | General disorders | 0 of 3 | 1 of 6 | 1 of 3 | 1 of 3 | 3 of 6 |
| Proteinuria | Renal and urinary disorders | 1 of 3 | 2 of 6 | 1 of 3 | 1 of 3 | 1 of 6 |
| Nausea | Gastrointestinal disorders | 0 of 3 | 0 of 6 | 1 of 3 | 0 of 3 | 3 of 6 |
| Vomiting | Gastrointestinal disorders | 0 of 3 | 2 of 6 | 0 of 3 | 0 of 3 | 2 of 6 |
| Malaise | General disorders | 1 of 3 | 0 of 6 | 1 of 3 | 1 of 3 | 1 of 6 |
| Oedema | General disorders | 0 of 3 | 1 of 6 | 0 of 3 | 1 of 3 | 2 of 6 |
| Alanine aminotransferase increased | Investigations | 0 of 3 | 0 of 6 | 1 of 3 | 2 of 3 | 1 of 6 |
| Oedema peripheral | General disorders | 0 of 3 | 0 of 6 | 0 of 3 | 1 of 3 | 2 of 6 |
Serious events with the highest arm-level rate: hepatic function abnormal (33.3%), alanine aminotransferase increased (33.3%), aspartate aminotransferase increased (33.3%), cerebral infarction (33.3%), general physical health deterioration (16.7%).
The registry reports serious adverse event counts by regimen. In monotherapy, 0 of 3 participants in the 360 mg BI 836880 group and 0 of 6 in the 720 mg group were reported with a serious adverse event. For combination therapy, the reported counts were 1 of 3 at 120 mg BI 836880 with 240 mg ezabenlimab, 1 of 3 at 360 mg with 240 mg ezabenlimab, and 3 of 6 at 720 mg with 240 mg ezabenlimab. No deaths were reported in any listed group.
Other adverse events were recorded for all participants at risk in each listed group. This broad category does not convey severity or establish that an event was caused by treatment. The serious-event terms listed by the registry include hepatic function abnormal, alanine aminotransferase increased, aspartate aminotransferase increased, and cerebral infarction, each reported as 33.3%; general physical health deterioration and central nervous system neoplasm were each reported as 16.7%.
These are descriptive registry figures from small, non-randomized groups. The counts should not be treated as a controlled comparison or as proof of a treatment-related effect. The registry record does not provide enough event-level detail to determine overlap among terms or to interpret the listed percentages as comparative group risks.
12. What the Result Does, and Does Not, Mean
The record establishes that the study was designed to investigate dose selection for BI 836880 as monotherapy and in combination with BI 754091. It describes an open-label, sequential Phase I design and identifies a Bayesian logistic regression approach with overdose control for the primary MTD assessment. It also reports group-level adverse event counts and lists pharmacokinetic measures as secondary outcomes. Those details clarify the question the study set out to address and the general method intended for dose finding.
The record does not report the actual MTD or RP2D for either treatment approach. It does not provide the model-derived probabilities, the DLT observations underlying the analysis, or numerical pharmacokinetic results. As a result, the posted information does not show which dose was selected, how much uncertainty surrounded that selection, or how drug exposure varied across doses or treatment parts.
The safety figures describe recorded events in the listed groups, but they do not show that treatment caused an event. The non-randomized design and small group sizes also mean that apparent differences across doses or treatment regimens cannot be interpreted as reliable comparative effects. No efficacy conclusion follows from these data: the primary endpoint was dose finding, and the registry information does not report tumour response or another clinical benefit result.
In general, early-phase dose-finding studies can inform the choice of doses for further research, but a dose-selection result is not by itself evidence of clinical benefit. In this case, even that dose-selection result is not reported in the registry record. The appropriate interpretation is therefore limited to the design, endpoint definition, stated statistical method, and posted descriptive safety information.
13. Why This Trial Matters Statistically
This study raises a central statistical challenge in early-phase research: how to use limited toxicity information to guide dose escalation while controlling the risk of selecting an overly toxic dose. The registry identifies a Bayesian logistic regression model and an escalation-with-overdose-control principle, making the intended dose-finding framework explicit. It also defines the evaluation window and the probability bands used to characterize estimated toxicity risk.
That framework is relevant because dose selection is not simply a matter of choosing the highest dose administered. A model-based decision uses the accumulating toxicity data and a stated risk rule to distinguish dose levels. In general, such methods are intended to make decisions that account for uncertainty and potential overdose risk. Their usefulness in a particular trial can only be judged by examining the actual model results, dose decisions, and uncertainty; those results are not reported in the registry record.
The study also illustrates why design features shape interpretation. Its open-label, non-randomized, sequential structure is appropriate to describe as dose escalation, but it does not create randomized comparisons among the treatment groups. The safety counts are useful as descriptive reporting, yet they cannot isolate a causal effect of dose or combination treatment. Keeping those two uses separate—dose finding and comparative treatment evaluation—is essential to reading the record accurately.
Finally, the primary endpoint is a toxicity-based dose-selection measure, while the listed secondary outcomes include pharmacokinetic exposure measures. These address different questions. A clear distinction between endpoint definition and reported result prevents the method itself from being mistaken for evidence that a particular dose was selected or that treatment produced a clinical benefit.
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 important limitation for interpretation is that the registry record does not report the primary dose-finding result. The MTD/RP2D objective and the BLRM/EWOC method are described, but there are no dose-specific model estimates, DLT counts, uncertainty intervals, or stated selected doses. Without those results, the precision and outcome of the central analysis cannot be assessed.
The groups are small and the study is non-randomized, with sequential dose escalation and no masking. They are not like-for-like control groups. Observed group differences in safety counts therefore cannot be attributed to dose or combination treatment, and the record does not support a causal comparison. The registry also does not report detailed event timing, duration, severity beyond serious-event classification, or treatment relationship for the counts described.
The available information does not specify the detailed dose-escalation sequence, the rules for participants who were not evaluable during the DLT window, or the handling of missing safety or pharmacokinetic observations. The registry record also does not report an interim-analysis plan, sample-size justification, or a broader statistical analysis plan. These gaps limit assessment of how completely the reported populations and outcomes reflect the study conduct.
Although pharmacokinetic outcomes are listed, numerical results are not reported in this record. Nor are clinical efficacy outcomes described in the registry record for this analysis. The trial’s dose-finding and safety information should therefore not be extended to conclusions about pharmacokinetic exposure, antitumour activity, or comparative safety.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: A Study to Find the Best Dose of BI 836880 Alone and in Combination With BI 754091 in Japanese Patients With Different Types of Advanced Cancer — NCT03972150.
- Registry record last updated 2025-10-06; status last verified 2025-09.
- Results first posted 2025-10-06.
- 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.
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18. Record Summary
NCT03972150 is a completed, open-label, non-randomized Phase I study of BI 836880 alone and with BI 754091 in Japanese patients with advanced solid tumours. The study enrolled 21 participants and used sequential dose escalation. Monotherapy was assessed at 360 mg and 720 mg of BI 836880; combination therapy used 240 mg of ezabenlimab with BI 836880 at 120 mg, 360 mg, or 720 mg.
The primary objective was to determine the MTD and/or RP2D for each treatment approach. The registry describes a Bayesian logistic regression model guided by escalation with overdose control and defines the DLT evaluation period as the first 21 days following treatment start. Secondary objectives included safety, tolerability, and pharmacokinetics.
The registry reports group-level adverse event counts and selected serious adverse event terms, but does not report the MTD/RP2D result, model estimates, or numerical pharmacokinetic results. The study started on 2019-06-12, reached primary completion on 2020-10-27, and is listed as completed.