A Study to Find a Safe and Effective Dose of BI 905711 in Patients With Advanced Gastrointestinal Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Find a Safe and Effective Dose of BI 905711 in Patients With Advanced Gastrointestinal Cancer (NCT04137289), a randomized phase 1 study. The primary outcome is Number of Patients With Dose-limiting Toxicity (DLT) During the MTD Evaluation Period in Phase 1a.

2. Clinical Question

This is an early-phase dose-finding study, rather than a confirmatory comparison of BI 905711 against standard care or placebo. Its central primary endpoint is a count of patients with a dose-limiting toxicity (DLT) during the specified evaluation window. The registry describes the study’s broader aims as exploring safety and establishing the maximum tolerated dose or recommended dose levels for Phase 1b. It also describes exploration of pharmacokinetics, pharmacodynamics and efficacy to guide a potentially effective dose range, followed by evaluation of efficacy and safety and determination of the Recommended Phase 2 Dose in Phase 1b.

The clinical question therefore concerns early characterization of dose-related tolerability and dose selection. The posted primary endpoint does not, by itself, answer whether BI 905711 improves a clinical outcome compared with another treatment. Nor does the DLT count capture every aspect of safety or efficacy. The listed endpoint applies specifically to Phase 1a and the MTD evaluation set, whose registry definition excludes treated patients replaced for MTD determination.

3. Trial Design

The registry describes a first-in-human Phase Ia/b, open-label, multicentre, dose-escalation study. It records the trial as Phase 1, randomized, unmasked and parallel, with an enrollment of 110. The study status is completed. Its start date is 2020-03-11 and its primary completion date is 2023-07-26. The sponsor is Boehringer Ingelheim.

Participants received BI 905711 in intravenous dose regimens. The listed regimens include 0.02 mg/kg, 0.06 mg/kg, 0.2 mg/kg, 0.6 mg/kg, 1.2 mg/kg, 2.4 mg/kg, 3.6 mg/kg and 4.8 mg/kg on a Q2W schedule, as well as 0.6 mg/kg on a QW schedule. The arm descriptions refer to single administration in Cycle 1 and multiple administrations in Cycle 3. They describe Q2W dosing on Day 1 of a 14-day cycle; the QW regimen is described as once every week for 3 weeks followed by 1 week off. The registry record does not report the allocation process or explain how randomization operated within this dose-escalation design.

The primary endpoint is the number of patients with DLT during the MTD evaluation period in Phase 1a. The period runs from Cycle 1 Day 1 until the day before Cycle 3 Day 1, described as two 14-day treatment cycles. The primary analysis population is the MTD evaluation set: treated patients who were not replaced for MTD determination. The posted primary outcome lists dose groups from 0.02 mg/kg through 4.8 mg/kg, but does not list the 0.6 mg/kg QW group for this endpoint. Reasons for this distinction are not reported in the registry record.

The study’s stated Phase 1a objectives include exploring safety and establishing MTD or dose levels for Phase 1b. Phase 1b is described as evaluating efficacy and safety at a potentially effective dose range and determining the Recommended Phase 2 Dose. The registry record does not report further design details such as the allocation procedure, planned number of participants per dose group, or the statistical plan.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: 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.

Only the first 6 of 9 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: MTD evaluation set (MTDS): This included all patients in the treated set (TS) who were not replaced for the MTD determination. The MTDS was used for the primary analyses of drug limiting-toxicities (DLTs) and MTD determination. This analysis was carried out for participants in the Phase 1a part of trial.

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): This included all subjects who were dispensed study medication and were documented to have been treated with at least one dose of BI 905711. This TS was used for both safety and efficacy analyses.

Only the first 6 of 10 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Patients With Dose-limiting Toxicity (DLT) During the MTD Evaluation Period in Phase 1a, measured over From cycle 1 Day 1 until the day before cycle 3 Day 1 (two 14-day treatment cycles)..

The primary endpoint counts patients who experienced at least one dose-limiting toxicity during the MTD evaluation period in Phase 1a. The registry defines that period as beginning at Cycle 1 Day 1 and ending the day before Cycle 3 Day 1, covering two 14-day treatment cycles. The outcome is a participant count, not a measure of the number of separate toxicities or their severity distribution.

In an early dose-escalation study, DLTs during a defined initial treatment window can inform decisions about tolerable dose levels. The registry states that this endpoint was used for MTD determination in Phase 1a, and that safety findings were intended to help establish dose levels for Phase 1b. This is a dose-selection purpose: the count provides information about observed toxicities within the specified window and analysis population.

The primary analysis population is the MTD evaluation set. It includes treated patients who were not replaced for MTD determination. As a result, the endpoint’s reported group sizes should not be assumed to represent every treated participant or everyone enrolled. The registry record does not report further criteria for identifying a DLT or details of adjudication.

DLT counts are not a comprehensive summary of all adverse events, and they do not establish that a dose is safe in every clinical context. The endpoint is limited to the stated evaluation period and analysis set. It also does not measure treatment benefit. Other outcomes, including pharmacokinetic measures and efficacy outcomes, are described in the record, but the primary result is the DLT participant count.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count represent?

The primary endpoint is a binary event summarized as a count: whether each patient had a DLT during the MTD evaluation period. The posted value for each group is the number of patients meeting that endpoint, while the group size indicates the number included in that group’s primary-endpoint summary. This type of result is straightforward to describe, but its precision depends strongly on how many observations contribute. With small groups, a zero count can coexist with considerable uncertainty about the underlying event frequency. No confidence intervals are reported in the registry record, so the posted counts do not quantify that uncertainty directly.

Why is the analysis window important?

The endpoint only counts DLTs during the specified evaluation period: Cycle 1 Day 1 through the day before Cycle 3 Day 1. A toxicity occurring outside that window would not be represented by this primary endpoint, although it could appear in other safety summaries. The window makes the endpoint relevant to the stated MTD evaluation, but it also limits what can be inferred from it. It is not a count of all toxicities throughout follow-up.

What does the MTD evaluation set mean?

The registry defines the MTD evaluation set as treated patients who were not replaced for MTD determination. This is the population used for the primary DLT analyses and MTD determination in Phase 1a. It is not necessarily identical to the full group enrolled or treated. The record does not report the replacement rules or additional details about how patients qualified for inclusion in the endpoint analysis. A careful interpretation therefore keeps the analysis set distinct from the enrollment figure.

Why are there no two-arm effect estimates?

The posted endpoint consists of dose-specific event counts, and the study does not list a placebo or untreated comparison group. The registry reports no analyses for the primary endpoint. Consequently, there is no posted effect estimate or test comparing two groups for this outcome. A difference between observed counts or proportions would not by itself establish a causal dose effect, particularly without a reported analysis plan and with small group sizes. The registry record does not report confidence intervals, p-values or an adjusted model for the primary outcome.

How should the planning illustrations be understood?

Planning sample-size illustrations are calculations intended to show the approximate group size that might be needed under specified assumptions to detect an effect. They are not observed results and do not describe the power achieved by this completed trial. The stated illustration assumptions are a two-sided significance level of 0.05, equal allocation between two arms and a normal approximation; the effect to detect is expressed as a fraction of the observed effect. For non-time-to-event outcomes, the illustration is expressed as participants per arm for the stated power. The registry record does not report the trial’s own sample-size justification, so these illustrations should not be mistaken for the original design calculation.

In general, an observed effect used for planning can be uncertain, especially when estimated from small groups. Planning for a fraction of an observed effect explores scenarios with a smaller target effect, but the illustration remains conditional on its assumptions. It is not a forecast of the result of a future trial and does not establish that the stated effect is clinically important. No specific planning sample-size figures are reported in the registry information.

What do confidence intervals and over-dispersion mean in general?

In general, a confidence interval describes a range of values reasonably compatible with data under a statistical model and its assumptions. For an event count or event proportion, an interval helps convey how much uncertainty remains beyond the observed count. A zero observed event count is not proof that the true event probability is zero; a confidence interval can make that distinction visible. No interval estimates are reported for this primary endpoint in the registry record.

In general, over-dispersion means that observed variation is greater than a model’s assumptions allow. It can matter when analyzing counts because standard errors may otherwise be too small and statistical evidence may appear more precise than warranted. The registry does not report a count model, a dispersion estimate or an adjustment for over-dispersion for this endpoint. The primary results are presented as participant counts, so there is no basis in the registry record to attribute a particular model or dispersion correction to the analysis.

What does the record leave unspecified?

The record does not report the statistical plan for primary endpoint analysis, the method of randomization, any interim analyses, or a sample-size justification. It also does not report a primary-endpoint comparison or inferential estimate. These omissions mean the descriptive results can be read as posted, but additional claims about planned testing, decision thresholds or the precision of dose comparisons cannot be reconstructed from the registry 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("BI 905711 0.02 mg/kg, Q2W", "BI 905711 0.06 mg/kg, Q2W", "BI 905711 0.2 mg/kg, Q2W", "BI 905711 0.6 mg/kg, Q2W", "BI 905711 1.2 mg/kg, Q2W", "BI 905711 2.4 mg/kg, Q2W")
n      <- c(1, 1, 6, 8, 7, 8)
events <- c(0, 0, 0, 0, 0, 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  BI 905711 0.02 mg/kg, Q2W  1  0  0.0  0.0  97.5  0.0  79.3  1.3  84.2
ARM  BI 905711 0.06 mg/kg, Q2W  1  0  0.0  0.0  97.5  0.0  79.3  1.3  84.2
ARM  BI 905711 0.2 mg/kg, Q2W  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  BI 905711 0.6 mg/kg, Q2W  8  0  0.0  0.0  36.9  0.0  32.4  0.3  33.6
ARM  BI 905711 1.2 mg/kg, Q2W  7  0  0.0  0.0  41.0  0.0  35.4  0.3  36.9
ARM  BI 905711 2.4 mg/kg, Q2W  8  0  0.0  0.0  36.9  0.0  32.4  0.3  33.6

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 16 outcome measures, 12 posted secondary outcomes and no analyses for the primary endpoint. The secondary outcomes include pharmacokinetic measures such as maximum measured plasma concentration and area under the concentration-time curve, with measurements described for the first and third cycles in Phase 1a and Phase 1b. The record does not report how multiplicity across these outcomes was handled, whether any outcomes were designated exploratory, or whether adjustments to statistical significance were planned. Without that information, the results should not be interpreted as a single, prespecified family of confirmatory tests.

Missing-data procedures for the primary endpoint are not reported in the registry record. The MTD evaluation set definition identifies treated patients who were not replaced for MTD determination, but the record does not describe how incomplete DLT observation, early discontinuation or missing endpoint information was handled. The endpoint’s specified time window is clear; the handling of patients without complete observation through that window is not.

The primary analysis population is distinct from the enrollment figure. The registry identifies the MTD evaluation set as the population for primary DLT analysis and defines it by treatment and replacement status. It does not provide a fuller account of the treated set, replacements or reasons for exclusion in the primary result information. These details matter because group counts should be interpreted using the endpoint-specific analysis population, not treated as counts for every enrolled participant.

Randomized allocation is recorded, but allocation methods and the role of randomization in dose escalation are not reported in the registry record. A statistical analysis plan, interim-analysis plan and sample-size justification are also not reported. The absence of those details prevents assessment of whether the posted results follow a prespecified testing strategy.

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: adrenal insufficiency (100.0%), hyponatraemia (100.0%), liver abscess (14.3%), blood bilirubin increased (14.3%), ischaemic stroke (14.3%).

The serious adverse-event summaries report, for each group, the number at risk and the number affected. For example, the 0.6 mg/kg Q2W group has 23 at risk and 14 affected for serious events; the 2.4 mg/kg Q2W group has 24 at risk and 10 affected. These values are safety counts and are separate from the primary DLT endpoint. Other adverse-event counts and deaths are also listed by group. They should not be treated as interchangeable outcomes or combined with the primary endpoint counts.

The serious-event terms listed include adrenal insufficiency and hyponatraemia, each with a reported 100.0%, as well as liver abscess, blood bilirubin increased, ischaemic stroke and dyspnoea, each with a reported 14.3%. The registry summary does not provide enough detail to reconstruct the denominators behind each term-level percentage, so those percentages should be read as reported rather than converted into counts. Multiple serious-event terms may also occur in the same patient; the term percentages should not be added together.

Deaths are listed as counts within the safety summaries. A death count does not establish that a death was caused by BI 905711. The registry record does not report causal attribution in these summaries. Differences in group sizes, exposure and follow-up can also affect raw counts; detailed exposure-adjusted comparisons are not reported in the registry record.

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

The primary result is a set of observed DLT counts during the Phase 1a MTD evaluation period. The posted count is zero in each of the listed dose groups, including groups with different sizes. This describes the recorded experience in the specified endpoint population and window. It does not demonstrate that the risk of DLT is zero, nor does it establish that all dose levels have the same safety profile. The small group sizes limit the precision with which event frequency can be characterized.

The result also does not identify a statistically established safest or best dose. The registry reports no primary endpoint analyses, comparative estimates or confidence intervals. The study is recorded as randomized, but no allocation details are reported, and no placebo or untreated control group is listed. The primary endpoint data are therefore descriptive rather than a reported test of a treatment effect or dose-response relationship.

The study’s stated purpose goes beyond the primary endpoint: it aimed to explore pharmacokinetics, pharmacodynamics and efficacy, and to use safety and other information to guide a potentially effective Phase 1b dose range. The DLT counts alone cannot establish efficacy, clinical benefit, a Recommended Phase 2 Dose or an MTD. Those determinations are not reported in the primary endpoint information.

Safety summaries include serious adverse events, other adverse events and deaths, which add context but must be interpreted separately. Their counts do not automatically indicate treatment causation, and the registry record does not report causal attribution in these data. Nor does a count in a safety summary necessarily describe the same patient population or time window as the primary MTD endpoint.

In short, the posted data show no recorded DLTs in the listed primary endpoint groups during the defined assessment period. They offer a descriptive component of an early dose-finding study, not a complete account of tolerability, a definitive comparison among dose regimens, or evidence that treatment improves outcomes.

14. Why This Trial Matters Statistically

This study illustrates a central statistical challenge in early-phase research: dose selection often depends on sparse event data collected in small, dose-specific groups. A zero count is informative as an observation, but it cannot eliminate uncertainty about the event rate. Readers need the group size, endpoint definition, assessment window and analysis population alongside the count to understand what the result does and does not support.

The endpoint is tightly connected to the study’s stated MTD objective. Its focus on DLTs during the first two treatment cycles offers a defined window for dose evaluation. At the same time, that focus makes it essential not to equate the primary result with all safety experience. Separate adverse-event summaries cover broader safety information, while pharmacokinetic and pharmacodynamic outcomes address different questions about drug exposure and activity.

The record also highlights the importance of transparent analysis details. It describes the study as randomized and lists multiple dose regimens, yet does not report the randomization procedure, primary endpoint analyses, missing-data methods, multiplicity approach or original sample-size justification. These omissions limit the ability to assess how dose comparisons were planned or how uncertainty was quantified.

Finally, planning illustrations should remain conceptually separate from observed trial results. They explore sample sizes under stated assumptions and are not observed power or a record of the trial’s original design rationale. Keeping planning calculations, descriptive endpoint counts and the broader safety summaries distinct helps prevent early-phase data from being interpreted as stronger evidence than the registry reports.

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 primary DLT result is limited to the MTD evaluation period and the MTD evaluation set, which excludes treated patients replaced for MTD determination. The registry record does not report replacement criteria or detailed missing-data handling. The listed groups are small, and no confidence intervals are reported, limiting assessment of precision around the zero counts.

The registry records randomization but does not report how it was performed or explain its role in the dose-escalation design. No placebo or untreated comparator is listed. The primary endpoint has no posted analyses, and the record does not report inferential comparisons among dose groups. The posted counts therefore cannot support a formal comparative conclusion.

The registry record does not report the primary statistical plan, interim analyses, multiplicity handling, sample-size justification, or criteria used to define and adjudicate DLTs. It also does not provide a reported MTD determination or selected Phase 1b dose in the primary outcome information. These gaps constrain interpretation of how the observations informed dose selection.

Safety summaries include serious adverse events, other adverse events and deaths, but causal attribution is not reported in the data. The available counts are not a substitute for a full safety analysis over a specified follow-up period. Results from this early-phase study in advanced gastrointestinal cancers also do not by themselves establish benefit or applicability beyond the enrolled study population.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study to Find a Safe and Effective Dose of BI 905711 in Patients With Advanced Gastrointestinal Cancer — NCT04137289.
• Registry record last updated 2025-03-25; status last verified 2025-03.
• Results first posted 2025-03-25.
• 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

This completed, open-label, multicentre, first-in-human Phase Ia/b dose-escalation study evaluated intravenous BI 905711 in advanced gastrointestinal cancers. The registry records randomized allocation, a parallel model and enrollment of 110. It lists multiple dose levels and schedules, with the primary Phase 1a endpoint defined as the number of patients with DLT during the first two treatment cycles.

The posted primary result reports zero DLTs in each of the eight listed dose groups, with group sizes ranging from 1 to 8. The primary analysis population is the MTD evaluation set, defined as treated patients not replaced for MTD determination. The record also posts safety summaries, including serious adverse events, other adverse events and deaths.

No primary endpoint analyses are reported. The registry record does not report confidence intervals, the statistical analysis plan, missing-data methods, multiplicity handling or the sample-size justification. The posted DLT counts are descriptive findings for the stated population and assessment window; they do not establish a zero underlying risk, comparative safety, efficacy, or a selected recommended dose.