This Study Aims to Find and Test a Safe Dose of BI 905677 in Patients With Different Types of Cancer (Solid Tumours): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for This Study Aims to Find and Test a Safe Dose of BI 905677 in Patients With Different Types of Cancer (Solid Tumours) (NCT03604445), a non-randomized phase 1 study. The primary outcome is Number of Participants With Dose Limiting Toxicities (DLTs).

2. Clinical Question

3. Trial Design

This was an open-label, Phase I, non-randomized, sequential trial of BI 905677 in people with advanced solid tumours. The registry describes the treatment as being given to humans for the first time. Its stated purpose was to identify a dose participants could tolerate while investigating safety, pharmacokinetics, and efficacy. The planned enrollment was 37 participants. The record lists the study as terminated.

Participants received intravenous BI 905677 at one of the listed dose levels: 0.05 mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.4 mg/kg, 0.8 mg/kg, 1.6 mg/kg, 2.4 mg/kg, 2.8 mg/kg, or 3.6 mg/kg. Arm descriptions specify treatment on Day 1 of each 3-week cycle and allow further cycles until disease progression or other stopping criteria. The brief summary describes dosing every 2 or 3 weeks and study-site visits at least once a week for health checks.

Because dose assignment was not randomized and there was no masking or control arm, the dose groups should not be interpreted as a controlled treatment comparison. The sequential model indicates that the study evaluated dose levels in sequence, but the registry record does not report the detailed dose-escalation rules, cohort decision criteria, or any stopping boundaries. It also does not report why the trial was terminated.

The registry lists a start date of 2018-08-08 and a primary completion date of 2022-07-27. These record dates do not by themselves describe the duration of treatment for individual participants. The record lists pharmacokinetic secondary outcomes based on serum concentration after the first infusion, including maximum measured concentration and area under the concentration-time curve from 0 to the last measured time point. It does not report their results in the registry record for this analysis.

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: Maximum Tolerated Dose (MTD) Evaluation Set (MTDS): includes all patients in the treated set who were not replaced for the MTD determination.

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): includes all patients who received at least one infusion of BI 905677.

Only the first 6 of 10 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Dose Limiting Toxicities (DLTs), measured over In the first treatment cycle, up to 3 weeks.

The primary endpoint is the number of participants with dose-limiting toxicities during the first treatment cycle, up to 3 weeks. It is a count of participants meeting the endpoint definition, rather than a measurement of tumour response or a continuous laboratory value. The registry describes review of adverse events by the Safety Monitoring Committee and Medical Monitor and gives examples of events that may qualify, including an event preventing a participant from starting Cycle 2 within 14 days of completing Cycle 1, a confirmed bone mineral density change of >5% from baseline, a β-CTX increase of more than two-fold from baseline, and Grade 3 osteoporosis. The definition also allows specified exceptions, such as events unequivocally due to the underlying malignancy or an extraneous cause.

In an early dose-evaluation study, counting dose-limiting toxicities helps characterize tolerability during a defined initial exposure period and informs dose decisions. The endpoint is especially tied to the study’s maximum-tolerated-dose objective; it is not, on its own, a comprehensive account of all safety outcomes over all treatment cycles. The primary endpoint results, including the number of affected participants at each dose and any maximum tolerated dose conclusion, are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The main inferential question in a dose-evaluation study is usually different from the question in a confirmatory comparative trial. Here the stated primary endpoint is a count of participants with dose-limiting toxicities in the first treatment cycle, up to 3 weeks. The trial’s sequential, non-randomized structure is consistent with examining safety as dose levels are evaluated, but the registry record does not report the detailed statistical plan or dose-escalation algorithm. No particular model, decision threshold, or formal hypothesis test can therefore be attributed to the study.

What a participant count represents

General statistical explanation: a count records how many people in a defined group meet an endpoint definition. Its meaning depends on the population, observation window, and event criteria. The primary endpoint specifies all three at a high level: the Maximum Tolerated Dose Evaluation Set, dose-limiting toxicity as reviewed by the safety monitors, and the first treatment cycle, up to 3 weeks. A count alone does not show how many participants were assessed, how many had incomplete follow-up, or how uncertain the underlying event probability may be. Those details are not reported in the registry record.

For a binary outcome such as whether a participant had a dose-limiting toxicity, a proportion can sometimes make group sizes easier to compare. But no primary endpoint counts or corresponding denominators are reported, so no endpoint proportion can be interpreted. Nor should counts from the adverse-event listings be treated as if they were the primary endpoint: the endpoint’s review criteria and defined period are specific, while the adverse-event listings cover separate safety categories.

Sequential dose evaluation and comparison

General statistical explanation: sequential dose-finding can use accumulating safety information to guide which dose is evaluated next. Such decisions can depend on prespecified rules, cohort results, and review by a safety committee. Without the protocol rules and actual decision record, the sequence of dose groups alone does not reveal how each escalation decision was made. The record does not report those rules or decisions.

Non-randomized dose groups are not interchangeable with randomized arms. Participants at one dose may differ from those treated at another dose for reasons related to enrollment sequence, participant characteristics, or study conduct. A pattern across doses can be useful descriptively, but it does not by itself isolate a causal dose effect. The listed groups also have different numbers at risk, so raw counts should not be compared without appropriate context. No adjusted or controlled dose comparison is reported.

Uncertainty and precision

General statistical explanation: a confidence interval describes a range of values compatible with data under a specified statistical method and assumptions. A narrower interval generally indicates more precision, while a wider interval indicates greater uncertainty. No confidence interval for the primary endpoint or adverse-event measures is reported in the registry record. Without endpoint counts and denominators, neither an interval nor a defensible estimate of precision can be interpreted.

Small early-phase cohorts can yield unstable estimates: a single event may have a substantial effect on a proportion when the group is small. This is a general feature of sparse binary data, not a calculated finding about the primary endpoint in this study. The listed groups show limited numbers at risk, while the main endpoint result itself is absent. Formal comparisons would also need to account for the sequential design and the purpose of dose selection rather than treat each dose as a randomized arm.

Planning illustrations are not trial results

General statistical explanation: sample-size calculations describe how many participants may be needed under stated assumptions to target a chosen precision or chance of detecting an effect. They are planning tools, not observed outcomes, and their meaning depends on the design and assumptions used. The planning assumptions associated with this record use 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 stated fraction of the observed effect. The record does not state that these assumptions governed the trial’s design. In particular, equal allocation between two arms does not match the described sequential, multi-dose, non-randomized structure. The observed primary effect is also not reported, so these assumptions do not establish a meaningful trial-specific sample-size conclusion.

Over-dispersion is a general issue for count data when variability exceeds what a simple model assumes; it can make model-based uncertainty too small if ignored. The primary endpoint is a participant count, but the registry record does not report a count model or an over-dispersion assessment. There is no basis for claiming that such a model was used or needed in the sponsor’s analysis.

Multiplicity and analysis choices

General statistical explanation: multiplicity arises when many outcomes, doses, time points, or statistical tests are assessed. Repeated testing can increase the chance of at least one apparently notable result by chance, so a protocol may specify a hierarchy or adjustment. This study lists multiple dose levels and several outcomes, but the registry record does not report a multiplicity strategy, planned hypothesis tests, or interim-analysis rules. The dose sequence itself does not prove that any particular adjustment was applied.

Analysis populations also matter. The primary endpoint description identifies the Maximum Tolerated Dose Evaluation Set and explains who belongs to it, but does not give its size or the number of participants excluded or replaced. The adverse-event groups report participants at risk, but those group counts should not be assumed to define every analysis population. Population membership and handling of missing endpoint assessments are not reported in 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 905677 0.05 mg/kg", "BI 905677 0.1 mg/kg", "BI 905677 0.2 mg/kg", "BI 905677 0.4 mg/kg", "BI 905677 0.8 mg/kg", "BI 905677 1.6 mg/kg")
n      <- c(3, 3, 3, 3, 3, 6)
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 905677 0.05 mg/kg  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  BI 905677 0.1 mg/kg  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  BI 905677 0.2 mg/kg  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  BI 905677 0.4 mg/kg  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  BI 905677 0.8 mg/kg  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  BI 905677 1.6 mg/kg  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0

11. Multiplicity, Missing Data and Analysis Populations

The registry record identifies a primary endpoint and an analysis population for it, but does not describe the statistical analysis plan in enough detail to determine how multiplicity was handled. Multiple dose levels, safety outcomes, and pharmacokinetic measures are listed. General statistical explanation: when many outcomes or comparisons are considered, an analysis plan may define which questions are primary and whether testing is adjusted or interpreted descriptively. The record does not report a multiplicity adjustment, a testing hierarchy, or a prespecified decision rule across dose levels.

Interim analyses and dose-escalation decision rules are also not reported in the registry record. The study is described as sequential, and the primary endpoint involved review by the Safety Monitoring Committee and Medical Monitor, but this does not specify how often data were reviewed, what thresholds guided decisions, or how any interim testing was incorporated.

The endpoint population is the Maximum Tolerated Dose Evaluation Set, defined as treated participants who were not replaced for the maximum-tolerated-dose determination. The record does not report the size of this set, the number replaced, or how a participant with incomplete first-cycle data was handled. It does not state an imputation method, missing-data assumption, or sensitivity analysis. Missing endpoint and follow-up information should therefore not be presumed absent or resolved by a particular method.

The record’s serious and other adverse-event summaries list participants at risk and affected, but do not explain missingness or completeness of event ascertainment. The record also does not report whether outcome analyses used additional populations. These omissions limit evaluation of how robust the results might be to population definitions or incomplete observations. Since the primary endpoint outcome itself is not reported, the effect of these analysis choices cannot be quantified.

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: diarrhoea (66.7%), abdominal pain (42.9%), vertigo (33.3%), nausea (33.3%), vomiting (33.3%).

The safety listings give, within each dose group, the number of participants at risk, the number with serious adverse events, the number with other adverse events, and the number of deaths. They are descriptive counts, not estimates from a randomized comparison. Group sizes differ, and the trial was non-randomized, so differences in counts cannot be attributed to dose alone. The record does not report whether deaths were considered related to treatment; a death listed in the safety information should not be read as proof of causation.

The registry lists diarrhoea at 66.7%, abdominal pain at 42.9%, vertigo at 33.3%, nausea at 33.3%, vomiting at 33.3%, and asthenia at 33.3% among the top serious-event terms. These percentages are recorded as term-level information. They should not be added together or assumed to represent distinct participants, since the record does not explain overlap or provide enough denominator detail for that interpretation. They also do not describe all adverse events or replace the dose-limiting-toxicity endpoint, which has its own definition and first-cycle observation period.

General statistical explanation: serious-event classification concerns regulatory seriousness criteria and is not synonymous with the intensity grade of every event. The registry record does not give the full event narratives or attribution assessments needed for further interpretation. The listed data can describe what was recorded, but not establish comparative safety or causation.

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

The record shows that BI 905677 was evaluated in a first-in-human, open-label, Phase I study of adults with advanced solid tumours. It describes sequential evaluation across nine listed dose levels and identifies dose-limiting toxicities during the first treatment cycle as the primary endpoint. It also records some adverse-event counts and serious-event terms. These registry entries establish the study’s focus and the kinds of information registered.

The record does not report the primary endpoint results, including the number of participants with dose-limiting toxicities, nor does it report a maximum tolerated dose conclusion. It also does not provide the outcome details needed to assess efficacy or interpret the listed pharmacokinetic outcomes. Accordingly, the registry record cannot establish whether any dose met a particular tolerability criterion or what clinical effects were observed.

Because the study had no randomized control group, the dose-group listings do not provide a like-for-like comparison of treatment strategies. They cannot establish that a difference in event counts was caused by dose, nor can they show how outcomes would compare with another treatment or no treatment. The death counts do not establish treatment causation. The serious-event term percentages do not provide a complete account of safety or demonstrate a comparative risk.

General statistical explanation: a result should be interpreted alongside its definition, population, observation period, uncertainty, and study design. Here, the endpoint definition and some design features are registered, but the endpoint outcome and its uncertainty are not. The study status is listed as terminated, but the reason for termination is not reported in the registry record. Neither that status nor the available safety listings should be used to infer an unreported result or reason.

The most defensible interpretation is therefore bounded: the registry documents a dose-finding study and selected safety information, but does not provide the primary result needed to answer its central tolerability question. Any conclusion about efficacy, the selected dose, treatment-related deaths, or the reason for termination would go beyond what the registry record reports.

14. Why This Trial Matters Statistically

Early-phase dose evaluation raises statistical questions that differ from those in a conventional randomized efficacy trial. The goal was to characterize tolerability and identify a dose for further investigation, while also examining pharmacokinetics and efficacy. The primary endpoint’s focus on dose-limiting toxicities during the first treatment cycle makes the observation window and event definition central to interpretation.

The sequential design also matters. In a dose-finding study, the order of evaluation and the rules for proceeding can shape which participants receive each dose and how safety information informs later decisions. The registry record does not report those rules, so a reader cannot reconstruct the decision process from the dose listings alone. This illustrates why design details are essential when assessing the evidential meaning of dose-group counts.

The record highlights another important distinction: descriptive safety counts are not a controlled estimate of a dose effect. Non-randomized cohorts can differ for reasons other than dose, and group sizes vary. Statistical interpretation should respect those design limits rather than treating each dose group as if it were a randomized arm.

Finally, registration of an endpoint is not the same as reporting its result. The registry describes the primary measure and the analysis population, but does not report the observed dose-limiting-toxicity counts or a maximum tolerated dose conclusion. That gap constrains what can be learned from the posted record, regardless of how clinically important the study question may be. Statistical transparency requires outcomes, denominators, analysis choices, and uncertainty to accompany endpoint definitions.

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.

A central limitation of the registry record is that it does not report the primary endpoint results. The stated endpoint is dose-limiting toxicity during the first treatment cycle, up to 3 weeks, but the record gives neither the affected-participant counts nor a maximum tolerated dose conclusion. This prevents direct evaluation of the study’s main question.

The design was open-label, non-randomized, and sequential, with no control group. Dose groups therefore cannot be treated as exchangeable comparison arms. The record does not report the detailed dose-escalation rules, cohort decision criteria, interim reviews, or analysis plan, limiting reconstruction of how evidence guided dose selection.

The listed safety counts and serious-event percentages have limited interpretive detail. The record does not specify enough about event overlap, attribution, or denominators to support broader risk comparisons. Deaths are listed, but cause and relationship to treatment are not reported. The primary endpoint analysis population is defined, but its size and missing-data handling are not reported.

The registry lists the study as terminated but does not report the reason. It also does not report efficacy or pharmacokinetic results in the registry record for this analysis, despite listing these as study aims or secondary outcomes. These absences do not establish that the outcomes were not measured; they mean the findings are not reported in the registry record. Consequently, conclusions about efficacy, dose selection, treatment causation, or termination rationale cannot be drawn from these registry entries.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: This Study Aims to Find and Test a Safe Dose of BI 905677 in Patients With Different Types of Cancer (Solid Tumours) — NCT03604445.
• Registry record last updated 2024-03-04; status last verified 2023-07.
• Results first posted 2024-03-04.
• 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

NCT03604445 is an open-label, non-randomized, sequential Phase I study of intravenous BI 905677 in adults with advanced solid tumours. The planned enrollment was 37. The registry lists nine dose groups, from 0.05 mg/kg to 3.6 mg/kg, and describes a first-in-human evaluation of safety, pharmacokinetics, and efficacy. Study dates are listed as 2018-08-08 for the start and 2022-07-27 for primary completion; status is terminated.

The primary endpoint is the number of participants with dose-limiting toxicities in the first treatment cycle, up to 3 weeks. The record defines the Maximum Tolerated Dose Evaluation Set but does not report the primary endpoint results or a maximum tolerated dose conclusion. Selected adverse-event counts and serious-event terms are listed, but the design does not support treating dose groups as randomized controls. Statistical analysis details, missing-data methods, and the reason for termination are not reported in the registry record.