Intravenous BI 836826 in Combination With Ibrutinib in Relapsed/Refractory CLL Patients Who Have Been Pre-treated With at Least One Prior Line of Systemic Therapy, and Who Are Eligible for Treatment With Ibrutinib: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Intravenous BI 836826 in Combination With Ibrutinib in Relapsed/Refractory CLL Patients Who Have Been Pre-treated With at Least One Prior Line of Systemic Therapy, and Who Are Eligible for Treatment With Ibrutinib (NCT02759016), a na phase 1 study. The primary outcome is Number of Participants With Dose Limiting Toxicities (DLTs) During the First Treatment Cycle.

2. Clinical Question

The trial’s stated objectives were to determine the recommended Phase 2 dose of BI 836826 and document the safety and tolerability of the combination. Its primary endpoint therefore focuses on toxicities meeting a prespecified definition during an early treatment period, rather than on a comparison of clinical benefit between treatment groups.

The registry record does not report a numerical result for the primary endpoint. It also does not report a recommended Phase 2 dose as an outcome in the information available for this analysis. The record lists Maximum Tolerated Dose of BI 836826 in Combination With Ibrutinib as a secondary outcome, but does not give a numerical result for it. The posted safety figures describe adverse events in the dose cohorts; they should not be treated as a substitute for the missing primary endpoint result.

Because the study has no randomized control group, it cannot estimate a comparative effect of the combination against another treatment from this design. Its question is principally about dose selection and safety in the specified population. The available information permits description of the recorded design and safety counts, but not a conclusion about comparative efficacy or a precise rate of dose-limiting toxicity.

3. Trial Design

This was a Phase Ib, open-label, single-arm, multicenter, dose-escalation trial. It studied intravenous BI 836826 in combination with ibrutinib in people with relapsed or refractory chronic lymphocytic leukemia who had received at least one prior line of systemic therapy and were eligible for ibrutinib. The registry lists the trial as completed, with enrollment of 7. The recorded start date is 2016-06-23 and the primary completion date is 2019-06-03.

The intervention description specifies BI 836826 administered with standard-of-care ibrutinib. Safety cohort labels identify BI 836826 doses of 100 mg and 200 mg, each combined with ibrutinib. The record does not describe a randomized allocation process, and allocation is recorded as NA. Masking is listed as none, consistent with the open-label design. Participants and investigators therefore were not described as blinded to treatment assignment.

There was no separate control arm. The two dose cohorts reflect different BI 836826 dose levels, not a randomized comparison of the combination against ibrutinib alone or another treatment. Any differences in event counts between these cohorts would be descriptive and would not establish a causal dose effect. The registry record does not report how dose escalation decisions were made, the precise rules for moving between doses, or the planned number of participants at each dose.

The primary objective measured dose-limiting toxicities during the first treatment cycle, defined as 4 weeks from the first BI 836826 administration. Other stated objectives concerned dose selection and safety and tolerability. The record identifies Maximum Tolerated Dose of BI 836826 in Combination With Ibrutinib as a secondary outcome. It does not report the full protocol, the schedule of later assessments, or a detailed statistical analysis plan. The study’s small enrollment and lack of a control group are central to interpreting the posted results: they support a descriptive safety reading, not a precise comparative estimate.

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 the subjects strictly met all inclusion and none of the exclusion criteria. Abbreviations: SD=Stable Disease, PR-MRDpos=Minimal Residual Disease positive Partial Response, PR-L=Partial Response with Lymphocytosis.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: As the study was prematurely discontinued, recruitment of participants into the dose escalation part was not fully completed, the MTD was not reached and hence the RP2D could not be determined.

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: The Treated Set (TS) included all participants who initiated at least one administration of BI 836826. The TS was used for all planned safety and efficacy analyses.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Dose Limiting Toxicities (DLTs) During the First Treatment Cycle, measured over First treatment cycle, 4 weeks from first administration of BI 836826..

The primary endpoint is the number of participants with dose-limiting toxicities during the first treatment cycle, defined as 4 weeks from the first administration of BI 836826. It is a count of participants meeting the toxicity definition, not a measure of all adverse events or of treatment benefit. The endpoint’s listed unit is participants.

The definition includes specified non-hematologic events of Grade 3 or higher related to BI 836826 and/or ibrutinib, with stated exceptions. These include infusion-related reactions of any grade, certain liver enzyme elevations without concomitant bilirubin elevation, and other asymptomatic Grade 3 laboratory abnormalities that recover spontaneously within 1 week. The definition also includes specified severe hematologic events related to either drug, such as Grade 4 neutropenia with concomitant infection, Grade 4 febrile neutropenia, and other listed blood-related toxicities. The criteria are intended to identify events considered sufficiently serious under the trial definition to inform dose evaluation.

A first-cycle DLT count is used in early dose-finding research because it provides a defined period and endpoint for considering tolerability at a dose. It does not capture every potential harm over the full course of treatment, and the DLT definition is narrower than the full set of adverse events that may be recorded. The registry states that the endpoint population consists of participants documented to have initiated at least one dose of BI 836826 and not replaced for the Maximum Tolerated Dose evaluation.

The registry record does not report the observed primary endpoint count. Consequently, the endpoint definition can be described, but the number meeting it cannot be assessed from the posted primary outcome information.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is a count: the number of participants who met the trial’s definition of a dose-limiting toxicity during the first treatment cycle. A count records how many participants had the specified outcome. It differs from a count of all events because one participant can experience more than one event, while the endpoint counts participants meeting the definition. The record’s endpoint population is restricted to those documented to have initiated at least one dose of BI 836826 and not replaced for the Maximum Tolerated Dose evaluation.

The time window matters. The primary outcome covers the first treatment cycle, defined in the record as 4 weeks from the first BI 836826 administration. Events outside that window are not part of this endpoint as defined, although they may be captured in broader safety reporting. The endpoint also applies a clinical classification: not every adverse event automatically counts as a DLT. The listed severity, relationship, and exception criteria determine which events qualify. This makes the result dependent both on what events occurred and on how they were assessed against the protocol definition.

In general, early dose-escalation studies use a defined toxicity endpoint to inform whether a dose warrants further study. A dose decision is not the same as demonstrating that a treatment is effective, and an observed count does not by itself identify a dose as suitable for another population or setting. The registry states that determining the recommended Phase 2 dose was an objective, but does not report the decision rules or the dose recommendation. The Maximum Tolerated Dose is listed as a secondary outcome, without a reported numerical result in the registry information analyzed.

The trial is single-arm and open-label. In a randomized comparison, treatment groups are assigned by a random process, which can support a more balanced comparison of outcomes. This study has no randomized control group; allocation is listed as NA. Its 100 mg and 200 mg cohorts are dose cohorts, not concurrent control arms established by randomization. Differences in counts between cohorts could reflect chance, differences in participant characteristics, follow-up, or other factors. The design does not permit those differences to be attributed to dose alone.

Open-label means masking is listed as none. In general, knowledge of treatment can influence event reporting, clinical assessment, and decisions about whether an event meets a definition, especially when those judgments involve clinical interpretation. A protocol’s explicit definitions can improve consistency, but the registry record does not report adjudication procedures or whether event assessments were independently reviewed. These details are not reported in the registry record.

The adverse-event summaries use participants at risk and participants affected for each cohort and category. In general, the number at risk describes the group considered for that summary, while the affected count describes participants with one or more events in the category. These counts are not necessarily mutually exclusive across terms. A participant can experience multiple serious adverse event types or both serious and other events. Accordingly, adding entries across terms or categories would not give a valid count of unique participants. No such total should be inferred from the registry entries.

A confidence interval, in general, expresses the statistical uncertainty around an estimated quantity under a specified method. It is not a guarantee that the true value lies within the interval, and it does not address biases caused by study design or incomplete reporting. The registry information analyzed does not report confidence intervals for the primary endpoint or the safety counts. With small descriptive groups, counts alone offer limited precision; without an interval or other analysis, the amount of uncertainty cannot be quantified from the record.

The registry lists 3 outcome measures and 0 analyses. It does not report a statistical analysis plan, a method for handling multiplicity, a plan for interim analyses, or a sample-size justification. The record includes planning assumptions for illustrations: two-sided significance level 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect expressed as a stated fraction of the observed effect. Such planning assumptions are not evidence of observed power and are not the design of this single-arm trial. The registry does not report the rationale for those assumptions or a sample-size calculation specific to the trial.

Any planning illustration based on an observed effect is distinct from an analysis of the trial’s outcomes. A planning calculation asks what sample size might be needed under selected assumptions; it does not show that the completed study had that power, nor does it remedy the absence of a control group. The record does not report the underlying effect estimate or calculated planning values in the information analyzed. For this trial, the central statistical limitation remains that the numerical primary endpoint result and the inferential analysis 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("Dose Cohort BI 836826 100 Milligram (mg) + Ibrutin", "Dose Cohort BI 836826 200 Milligram (mg) + Ibrutin")
n      <- c(3, 3)
events <- c(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  Dose Cohort BI 836826 100 Milligram (mg) + Ibrutin  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Dose Cohort BI 836826 200 Milligram (mg) + Ibrutin  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 3 outcome measures and 0 analyses. It identifies the number of participants with DLTs during the first treatment cycle as the primary outcome and Maximum Tolerated Dose of BI 836826 in Combination With Ibrutinib as a secondary outcome. The information analyzed does not include numerical results for these outcomes. A complete list of the remaining outcome measures and their results is not reported in the registry record.

Multiplicity arises when a study assesses several outcomes, time points, subgroups, or statistical tests. In general, the more tests considered, the greater the chance that at least one may appear notable by chance if no adjustment or prespecified interpretation is used. The registry record does not report a multiplicity strategy, a hierarchy for interpreting outcomes, or a statistical analysis plan. No conclusion can therefore be drawn about whether or how multiplicity was addressed.

The endpoint population is described as participants documented to have initiated at least one dose of BI 836826 and not replaced for the Maximum Tolerated Dose evaluation. The record does not report the number included in the primary endpoint analysis, the number with missing endpoint assessments, or how missing data were handled. It also does not report detailed analysis populations for the other outcomes. These omissions limit assessment of how the enrolled participants relate to the analyzed groups.

The registry provides enrollment of 7 and adverse-event denominators by dose cohort, but it does not explain any differences between those figures. Reasons for replacement, withdrawal, or exclusion from an analysis are not reported in the registry record. The numerical primary endpoint result is also not reported, so the completeness of outcome ascertainment cannot be assessed. These are reporting gaps, not evidence that missing data or exclusions did or did not occur.

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: neutropenia (33.3%), acute coronary syndrome (33.3%), duodenal ulcer (33.3%), intestinal ischaemia (33.3%), intestinal obstruction (33.3%).

The adverse-event record reports safety figures separately for the BI 836826 100 mg and 200 mg cohorts, both combined with ibrutinib. In the 100 mg cohort, 2 participants had a serious adverse event and 3 had an other adverse event; 3 participants are listed at risk for each category. In the 200 mg cohort, 3 participants had a serious adverse event and 3 had an other adverse event; again, 3 participants are listed at risk for each category. The record reports 0 deaths in each cohort.

The listed serious adverse event terms are neutropenia, acute coronary syndrome, duodenal ulcer, intestinal ischaemia, intestinal obstruction, and cellulitis, each reported at 33.3%. The registry does not specify in this information how these terms were distributed by dose cohort, whether participants experienced more than one term, or how events relate to the primary DLT definition. Serious adverse events and DLTs are not interchangeable categories: DLT status depends on the endpoint’s timing and specific severity, relationship, and exception criteria.

These are descriptive registry figures, not a controlled comparison. The cohort counts cannot establish that one dose caused more events, and no risk difference or uncertainty interval is reported. The adverse-event figures should not be added across categories to estimate unique participants, since a participant may appear in more than one category. The registry record does not explain the relationship between the enrollment figure and the cohort denominators.

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

The results describe a Phase Ib study designed to assess dose selection and safety for intravenous BI 836826 given with ibrutinib in pre-treated people with relapsed or refractory chronic lymphocytic leukemia. They do not provide the numerical primary endpoint result: the count of participants with dose-limiting toxicities during the first treatment cycle is not reported in the registry record. The stated recommended Phase 2 dose is also not reported in the information analyzed.

The adverse-event summaries document serious and other adverse events in two dose cohorts and report 0 deaths in each cohort. These observations give a descriptive account of the events recorded for those groups. They do not establish how often DLTs occurred, because DLTs are a specifically defined endpoint and the primary count is absent. Nor do the safety counts establish that the combination is safe or unsafe overall: the study is small, the record lacks a randomized comparator, and the available event summaries do not include measures of statistical uncertainty.

The absence of a comparator is especially important when interpreting differences between the 100 mg and 200 mg cohorts. This was a single-arm dose-escalation study, not a randomized dose comparison. Cohort differences can be described, but cannot be attributed to the dose on the basis of this design alone. The registry also does not report a comparative efficacy outcome or an analysis of treatment benefit.

These limitations do not mean that the trial has no value. Early-phase research can provide information relevant to dose development and safety monitoring. However, the specific conclusions supported by this registry record are constrained by missing primary outcome results, limited cohort sizes, and the lack of a control group. The data should not be used to infer a treatment effect, a precise DLT frequency, or a result beyond what the registry records.

14. Why This Trial Matters Statistically

This trial illustrates a common statistical challenge in early-phase research: the primary aim is dose selection and safety characterization, not a randomized estimate of comparative benefit. Its primary outcome is defined around dose-limiting toxicities in the first treatment cycle, a focused measure intended to inform evaluation of an investigational dose. That definition makes clear what qualifies as a DLT, but the numerical result is not reported in the registry record.

The distinction between a primary DLT endpoint and broader adverse-event summaries matters. Serious adverse events are reported by dose cohort, but they do not necessarily meet the DLT criteria, and DLTs may depend on timing, severity, attribution, and specified exceptions. Reading the categories as though they were interchangeable could misstate what the trial measured. Similarly, a list of event terms does not reveal whether the same participant experienced multiple events.

The study’s single-arm structure also sets a boundary on interpretation. It can describe what was recorded among treated participants, but it cannot provide a randomized estimate against a control treatment. The dose cohorts are not a like-for-like control comparison. Small groups make descriptive counts especially sensitive to individual observations, while the absence of confidence intervals or a reported primary result leaves precision difficult to judge.

Finally, the record demonstrates why registry reporting completeness is part of statistical interpretation. Enrollment, cohort-specific safety counts, outcome definitions, and the actual primary result serve different purposes. The available details allow readers to understand the intended endpoint and some recorded safety events, but not to evaluate the primary endpoint result, the dose recommendation, or the analysis procedures. Recognizing that distinction prevents a descriptive safety listing from being mistaken for a complete statistical account of the trial.

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 limitation is that the numerical result for the primary endpoint is not reported in the registry record. Without the number of participants meeting the DLT definition, the main outcome cannot be evaluated. The registry also does not report the recommended Phase 2 dose, despite dose selection being a stated objective, or a numerical result for the listed Maximum Tolerated Dose secondary outcome.

The study is single-arm and open-label, with allocation recorded as NA and masking listed as none. There is no randomized comparator to support a controlled estimate of treatment effect, and the dose cohorts do not constitute a randomized comparison. Differences in their event counts should therefore be interpreted descriptively rather than causally.

Enrollment is reported as 7, while each adverse-event cohort lists 3 participants at risk. The registry record does not explain how these figures relate to one another, or report details on replacement, withdrawal, or exclusions. The primary endpoint’s analysis population is defined, but the record does not give its analyzed count or describe missing-data handling. These gaps prevent a full accounting of participant flow and analysis coverage.

Further limitations include the absence of reported confidence intervals, a statistical analysis plan, multiplicity procedures, and a sample-size justification. The registry does not describe event adjudication or provide enough detail to determine overlap among serious adverse event terms. The listed safety information is therefore insufficient to quantify uncertainty or to reconstruct the trial’s full analysis. These limitations concern what the registry record reports; they do not establish what procedures may have been carried out outside the record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Intravenous BI 836826 in Combination With Ibrutinib in Relapsed/Refractory CLL Patients Who Have Been Pre-treated With at Least One Prior Line of Systemic Therapy, and Who Are Eligible for Treatment With Ibrutinib — NCT02759016.
• Registry record last updated 2020-09-29; status last verified 2020-09.
• Results first posted 2020-07-24.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

NCT02759016 is a completed Phase Ib, open-label, single-arm, multicenter dose-escalation trial of intravenous BI 836826 with ibrutinib in people with relapsed or refractory chronic lymphocytic leukemia who had received at least one prior line of systemic therapy and were eligible for ibrutinib. Enrollment is listed as 7. The recorded start date is 2016-06-23, and the primary completion date is 2019-06-03.

The primary outcome is the number of participants with DLTs during the first treatment cycle, defined as 4 weeks from first BI 836826 administration. The registry record does not report its numerical result. Safety summaries list BI 836826 100 mg and 200 mg cohorts, each with ibrutinib, and report serious and other adverse events by cohort. The record lists Maximum Tolerated Dose as a secondary outcome but does not report its numerical result. With no randomized comparator and limited outcome reporting, the available information supports descriptive interpretation only.