Ibrutinib and Lenalidomide With Dose Adjusted EPOCH-R in Subjects With Relapsed/Refractory Diffuse Large B-cell Lymphoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Ibrutinib and Lenalidomide With Dose Adjusted EPOCH-R in Subjects With Relapsed/Refractory Diffuse Large B-cell Lymphoma (NCT02142049), a non-randomized phase 1, phase 2 study. The primary outcome is Number of Participants With Dose-Limiting Toxicities as a Measure of Safety and Tolerability.

2. Clinical Question

3. Trial Design

This was a multicenter Phase 1b/2 study, listed in the registry under Phase 1 and Phase 2. It was open-label, non-randomized, and sequential. The registry record lists enrollment as 35 and status as completed. The recorded start was 2014-05, and primary completion was 2017-08.

Part 1 tested four dose levels. Dose Level 1 combined ibrutinib 560 mg with DA-EPOCH-R. Dose Levels 2, 3, and 4 added lenalidomide at 15 mg, 20 mg, and 25 mg, respectively, while ibrutinib remained 560 mg. Part 2 used the recommended Phase 2 dose, consisting of ibrutinib 560 mg, lenalidomide 25 mg, and DA-EPOCH-R. These descriptions identify the regimens; the rules for moving between dose levels are not reported in the registry record.

The non-randomized sequential design is suited to describing experience across planned dose levels, but it does not create a randomized comparison of regimens. Participants were not assigned by random allocation to a concurrent control treatment, and masking was absent. Differences across dose groups may reflect their sequential design or other group differences as well as any regimen-related effects.

The record lists secondary outcomes for complete and partial responses, adverse events, progression-free survival, overall survival, and duration of response. Numerical results for these outcomes are not reported in the registry record. The primary endpoint is also listed, but its dose-limiting toxicity results are not reported. The record does not describe the dose-escalation decision procedure, the planned statistical analysis, or the criteria used to select the recommended Phase 2 dose.

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.

Overall Study

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.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Dose-Limiting Toxicities as a Measure of Safety and Tolerability, measured over 1 year after last subjects received the first dose.

The primary endpoint was the number of participants with dose-limiting toxicities, described as a measure of safety and tolerability. The stated Part 1 objective was to determine the maximum tolerated dose of ibrutinib and lenalidomide with dose-adjusted EPOCH-R. The endpoint timeframe was one year after the last subjects received the first dose.

A count of participants with a dose-limiting toxicity can describe how often the protocol-defined safety event occurred in the population assessed. In a dose-finding study, such information can inform evaluation of the tolerability of dose combinations. The count alone does not describe the type, timing, severity, or duration of each toxicity, and it does not establish that a toxicity was caused by a particular drug. Those details depend on the endpoint definitions and supporting safety information.

The registry record does not state the operational definition of a dose-limiting toxicity, how such events were adjudicated, or which participants were included in the primary endpoint analysis. Most importantly, the primary endpoint result is not reported in the registry record. The stated purpose and timeframe therefore describe what the endpoint was intended to assess, not what the study found.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry characterizes the study as non-randomized, open-label, and sequential. These features matter when interpreting both the endpoint and the adverse-event counts. Random allocation is a method for making treatment groups comparable, on average, with respect to measured and unmeasured characteristics. This study did not use random allocation. Its sequential dose-level structure is therefore not a controlled comparison of one regimen against another. Open-label means masking was absent; the record does not report further details about how knowledge of treatment may have affected event assessment or reporting.

What does a participant count measure?

General statistical explanation: a count records the number of people meeting a defined event criterion. Interpretation usually depends on a clear event definition, a specified analysis population, and a time period over which participants could experience the event. A count by itself does not show the distribution of event timing, recurrence, severity, or duration. The registry record lists a dose-limiting toxicity count as its primary endpoint, but the event definition and analysis population are not reported in the registry record. The count result itself is also not reported.

The adverse-event record separates participants at risk from participants affected for serious events and other events, and separately lists deaths. Those categories should be read as the registry reports them, rather than assumed to represent mutually exclusive outcomes. A participant may experience more than one event, and the record does not clarify the relationship between the adverse-event categories and deaths. The reported counts do not identify causation.

Why does the design limit comparisons?

General statistical explanation: a randomized concurrent control group can support a more interpretable estimate of the difference between assigned treatments because randomization helps balance prognostic factors. In a non-randomized sequential study, treatment groups may differ in participant characteristics, timing, or other factors. A contrast between their observed counts cannot, on its own, isolate a causal treatment effect. This is especially important when interpreting dose-level data as if they were head-to-head comparisons. The registry record does not report adjusted comparative analyses, and the analyses count is 0.

The registry lists Phase 1 and Phase 2 and describes the study as Phase 1b/2. Part 1 had four dose levels, and Part 2 used the recommended Phase 2 dose. General statistical explanation: early dose-finding studies commonly focus on safety and tolerability while evaluating dose choices; later-stage evaluation may address efficacy questions. The specific dose-escalation algorithm, decision thresholds, and basis for selecting the recommended Phase 2 dose are not reported in the registry record. It is therefore not possible to reconstruct those decisions from the posted record.

How should uncertainty be considered?

General statistical explanation: a confidence interval describes a range of values compatible with the observed data under the assumptions of the analysis. Its width reflects precision, and its interpretation depends on the sampling and analysis methods. The registry record does not report confidence intervals for the primary endpoint or the listed secondary outcomes. It also does not report p-values or model-based estimates. Without those results, the precision of any outcome estimate cannot be assessed from the registry.

General statistical explanation: for count outcomes, estimates can be imprecise when the available event information is limited. For time-to-event outcomes such as progression-free survival and overall survival, interpretation ordinarily requires details such as follow-up, event definitions, censoring, and an analysis method. These details and numerical survival results are not reported in the registry record. The same limitation applies to duration of response: the registry lists the outcome but does not report its definition, analysis population, or results.

What does the planning illustration represent?

The record describes a planning illustration based on an observed effect, not the trial's own design. Its stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is a stated fraction of the observed effect. For time-to-event outcomes, the illustration concerns a total number of events; for other outcomes, it concerns participants per arm. These are planning assumptions, not observed trial results and not evidence of the trial's power. The registry record does not report numerical sample-size illustrations in the registry record for this analysis. Because the study itself was non-randomized and sequential, the two-arm planning assumptions should not be mistaken for the study's actual allocation or design.

The record lists 35 for enrollment, but does not report the number included in each outcome analysis or the completeness of outcome follow-up. No analysis methods for the primary or secondary outcomes are reported. These omissions prevent a detailed appraisal of endpoint estimation, uncertainty, handling of missing observations, or sensitivity analyses.

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("Part 1: Dose Level 1", "Part 1: Dose Level 2", "Part 1: Dose Level 3", "Part 1: Dose Level 4", "Part 1: All Treated")
n      <- c(3, 3, 3, 6, 15)
events <- c(0, 0, 0, 1, 1)
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  Part 1: Dose Level 1  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Part 1: Dose Level 2  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Part 1: Dose Level 3  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Part 1: Dose Level 4  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  Part 1: All Treated  15  1  6.7  0.2  31.9  1.2  29.8  1.6  30.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists multiple outcomes: the primary dose-limiting toxicity count and secondary outcomes for complete and partial responses, adverse events, progression-free survival, overall survival, and duration of response. It does not report a statistical analysis plan, a hierarchy of hypotheses, or a method for addressing the possibility of chance findings across multiple outcomes. Whether multiplicity adjustments were planned is not reported in the registry record.

Missing-data handling is not reported in the registry record. The record does not describe how participants with incomplete follow-up, unavailable assessments, or discontinuation were handled for the primary or secondary outcomes. It does not give analysis-population definitions, outcome-specific denominators, or sensitivity analyses. The enrollment figure alone does not establish how many participants contributed to each result.

The registry lists 0 analyses. This limits the available statistical detail: no model specification, estimate, confidence interval, p-value, or inferential result is reported for the listed outcomes. The primary dose-limiting toxicity result is also not reported. Without outcome-specific analysis populations and missing-data methods, it is not possible to judge whether reported event counts reflect all participants enrolled, treated participants, or another defined group. These reporting gaps restrict assessment of both precision and potential bias.

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: febrile neutropenia (33.3%), anaemia (33.3%), thrombocytopenia (33.3%), atrial fibrillation (33.3%), gastrointestinal haemorrhage (33.3%).

The serious adverse-event figures are presented by registry group as counts of participants at risk and affected. For Part 1 Dose Levels 1, 2, and 3, each group lists 3 at risk and 3 affected. Dose Level 4 lists 6 at risk and 5 affected. The group of all subjects treated at the recommended Phase 2 dose lists 26 at risk and 19 affected. The record also lists deaths as 3, 3, 3, 5, and 3 for those respective groups.

For other adverse events, the record lists 3 at risk and 3 affected at Dose Levels 1, 2, and 3; 6 at risk and 6 affected at Dose Level 4; and 26 at risk and 26 affected among all subjects treated at the recommended Phase 2 dose. These are group-specific counts and should not be added or treated as separate, non-overlapping populations. The registry does not report whether the group definitions overlap or how the event categories relate to one another.

The listed serious terms are febrile neutropenia, anaemia, thrombocytopenia, atrial fibrillation, gastrointestinal haemorrhage, and vomiting, each reported at 33.3%. A frequency listing does not establish causation or describe the clinical course of an event. The record does not provide further event-level detail or explain attribution to study treatment.

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

The record establishes that a multicenter, open-label, non-randomized Phase 1b/2 study evaluated ibrutinib and lenalidomide with DA-EPOCH-R in participants with relapsed or refractory diffuse large B-cell lymphoma. It identifies the primary endpoint as a count of participants with dose-limiting toxicities and states that Part 1 aimed to determine the maximum tolerated dose. It also identifies a recommended Phase 2 dose regimen and reports selected adverse-event counts.

Those descriptions do not establish the primary endpoint result. The number of participants with dose-limiting toxicities is not reported in the registry record, and the record does not state the maximum tolerated dose determination. The listed adverse-event counts and serious-event terms provide descriptive safety information, but they do not show that the regimen caused the events or deaths. The available figures also do not answer whether the regimen improved response or survival.

The record lists response, progression-free survival, overall survival, and duration of response as secondary outcomes, but their numerical results are not reported. No statistical analyses are reported. As a result, the posted information does not quantify treatment effects, their uncertainty, or comparative differences against another treatment. In addition, the non-randomized sequential design does not support treating the dose groups as equivalent randomized arms.

In general, a registry entry can describe the study question, design, interventions, endpoints, and selected results, but interpretation depends on transparent outcome definitions and analyses. Here, the missing primary endpoint result, absent analysis methods, and lack of reported secondary outcome estimates leave important questions unresolved. The study record should therefore be read as a description of the planned and recorded study structure, with limited descriptive safety data, rather than as a complete statistical account of efficacy or dose-finding conclusions.

14. Why This Trial Matters Statistically

This study raises a central statistical challenge in early-phase research: describing safety across sequential dose levels without presenting those groups as randomized comparisons. Its Part 1 structure evaluated ibrutinib with DA-EPOCH-R and then added lenalidomide at three listed dose levels. Part 2 used the recommended Phase 2 dose. The primary question concerned dose-limiting toxicities and the maximum tolerated dose, a safety-oriented objective that differs from testing comparative efficacy.

The distinction matters because counts across sequential dose groups can be informative descriptions, but they do not by themselves estimate what would have happened to comparable participants under a different regimen. Non-random allocation, absent masking, and the lack of a randomized control group limit causal interpretation. Clear reporting of dose-level decisions, event definitions, analysis populations, and uncertainty would help readers understand how the safety findings informed the chosen regimen.

The registry also illustrates why outcome completeness matters. It lists response and survival outcomes, yet their numerical results are not reported in the registry record. The primary dose-limiting toxicity result is likewise absent. The posted adverse-event counts supply some descriptive context, but cannot substitute for those endpoint results or for an analysis plan. In statistical terms, design details and endpoint results are both necessary to assess what a study can establish. The record documents a relevant dose-finding question, while leaving the central result and its precision unreported.

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 for interpretation is that the primary endpoint result is not reported in the registry record. Although the endpoint is defined as the number of participants with dose-limiting toxicities and the stated aim was to determine the maximum tolerated dose, neither the result nor the dose-finding conclusion is given. The record also does not state the operational definition of dose-limiting toxicity, the analysis population, or the decision rules used across dose levels.

The study was non-randomized, open-label, and sequential, with no like-for-like control comparison. The adverse-event counts cannot establish a causal effect, and differences across groups cannot be attributed to dose alone. The relationship between the Part 1 groups and the group of all subjects treated at the recommended Phase 2 dose is not explained sufficiently to infer that these groups are independent. Counts should therefore remain separate and descriptive.

Additional limitations include the absence of numerical results for the listed response, survival, and duration-of-response outcomes, and the absence of reported analyses. The record does not report confidence intervals, p-values, missing-data methods, analysis-population definitions, or outcome-specific denominators. It does not describe follow-up completeness or explain the relationship between deaths and adverse-event categories. These gaps limit assessment of precision, bias, and endpoint interpretation. The enrollment figure of 35 does not resolve how many participants contributed to any specific endpoint.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Ibrutinib and Lenalidomide With Dose Adjusted EPOCH-R in Subjects With Relapsed/Refractory Diffuse Large B-cell Lymphoma — NCT02142049.
• Registry record last updated 2019-02-05; status last verified 2018-05.
• Results first posted 2019-02-05.
• 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

NCT02142049 is a completed, multicenter, open-label, non-randomized Phase 1b/2 study of ibrutinib and lenalidomide with dose-adjusted EPOCH-R for relapsed or refractory diffuse large B-cell lymphoma. The registry lists enrollment as 35, a start of 2014-05, and primary completion in 2017-08.

Part 1 evaluated four dose levels; Part 2 used ibrutinib 560 mg, lenalidomide 25 mg, and DA-EPOCH-R as the recommended Phase 2 dose. The primary endpoint was the number of participants with dose-limiting toxicities, with the aim of determining the maximum tolerated dose. Its result is not reported in the registry record. Selected serious and other adverse-event counts and serious-event terms are listed. Numerical results for the secondary response and survival outcomes, and statistical analyses, are not reported.