Dose Finding Study of Ibrutinib Plus Lenalidomide / Rituximab in Relapsed or Refractory Mantle Cell Lymphoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Dose Finding Study of Ibrutinib Plus Lenalidomide / Rituximab in Relapsed or Refractory Mantle Cell Lymphoma (NCT02446236), a na phase 1 study. The primary outcome is Determine the MTD (Measured in mg) Based on the Number of Patients With Adverse Events.

2. Clinical Question

3. Trial Design

This is a Phase Ib, dose-finding study of ibrutinib with lenalidomide and rituximab in relapsed or refractory mantle cell lymphoma. Its stated aim is to determine the maximum tolerated dose and/or recommended phase II dose by assessing dose-limiting toxicities in cycle 1 through review of adverse events. The listed primary outcome timeframe is 28 Days.

The registry describes the study as single group, with allocation listed as NA and masking as NONE. It is therefore not a randomized comparison, and the dose-level groups are not like-for-like control arms. The group labels are Phase I - Dose Level 1, Phase I - Dose Level 2, and Phase II Expansion. The registry reports group counts of 4, 3, and 18, respectively; it does not explain how those group counts relate to the enrollment figure of 27.

The dose-escalation description lists ibrutinib 560 mg/daily, rituximab 375mg/m2 IV Day 1, and lenalidomide 10-25 mg PO days 1-21. This describes the regimen recorded for the study; the registry record does not provide more detail about how dose escalation proceeded or how dose decisions were made.

The sponsor is Hackensack Meridian Health. The record lists a start date of 2015-06-18, primary completion of 2017-01-03, and status active, not recruiting. These administrative details do not establish that all results are posted. Although five outcome measures are listed, the record does not report a statistical analysis for them.

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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Phase I Cohorts

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 Determine the MTD (Measured in mg) Based on the Number of Patients With Adverse Events, measured over 28 Days.

The primary outcome is titled as determining the maximum tolerated dose, measured in mg, based on the number of patients with adverse events. Its description specifies that the study sought to define the maximum tolerated dose and/or recommended phase II dose by assessing the incidence of dose-limiting toxicities during cycle 1. The outcome timeframe is 28 Days and its population is identified as Phase I cohorts.

In dose-finding research, adverse events are used to identify whether a dose produces unacceptable toxicity under the study's criteria. The purpose is to guide dose selection for further study, rather than to estimate a comparative treatment effect against a control group. This is a general description of the role of such an endpoint; the exact dose-limiting toxicity criteria and decision rules are not reported in the registry record.

The outcome title and description explain what was to be measured, but the record does not report the observed number of patients with dose-limiting toxicities, a resulting maximum tolerated dose, or a recommended phase II dose. Therefore, the endpoint's numerical result and the precision of any dose estimate cannot be assessed from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The statistical approach must be interpreted in light of the study's dose-finding purpose. A dose-finding study generally uses observed toxicity to inform dose selection, rather than relying on a comparison between randomized groups. Here, the stated primary objective was to determine the maximum tolerated dose and/or recommended phase II dose from dose-limiting toxicities in cycle 1. The exact rules for classifying a dose-limiting toxicity, escalating or stopping doses, and selecting a final dose are not reported in the registry record.

What does the primary outcome measure?

The primary outcome is described as the maximum tolerated dose, measured in mg, based on the number of patients with adverse events. Its description focuses more specifically on the incidence of dose-limiting toxicities in cycle 1, with a timeframe of 28 Days. In general, an event count describes how many people in a defined group experienced an event. A dose-finding decision additionally depends on the protocol's definition of a qualifying toxicity and its decision rule. The registry record does not report those details or a numerical primary outcome result, so the dose-selection process cannot be reconstructed from the posted record.

What can counts and percentages tell us?

Counts can show the number of participants recorded as affected within each stated group. The serious-event summaries list both a group count and an affected count; the other-event summaries do likewise. Counts are descriptive. Without a prespecified comparative analysis and an appropriate design, they do not estimate a randomized treatment effect. A percentage can aid interpretation of a count, but its meaning depends on its denominator, event definition, and observation period. The serious-event term percentages are listed without those details in the information, so they should be read cautiously rather than as directly comparable group-specific risks.

In general, a confidence interval expresses uncertainty around an estimated quantity. Its width depends on factors such as the amount of information and the variability of the data. No confidence interval for the primary endpoint or the listed secondary outcomes is reported in the registry record. Likewise, no p-value or inferential analysis is listed. The absence of such results means that statistical precision cannot be judged; it is not evidence that an effect is absent or that an analysis found no difference.

Why is the design important for interpretation?

The allocation is listed as NA, masking as NONE, and model as SINGLE GROUP. This is not a randomized comparison. The Phase I dose levels and Phase II Expansion are labels for study groups, but the record does not describe random assignment between them. A comparison of their crude counts would therefore not separate dose effects from differences in who entered each group or how and when outcomes were observed. In general, randomization helps balance measured and unmeasured characteristics on average, while an uncontrolled design does not offer that protection. No adjusted comparison is reported.

The regimen description records ibrutinib 560 mg/daily, rituximab 375mg/m2 IV Day 1, and lenalidomide 10-25 mg PO days 1-21. The range in the lenalidomide dose is part of the recorded dose description; the registry does not explain the exact assignment of doses to participants or cohorts. The group counts are reported as 4, 3, and 18. The registry separately lists enrollment as 27 and does not reconcile that figure with the group counts. The record does not describe an analysis population or explain whether all enrolled participants contributed to each endpoint.

How should planning calculations be understood?

Any sample-size illustration accompanying these results is a planning exercise, not an observed property of the trial. The stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect to detect defined as a stated fraction of the observed effect. For time-to-event outcomes, the illustration uses a total number of events; other illustrations are expressed as participants per arm. These assumptions do not describe the actual single-group dose-escalation design, and the illustration should not be interpreted as the trial's own design or as observed power. Sample sizes are planning illustrations, not evidence that an outcome was adequately powered.

More generally, a normal approximation is a mathematical method for approximating sampling distributions. Its suitability depends on the data structure and amount of information. The registry record does not report the trial's own sample-size justification or statistical plan, so the planning assumptions should not be used to infer what methods investigators intended for the enrolled study. The record lists zero analyses, which means no analysis results are posted in the registry information. That absence prevents evaluation of model choice, uncertainty, adjustment, or sensitivity analyses.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists five outcome measures, but the information available does not give results for them or describe a statistical analysis plan. It does not report whether the study prespecified a hierarchy among outcomes, adjusted for multiple testing, or treated the additional outcomes as exploratory. Multiplicity refers generally to the interpretive problem created when several hypotheses or outcomes are assessed: the more opportunities there are to find an apparently unusual result, the more important it is to know the planned testing strategy. No particular multiplicity procedure can be attributed to this trial from the registry record.

The listed secondary outcomes include assessment of the safety profile through adverse-event review, radiologic progression-free survival, radiologic response rate, and drug-drug interaction of combination therapy. Their definitions, assessment schedules, analysis populations, censoring rules, and numerical results are not reported in the registry record. The registry also does not report a statistical plan for the primary endpoint beyond its general dose-finding description.

Missing-data handling is not reported in the registry record. There is no description of how incomplete outcome assessments, withdrawals, or unavailable imaging were handled. The analysis populations are also not reported: the record does not state whether analyses used all enrolled participants, participants who received treatment, or another defined group. These omissions matter because the set of participants included and the handling of missing observations can influence estimates.

The registry lists zero analyses. This indicates that no statistical analysis results are posted in the record; it does not establish why results are absent, whether analyses were conducted elsewhere, or what they would show. Without reported estimates and methods, statistical significance, precision, and robustness cannot be evaluated.

11. 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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: cardiac arrest (33.3%), gi bleed (33.3%), vomiting (33.3%), neutropenic fever (25.0%), fever (16.7%).

The registry reports serious adverse-event counts by group. Phase I - Dose Level 1 lists 1 affected participant among 4 at risk; Phase I - Dose Level 2 lists 2 among 3; and Phase II Expansion lists 11 among 18. For other adverse events, the corresponding counts are 2 among 4, 2 among 3, and 10 among 18. These are descriptive group summaries, not adjusted comparisons. The group labels and counts do not make the groups randomized control arms.

The record lists deaths as 1 for Phase I - Dose Level 1, 2 for Phase I - Dose Level 2, and 2 for Phase II Expansion. It does not report timing, causes, or attribution for these deaths. They should not be presumed to be treatment-related on the basis of these counts alone.

The listed serious-event terms are Cardiac Arrest, GI Bleed, and Vomiting, each at 33.3%; Neutropenic Fever at 25.0%; Fever at 16.7%; and Diarrhea at 11.1%. The registry information does not specify the denominator, observation period, or whether participants could contribute more than one term to these percentages. The percentages therefore cannot be assumed to represent risks among all enrolled participants or directly compared with group counts without further definitions. The registry record also does not provide severity grades or event-level timing in the information considered.

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

This trial is designed to address a dose-selection question for ibrutinib combined with lenalidomide and rituximab in relapsed or refractory mantle cell lymphoma. Its primary objective is to use dose-limiting toxicities in cycle 1 to define a maximum tolerated dose and/or recommended phase II dose. That is a different statistical aim from testing whether a treatment is superior to a control. The record describes no randomized control group.

The posted information does show group-level adverse-event counts and several serious-event term percentages. Those summaries describe recorded events in the listed groups, but they do not establish causal effects of treatment. The group structure is not a like-for-like randomized comparison, and the registry record does not report adjustment for group differences, event timing, or attribution. The listed deaths likewise cannot be linked to treatment from the information reported.

The record does not report the primary endpoint result, the selected dose, or numerical results for the secondary outcomes. It also does not report confidence intervals, p-values, or analyses. As a result, the precision of any estimates and the statistical evidence for any outcome cannot be assessed from the registry record. The lack of posted analysis is not proof that no analysis was performed, and it does not establish that the intervention is effective or ineffective.

Planning sample-size calculations, if consulted alongside the posted results, are illustrations based on stated assumptions, not a retrospective measure of power. In particular, an illustration assuming equal allocation between two arms does not describe this single-group dose-finding design. It should not be used as evidence that the actual study was designed or analyzed as a two-arm trial.

The appropriate interpretation is therefore limited: the registry outlines the dose-finding objective and reports certain adverse-event counts, but does not provide enough outcome or analysis detail to determine the dose-selection result, quantify uncertainty, or draw comparative conclusions.

13. Why This Trial Matters Statistically

This study illustrates why the statistical question should be matched to the trial's purpose. Dose-finding focuses on toxicity and selection of a dose for further evaluation; it is not automatically a comparative efficacy test. The primary endpoint description explicitly targets dose-limiting toxicities in cycle 1 and a maximum tolerated dose and/or recommended phase II dose. A reader who treats the dose-level groups as randomized arms would ask a different question from the one the registry describes.

The record also shows how descriptive safety counts require context. Counts are attached to group sizes, while term-specific percentages are listed without a denominator explanation in the information considered. Knowing the event definition, observation period, and analysis population is essential to understanding what a count or percentage represents. A percentage on its own is not a complete estimate of risk.

Statistical interpretation depends not only on the outcome labels but also on transparent methods and results. The registry lists five outcome measures but zero analyses, and it does not report a numerical primary endpoint result. Thus, readers cannot assess uncertainty, missing-data handling, or multiplicity, nor determine whether any planned dose-selection rule was followed. In general, reporting estimates with a clear analysis population and uncertainty measure helps distinguish a noisy observation from a more precise estimate.

Finally, planning calculations should not be mistaken for evidence about the conducted trial. The stated sample-size assumptions include equal allocation between two arms, whereas the registry describes a single-group design. Recognizing that mismatch prevents a planning illustration from being read as trial design or observed power. These distinctions matter for interpreting early-phase evidence and for understanding exactly what conclusions a registry record can support.

14. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The registry record does not report the numerical primary endpoint result, the dose selected, or the number of participants meeting the protocol definition of a dose-limiting toxicity. It also does not provide the toxicity definition or dose-escalation decision rules. These omissions prevent readers from evaluating how the stated dose-finding objective was resolved.

The record lists enrollment as 27 and reports group counts of 4 for Phase I - Dose Level 1, 3 for Phase I - Dose Level 2, and 18 for Phase II Expansion, without reconciling those figures. It does not explain the analysis populations or whether each group count applies uniformly to every outcome. This limits interpretation of the adverse-event summaries.

The registry lists deaths by group but does not report causes, timing, or attribution. The serious-event terms have percentages, but the denominator and counting method are not specified in the information available. The record does not report event grades, exposure duration, or follow-up details needed to interpret safety frequency in depth.

Radiologic progression-free survival, radiologic response rate, and drug-drug interaction are listed among the secondary outcomes, but their definitions and numerical results are not reported. Statistical methods for those outcomes, missing-data handling, multiplicity procedures, and analysis populations are also not reported in the registry record. The registry lists zero analyses, so estimates and their precision cannot be evaluated.

Finally, the trial is single group, with allocation listed as NA and masking as NONE. It cannot provide a randomized, like-for-like control comparison. The record does not report enough detail to infer the reasons for these design choices or to make causal comparisons across the labeled cohorts.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Dose Finding Study of Ibrutinib Plus Lenalidomide / Rituximab in Relapsed or Refractory Mantle Cell Lymphoma — NCT02446236.
• Registry record last updated 2026-09-16; status last verified 2026-08.
• Results first posted 2024-01-26.
• 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.

18. Record Summary

NCT02446236 is a Phase Ib dose-finding study of ibrutinib plus lenalidomide and rituximab in relapsed or refractory mantle cell lymphoma. The registry describes a single-group, unmasked study with allocation listed as NA. Its primary objective is to determine the maximum tolerated dose and/or recommended phase II dose by assessing cycle 1 dose-limiting toxicities; the outcome timeframe is 28 Days.

The dose-escalation description lists ibrutinib 560 mg/daily, rituximab 375mg/m2 IV Day 1, and lenalidomide 10-25 mg PO days 1-21. The registry reports serious and other adverse-event counts for Phase I - Dose Level 1, Phase I - Dose Level 2, and Phase II Expansion, as well as deaths by group. It does not report the numerical primary endpoint result, secondary outcome results, or statistical analyses.

The sponsor is Hackensack Meridian Health. The record lists enrollment of 27, a start date of 2015-06-18, primary completion of 2017-01-03, and status active, not recruiting.