Pembrolizumab in Combination With Ibrutinib for Advanced, Refractory Colorectal Cancers: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pembrolizumab in Combination With Ibrutinib for Advanced, Refractory Colorectal Cancers (NCT03332498), a na phase 1, phase 2 study. The primary outcome is Phase I - Recommended Phase II Dose (RP2D).

2. Clinical Question

3. Trial Design

This was a Phase I/II study using a sequential model. The registry lists allocation as not applicable and masking as none. The intervention combined pembrolizumab with ibrutinib; there is no randomized comparator described. This matters statistically because differences between dose cohorts or study phases cannot be interpreted as controlled treatment effects. Cohorts may differ in dose and place in the study, and there is no randomized allocation to balance other factors.

The Phase I portion was described as a standard 3+3 dose-escalation design. Participants received pembrolizumab at 200 mg every 3 weeks, with ibrutinib at 420 mg daily in cohort 0 or 560 mg daily in cohort 1. Phase II treatment was to use the Recommended Phase II Dose. The registry record does not state which dose was recommended or report the decision that led to it.

The registry description defines the dose-limiting toxicity evaluation period as the time from the first dose of both study drugs to 42 days after the first dose, or to an earlier DLT experienced within that period. Its stated decision rules begin with a minimum of 3 participants in the first cohort. If 0 of the first 3 participants have a DLT, escalation continues as planned. If 1 of the first 3 has a DLT, the cohort expands to 6; if no more than 1 of 6 has a DLT, escalation continues. If >= 2 DLTs occur in the first dose cohort, the principal investigator is to discuss how to proceed with Janssen.

The record lists a total enrollment of 40 and a completed status. Start and primary completion dates are 2018-01-24 and 2019-12-05. These administrative details do not substitute for an endpoint result: the selected dose and the outcome of the DLT decision process are not reported in the registry record.

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: All participants in Phase 1 portion of study who received at least one dose of study drugs

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: All participants who consented to study.

6. Primary Endpoint

The registry lists the primary outcome as Phase I - Recommended Phase II Dose (RP2D), measured over 42 days post first dose.

The primary outcome is titled “Phase I - Recommended Phase II Dose (RP2D),” with a unit of mg and a timeframe of 42 days post first dose. It concerns dose selection rather than a direct comparison of clinical benefit. In an early-phase dose-finding study, monitoring DLTs over a prespecified period helps characterize whether a dose level is tolerable enough to carry forward. The registry’s stated 3+3 rules use the number of participants experiencing DLTs within a cohort to guide escalation or further evaluation.

The record describes the intended measurement and decision rules, but it does not report the dose selected as the RP2D or the number of DLTs observed. Thus, the endpoint result itself is not available in the registry record. The 42-day timeframe defines the stated DLT evaluation window; it does not mean that later safety or clinical outcomes were measured only during that period. The record does not report a comparative efficacy endpoint result that would establish whether the combination performs better than another treatment.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The study’s statistical structure is primarily dose-finding and descriptive. Its sequential Phase I/II design does not provide the same basis for causal comparison as a randomized trial. Allocation is listed as not applicable, and masking is listed as none. The registry does not report a statistical analysis plan beyond the described dose-escalation rules, so details such as planned inferential models, adjustment methods, or interim analyses are not reported in the registry record.

The Phase I decision procedure is described as a standard 3+3 design. In general, this type of design evaluates toxicity in small groups at successive dose levels. The study description specifies that the first cohort enrolls a minimum of 3 participants. If 0 of the first 3 experience a DLT, dose escalation continues as planned. If 1 of the first 3 experiences a DLT, the cohort expands to 6; escalation continues if no more than 1 of 6 experiences a DLT. If >= 2 DLTs are observed in the first dose cohort, the principal investigator discusses how to proceed with Janssen. These rules describe the intended decision process; without reported DLT counts, they do not reveal what decision was made.

The DLT evaluation window begins with the first dose of pembrolizumab and ibrutinib and extends to 42 days after the first dose, or to a DLT occurring within that period. A defined window helps make toxicity assessments interpretable by specifying when events count for the dose-escalation decision. It does not, by itself, describe longer-term safety, tumor response, or survival. The record does not report how participants with incomplete DLT observation were handled, or whether any were excluded from the primary analysis.

The study regimen combined pembrolizumab at 200 mg every 3 weeks with oral ibrutinib. Phase I cohort 0 received 420 mg daily and cohort 1 received 560 mg daily. Phase II was to use the RP2D, but the selected dose is not reported. Since the cohorts were sequential, observed differences in their safety counts cannot be separated from differences in dose, timing, participant characteristics, or study phase. No randomized control is described, and the registry cautions against treating the groups as a like-for-like comparison.

General statistical interpretation: an event count is a descriptive summary, not an estimate of how much risk a treatment causes. A confidence interval, when reported, describes the statistical uncertainty around an estimate under the method used; no such interval is reported for the safety counts in this record. Likewise, a hypothesis test would address a defined comparison, but the registry does not report a comparative analysis for these groups. Without those estimates and a valid control group, one should not infer comparative effects from the raw counts.

The record reports serious adverse event counts, other adverse event counts, and deaths by group. These categories should remain distinct. Seriousness is a classification of an event, while “other adverse events” is a separate reported category in these results. The record does not specify event-level detail, whether counts refer to people or repeated events beyond the labels used, or how overlapping categories were handled. The reported numbers therefore support the registry’s stated group summaries, but not reconstruction of individual-level outcomes.

Planning illustrations use the observed effect as a reference and vary the fraction of that effect to be detected. Their stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. For time-to-event outcomes, the illustration is based on the total number of events; for other outcomes, it is based on participants per arm. These are planning calculations, not features of the trial’s sequential dose-escalation design and not observed power. Because the trial is not a randomized comparison and no effect estimate is reported in the primary endpoint result, such illustrations should not be mistaken for evidence about the trial’s actual ability to detect a treatment effect. Sample-size justification for this study is not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry record does not report a multiplicity strategy. It lists two outcome measures and zero analyses, but does not describe a hierarchy for testing outcomes, adjustment for multiple comparisons, or an inferential testing plan. The primary endpoint is dose selection based on DLTs; the safety summaries are descriptive counts. Without a reported plan, it is not possible to determine whether other outcomes were intended to be tested formally or how any multiple testing would have been handled.

Missing-data methods are also not reported in the registry record. The primary endpoint population is described as Phase I participants who received at least one dose of study drugs, but the record does not state how participants with missing or incomplete DLT follow-up were treated. It does not report withdrawals, exclusions, or whether all participants in the listed safety groups contributed to every outcome. The specified 42-day DLT window does not itself explain how incomplete observation was handled.

The analysis populations are not fully described beyond the stated primary endpoint population and the group-specific safety counts. The record does not report an intention-to-treat analysis population, a per-protocol population, or analysis exclusions. It also does not report participant-level data or methods for handling repeat events. These omissions limit assessment of whether the reported counts represent complete follow-up and how consistently outcomes were classified.

As a result, readers can describe the listed counts but cannot assess the influence of missing outcomes or selective reporting from the registry record alone. Details about multiplicity, missingness, and analysis populations should not be inferred from the dose-escalation design.

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: abdominal pain (50.0%), nausea (25.0%), vomiting (25.0%), cholangitis (25.0%), blood bilirubin increased (25.0%).

The registry reports serious adverse events, other adverse events, and deaths separately for each study group. For cohort 0, the serious-event summary lists 4 at risk and 2 affected; the other-event summary lists 4 at risk and 4 affected, with 3 deaths. For cohort 1, the corresponding counts are 4 and 3 for serious events, 4 and 4 for other events, and 4 deaths. For Phase 2 treatment at RP2D, the counts are 32 and 13 for serious events, 32 and 29 for other events, and 26 deaths.

These are descriptive registry figures, not estimates of treatment-caused risk. The record does not state whether the deaths were attributed to study drugs, cancer, or other causes, and the groups are not randomized comparison arms. The listed serious-event terms include abdominal pain at 50.0%; nausea, vomiting, cholangitis, blood bilirubin increased, and infections and infestations - other are each listed at 25.0%. The record does not provide additional event-level context for these percentages, so they should not be read as incidence estimates beyond the registry’s stated summary.

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

The registry describes an early-phase study asking whether a dose of ibrutinib could be selected for combination with pembrolizumab in advanced, refractory colorectal cancers. The Phase I rules specify how observed DLTs during a 42-day period would inform dose escalation. This is a dose-selection framework, not a randomized test of whether the combination improves outcomes relative to another treatment.

The posted results include group-specific safety counts and serious adverse event terms. They do not include the primary endpoint result identifying the RP2D, the DLT counts used to make that decision, or a comparative efficacy estimate. The record therefore does not establish which dose was selected or whether the treatment combination provides clinical benefit. The safety counts also do not establish that reported events or deaths were caused by study treatment.

Because the study used a sequential design and has no randomized comparator described, comparisons among its dose cohorts are not controlled treatment comparisons. Differences in counts may reflect the different cohort sizes, doses, timing, participant characteristics, or other factors. The registry does not report analyses that adjust for these differences. General statistical principle: a descriptive count can characterize what was recorded in a study group, but it cannot isolate a treatment effect when there is no appropriate comparison and no adjustment for relevant differences.

The record’s completed status and enrollment of 40 indicate that the study reached its recorded administrative status, not that every planned scientific question has a reported answer. Readers should distinguish the protocol’s intended endpoint from an outcome result: the record gives the former but not the latter. These limitations mean the available registry information is useful for understanding the design and the reported safety summaries, while leaving the central dose-selection result and efficacy questions unresolved.

13. Why This Trial Matters Statistically

This trial is statistically notable because it combines a dose-finding question with a later Phase II treatment portion. The Phase I design uses explicit DLT-based escalation rules, giving the dose-selection process a stated structure. At the same time, the sequential design means that the reported groups are not randomized controls. That distinction is essential: cohort-specific counts can describe the study experience, but they cannot by themselves estimate comparative treatment effects.

The endpoint also illustrates why a trial’s stated outcome and its posted result must be distinguished. The registry identifies the Recommended Phase II Dose as the primary outcome and describes a 42-day DLT window, yet it does not report the dose selected or the underlying DLT counts. The protocol description alone cannot answer the dose-selection question. An absent result is not evidence that no DLTs occurred, nor evidence that a particular dose was tolerated.

The record’s safety summaries are useful for seeing the scale and distribution of reported counts across study groups. However, they do not include uncertainty intervals, event-level context, or causal attribution for deaths. The groups also differ in their place in the study and are not like-for-like control arms. General statistical principle: interpretation depends not only on observed counts but also on the design, population definitions, follow-up, and analysis methods.

For clinical researchers, the case underscores the importance of complete registry outcome reporting. A clear dose-escalation algorithm supports transparency about the intended method; a reported result is needed to assess how the algorithm was applied. Without that result and a comparative design, the registry record supports a careful description rather than a conclusion about efficacy or relative safety.

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 main trial-specific limitation is that the primary endpoint result is not reported in the registry record. Although the record describes the DLT rules and a 42-day evaluation period, it does not report DLT counts by dose cohort or the selected RP2D. The Phase II dose therefore cannot be identified from this record.

The sequential Phase I/II design does not include a randomized comparator in the registry description. The cohorts received different study roles and, in Phase I, different ibrutinib doses. Their safety counts cannot be interpreted as a controlled comparison. The Phase II group is described as receiving treatment at RP2D, but that dose is not specified in the record.

The safety summaries do not report confidence intervals, adjusted estimates, event timing, or attribution of deaths. The record also does not explain whether the event figures count participants or repeated events beyond the labels used, how overlapping events were handled, or whether all participants had complete follow-up. Missing-data methods and detailed analysis populations are not reported in the registry record.

The registry lists enrollment of 40, while the safety counts are presented by group. It does not provide further information in this record about participant characteristics or comparability across cohorts. These gaps restrict interpretation of the safety summaries and prevent assessment of how well they generalize beyond the study participants. The record also does not report a sample-size justification or detailed statistical analysis plan. These limitations do not invalidate the reported counts, but they narrow the conclusions that can be drawn from them.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Pembrolizumab in Combination With Ibrutinib for Advanced, Refractory Colorectal Cancers — NCT03332498.
• Registry record last updated 2022-06-03; status last verified 2022-06.
• Results first posted 2021-01-22.
• 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

The registry describes a completed Phase I/II sequential study of pembrolizumab with ibrutinib for advanced, refractory colorectal cancers. Participants received pembrolizumab at 200 mg every 3 weeks; Phase I ibrutinib doses were 420 mg daily and 560 mg daily, followed by Phase II treatment at the RP2D. The Phase I endpoint used DLT-based dose-escalation rules over a 42-day period.

The record lists enrollment of 40 and group-specific adverse event and death counts. It does not report the DLT counts, the selected RP2D, or a primary endpoint result. Allocation is listed as not applicable, and no randomized comparator is described. The available information supports descriptive interpretation of the registry’s safety summaries, not conclusions about comparative efficacy or treatment causation.