Study to Evaluate Ibrutinib Combination Therapy in Patients With Selected Gastrointestinal and Genitourinary Tumors: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Evaluate Ibrutinib Combination Therapy in Patients With Selected Gastrointestinal and Genitourinary Tumors (NCT02599324), a non-randomized phase 1, phase 2 study. The primary outcome is Phase 1b: Number of Participants With Dose-Limiting Toxicities (DLTs) in Cohorts 1 to 6.

2. Clinical Question

The broader purpose was to evaluate safety, tolerability, and efficacy across the selected tumor types, using ibrutinib as a single agent in one cohort and in combinations in others. The primary endpoint focused specifically on dose-limiting toxicities in phase 1b, rather than on tumor response or survival. That focus is relevant to the study’s dose-finding objective: the trial sought to determine the recommended phase 2 dose separately for each cohort.

Secondary outcomes included objective response, disease control, progression-free survival, overall survival, duration of response, and pharmacokinetic measures. The registry record lists those outcomes but does not report their results in the information available. As a result, the record supports a description of the questions the trial set out to examine, but not a conclusion about the magnitude or precision of tumor-control or survival outcomes.

3. Trial Design

This was a phase 1b/2, parallel, non-randomized study with no masking. The registry record lists an enrollment of 263 and describes six cohorts covering renal cell carcinoma, urothelial carcinoma, gastric adenocarcinoma, and colorectal adenocarcinoma. The study started on 2015-12-01, had a primary completion date of 2021-08-20, and is listed as completed.

The regimen differed by cohort. Participants with renal cell carcinoma received ibrutinib with everolimus; the urothelial carcinoma cohorts evaluated ibrutinib with paclitaxel, ibrutinib alone, or ibrutinib with pembrolizumab. The gastric adenocarcinoma cohort evaluated ibrutinib with docetaxel, and the colorectal adenocarcinoma cohort evaluated ibrutinib with cetuximab. Phase 1b explored ibrutinib dose levels to establish a recommended phase 2 dose separately for each cohort. Phase 2 used the dose selected for the relevant cohort.

Because allocation was non-randomized and the study had no masking, the cohorts do not constitute randomized comparisons. Differences in observed outcomes across regimens could reflect differences among participants, tumor types, cohorts, or treatment settings, as well as treatment. A direct causal comparison between the regimens is not supported by this design.

The registry record does not report a detailed randomization or allocation procedure beyond identifying the study as non-randomized, nor does it describe a blinded assessment process. Detailed eligibility criteria, the planned size of each cohort, and the full protocol-level design rationale are not reported in the registry record. The overall enrollment figure is not a substitute for cohort-specific enrollment or an analysis-population count.

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: For Cohorts 1 to 4 and 6, participants enrolled into 5 distinct disease specific cohorts to receive ibrutinib at the RP2D determined in Phase 1b for that cohort in combination with the relative cancer agent. Treatment was to follow the same dosing schedule used in Phase 1b, and all cohorts were to continue on ibrutinib RP2D and respective anticancer agents until disease progression or unacceptable toxicity. For Cohort 5, single agent ibrutinib was given at the RP2D PO daily in 21-day cycles.

Only the first 6 of 9 groups are shown.

Phase 1b

Phase 2 (RP2D)

Analysis population for the primary outcome, as defined in the registry: DLT Evaluable Population: participants from Phase 1b who completed at least 21 days of treatment with ibrutinib in combination with the relevant anticancer agent after the initiation of study treatment at the start of Cycle 1, or those who discontinued from study treatment due to a DLT event prior to completion of DLT observation period. For UC Cohorts 5 and 6, a DLT-evaluable participant had ≥ 90% compliance with ibrutinib during Cycle 1 (the first 21 days).

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 treated population: all unique participants enrolled and treated in Phase 1b and Phase 2.

Only the first 6 of 10 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Phase 1b: Number of Participants With Dose-Limiting Toxicities (DLTs) in Cohorts 1 to 6, measured over 21 days after the initiation of therapy at the start of Cycle 1.

The primary endpoint was the number of participants with dose-limiting toxicities in phase 1b, assessed across cohorts 1 to 6. The observation period was 21 days after initiation of therapy at the start of Cycle 1. A dose-limiting toxicity was defined as a Grade 3 or higher non-hematologic adverse event, or a Grade 4 hematologic adverse event, occurring within that observation period and considered at least possibly related to study treatment, whether ibrutinib alone or a combination.

This kind of endpoint is used in dose-finding because serious treatment-related events during a defined early period can inform selection of a dose for later study. The trial’s stated objective was to determine the recommended phase 2 dose of ibrutinib separately for each cohort. The endpoint is a participant count, not a measure of tumor response, long-term tolerability, or survival.

The registry describes the DLT-evaluable population as participants who completed at least 21 days of treatment with ibrutinib and the relevant anticancer agent, or who discontinued study treatment because of a DLT before completing that period. The remainder of the population description is not reported in the registry record. The number of participants with a DLT and the corresponding cohort-level results are not reported in the registry record, so the endpoint’s observed values and their precision cannot be assessed from this record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count convey?

General statistical explanation: A count reports how many participants met an event definition in a specified group. For a dose-limiting toxicity endpoint, interpretation depends on the definition, the observation window, and which participants are included in the evaluable population. A count alone does not describe the uncertainty around the underlying event probability. To interpret it as a proportion, the corresponding denominator must be known and the analysis population must be clear.

The primary endpoint is specifically a count of participants with DLTs during the defined period. Its event rule includes severity thresholds, event type, timing, and a relationship to study treatment judged to be at least possible. The event rule therefore does not encompass every adverse event, and the primary endpoint should not be conflated with the broader adverse-event counts listed for treatment groups. The registry record gives the DLT definition but not the observed DLT counts.

Why does the phase 1b dose-finding purpose matter?

General statistical explanation: Early dose-finding commonly uses observed toxicity information to guide dose selection for subsequent study. The selected dose is an estimate informed by the participants and events observed in the dose-finding stage; it is not automatically a guarantee of a particular toxicity level in a later population. Here, the registry states that dose levels of ibrutinib were explored in phase 1b and that a recommended phase 2 dose was determined separately for each cohort. The detailed decision rule, dose-escalation algorithm, and statistical procedure are not reported in the registry record, so they cannot be reconstructed from the endpoint definition alone.

How should uncertainty and event counts be considered?

General statistical explanation: Confidence intervals express the uncertainty associated with an estimate under a specified statistical model. For binary event outcomes, the interval depends on the number of observed events, the denominator, and the interval method. Small groups generally offer less precision than larger groups, and an estimate can remain uncertain even when it appears numerically high or low. No confidence intervals for the primary DLT endpoint are reported in the registry record.

Counts of adverse events can also be affected by differing observation time. A participant followed longer has more opportunity to experience an event than a participant followed for less time. Rates based on person-time or time-to-event methods require follow-up information and specified methods; those details are not reported for the adverse-event summaries. The group counts should therefore be read as descriptive counts, not exposure-adjusted risks.

General statistical explanation: Over-dispersion occurs when variation in counts is greater than a simple statistical model assumes. It can make standard errors from an overly restrictive model too small and uncertainty appear narrower than warranted. Whether over-dispersion is relevant depends on the outcome and model. The registry record does not report a count-model analysis for the primary endpoint, so there is no basis to say whether this issue was assessed or what model was used.

What do the planning illustrations mean?

General statistical explanation: A sample-size calculation asks how much information a future or planned study might need under stated assumptions. It is not a measure of the probability that a completed study found a real effect, and it is not observed power. The stated planning assumptions use a two-sided significance level of 0.05, equal allocation, and a normal approximation; the target effect is expressed as a fraction of the observed effect. For time-to-event outcomes, the stated convention is a total event count using the Schoenfeld approach; other illustrations are expressed as participants per arm. These are planning illustrations and should not be mistaken for the trial’s original design justification, which is not reported in the registry record.

Such illustrations are conditional on their assumptions. If the assumed effect, event rate, follow-up, or analysis differs from the setting being planned, the resulting sample-size requirement may not apply. Since no observed primary or secondary outcome estimates are reported in the registry record, the illustrations do not provide an independent estimate of treatment benefit or safety.

What can be inferred from the analysis record?

The registry record lists no analyses for the outcome measures. This means that model choices, estimation procedures, hypothesis tests, interval methods, and adjustments cannot be evaluated from the record. It does not establish that no analysis was conducted outside the registry; it means the statistical analysis results and methods are not reported in the registry record. The descriptive safety counts remain useful as counts, but they do not replace inferential results or a clearly specified analysis plan.

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("Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus", "Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus", "Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel", "Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel", "Cohort 3 (GA): Ibrutinib 560 mg + Docetaxel", "Cohort 4 (CRC): Ibrutinib 560 mg + Cetuximab")
n      <- c(3, 6, 4, 6, 7, 3)
events <- c(0, 1, 0, 0, 2, 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  Cohort 1 (RCC): Ibrutinib 560 mg + Everolimus  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Cohort 1 (RCC): Ibrutinib 840 mg + Everolimus  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  Cohort 2 (UC): Ibrutinib 560 mg + Paclitaxel  4  0  0.0  0.0  60.2  0.0  49.0  0.5  52.2
ARM  Cohort 2 (UC): Ibrutinib 840 mg + Paclitaxel  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Cohort 3 (GA): Ibrutinib 560 mg + Docetaxel  7  2  28.6  3.7  71.0  8.2  64.1  8.5  65.1
ARM  Cohort 4 (CRC): Ibrutinib 560 mg + Cetuximab  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2

11. Multiplicity, Missing Data and Analysis Populations

The study included multiple tumor cohorts, regimens, phases, and outcome measures. The registry lists 18 outcome measures, including response and disease-control outcomes, survival outcomes, duration of response, and pharmacokinetic measurements. Assessing many endpoints or making many comparisons can increase the chance of at least one apparently notable result arising by chance. Statistical approaches to this issue can include prespecifying a primary comparison, controlling a family-wise error rate, or treating analyses as exploratory. Which approach, if any, was planned or used is not reported in the registry record.

The primary endpoint is described for phase 1b across cohorts 1 to 6, while the secondary outcome list distinguishes phases, cohorts, and some RP2D analyses. The record does not supply a complete analysis hierarchy, endpoint-specific hypotheses, or adjustment procedures. The registry also lists no analyses, so multiplicity handling cannot be assessed from reported tests or estimates.

Missing-data methods are not reported in the registry record. The DLT-evaluable population description specifies participants who completed at least 21 days of treatment or discontinued because of a DLT before that point, but the remaining population criteria are not reported in the registry record. The record does not state how participants who stopped for other reasons, lacked outcome assessments, or had incomplete follow-up were handled for each endpoint.

Different outcome types require different approaches to incomplete data. For example, a binary response outcome may depend on whether response assessments are available, while survival outcomes depend on event times and censoring rules. These are general considerations; the specific definitions and missing-data procedures for this trial are not reported in the registry record. Without that information, the extent to which missing observations could affect the outcome estimates cannot be evaluated.

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%), acute coronary syndrome (33.3%), cardiac failure congestive (33.3%), diarrhoea (33.3%), amyloidosis (33.3%).

The registry lists treatment-group counts for participants with serious adverse events, participants with other adverse events, and deaths. These are counts of participants, not event rates. For example, the Cohort 2 urothelial carcinoma phase 2 group of ibrutinib 840 mg plus paclitaxel lists 32 participants with serious adverse events among 55 at risk, and 51 deaths. These figures should be read as separate entries in the record; the death count does not, by itself, identify cause or timing.

The serious adverse-event term list gives six terms, each with a reported percentage of 33.3%: febrile neutropenia, acute coronary syndrome, congestive cardiac failure, diarrhoea, amyloidosis, and respiratory tract infection. The denominator, event-counting method, and whether participants could contribute to more than one term are not reported in the registry record. Those percentages therefore cannot be translated into group-specific risks from the information available.

Because the study was non-randomized and groups differed by tumor cohort and regimen, their safety counts are descriptive, not controlled comparative evidence. Exposure duration, follow-up, and attribution details are not reported for these summaries. The counts alone do not establish that treatment caused an event.

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

The registry record describes a clinical investigation of ibrutinib alone and in combinations across selected advanced gastrointestinal and genitourinary tumors. Its phase 1b objective included determining a recommended phase 2 dose separately for each cohort, and its primary endpoint was the number of participants with DLTs during a defined early observation period. The record also identifies a broad set of secondary questions concerning response, disease control, survival, and pharmacokinetics.

What the record does not establish is the observed result for the primary endpoint or the secondary outcomes. DLT counts, response estimates, survival estimates, confidence intervals, and analysis results are not reported in the registry record. Therefore, the study’s stated objectives cannot be treated as evidence that a regimen achieved a particular level of safety, tumor response, or survival.

The safety counts offer a descriptive view of participants recorded with serious or other adverse events and deaths in listed groups. They do not reveal the causal contribution of treatment, the timing of the events, or the effect of different exposure durations. The serious-event term percentages lack the denominator and calculation details needed for a fuller interpretation.

The non-randomized design also limits causal conclusions. Comparisons across cohorts are not randomized comparisons, and the cohorts differ in tumor type and treatment regimen. Even when two groups have reported counts, a difference cannot be attributed to treatment alone on the basis of this design description. The record is most informative as documentation of study structure, endpoint definitions, and selected descriptive safety data; it is not a complete statistical report of clinical outcomes.

14. Why This Trial Matters Statistically

This trial illustrates the distinction between dose-finding and treatment-effect estimation. The phase 1b component was designed to inform a recommended phase 2 dose for each cohort, while phase 2 evaluated regimens at the dose selected for that cohort. The primary endpoint’s time-limited DLT definition is closely connected to that dose-finding objective. It is not interchangeable with long-term safety or with outcomes such as tumor response and survival.

The study also demonstrates why an overall enrollment figure cannot explain the precision of every cohort result. The six cohorts address different diseases and regimens, and their participant counts vary in the adverse-event summaries. A study-wide enrollment of 263 does not indicate how much information is available for any one cohort or endpoint. Cohort-specific denominators and outcome estimates are needed for that assessment.

Non-randomized parallel cohorts can be useful for evaluating several regimens, but they do not provide the same protection against confounding as randomized allocation. This matters especially when cohorts differ by tumor type and combination partner. Descriptive comparisons may generate questions, but causal comparisons require a design and analysis that address those differences.

Finally, the registry record shows how endpoint listings and safety summaries can coexist with absent inferential results. Statistical interpretation requires the outcome values, analysis populations, methods, and uncertainty measures—not only a stated objective or a list of intended endpoints. The distinction between planned questions and reported findings is essential when reading clinical trial records.

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 principal limitation for interpretation is that the registry record does not report the primary DLT counts or the listed secondary outcome results. Without observed endpoint values, there is no basis for evaluating the magnitude, precision, or direction of those outcomes. The record lists 18 outcome measures but no analyses, leaving the statistical methods and results unavailable for review.

The study was non-randomized, unmasked, and organized into cohorts with different tumor types and regimens. There is no like-for-like randomized control comparison, so comparisons among regimens would be vulnerable to differences between the cohorts. The registry record does not report sufficient detail to assess whether or how such differences were addressed analytically.

Although the overall enrollment is listed as 263, cohort-specific enrollment for the primary endpoint is not stated in the information available. The DLT-evaluable population description is incomplete, and endpoint-specific missing-data rules are not reported in the registry record. The adverse-event summaries do not include exposure-adjusted rates or the follow-up information needed to interpret differences in opportunity for events. The serious-event term percentages are also not accompanied by denominator details.

Other details needed for a fuller statistical assessment are not reported in the registry record, including the original sample-size justification, dose-escalation decision procedure, analysis methods, multiplicity handling, and interval estimates. These gaps limit assessment of both the design rationale and the uncertainty around any findings. They do not establish that analyses or procedures were absent outside the registry; they identify what the registry record does not document.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study to Evaluate Ibrutinib Combination Therapy in Patients With Selected Gastrointestinal and Genitourinary Tumors — NCT02599324.
• Registry record last updated 2023-11-18; status last verified 2022-09.
• Results first posted 2022-10-26.
• 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.

19. Record Summary

The registry record describes a completed, non-randomized, unmasked phase 1b/2 study of ibrutinib alone or in combinations for selected advanced gastrointestinal and genitourinary tumors. Listed combinations used everolimus, paclitaxel, docetaxel, cetuximab, or pembrolizumab. The study enrolled 263 participants and had a primary completion date of 2021-08-20.

The phase 1b primary endpoint was the number of participants with DLTs during 21 days after therapy initiation at the start of Cycle 1. The study sought to determine a recommended phase 2 dose separately for each cohort. The registry lists 18 outcome measures and descriptive safety counts, but primary and secondary outcome analyses are not reported in the registry record. Since cohorts were not randomized comparators, their counts should be interpreted descriptively rather than as treatment-effect comparisons.