Durvalumab And Radiation Therapy Followed by Adjuvant Durvalumab in Patients With Urothelial Cancer (T2-4 N0-2 M0) of the Bladder: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Durvalumab And Radiation Therapy Followed by Adjuvant Durvalumab in Patients With Urothelial Cancer (T2-4 N0-2 M0) of the Bladder (NCT02891161), a non-randomized phase 1, phase 2 study. The primary outcome is Phase Ib: Safety Assessment - Evaluation of DLT (Dose Limiting Toxicity) Rate.

2. Clinical Question

3. Trial Design

This was an open-label, multi-institutional phase Ib/II study of durvalumab given concurrently with radiation therapy and followed by adjuvant durvalumab in patients with bladder urothelial cancer described as T2-4 N0-2 M0. The registry identifies the allocation as non-randomized, masking as none, and the model as sequential. The trial was therefore not designed as a blinded randomized comparison between the listed arms.

The phase Ib portion was a safety run-in. Its primary endpoint was evaluation of the dose-limiting toxicity rate. The phase II portion was described as investigational treatment. The registry lists the groups as Arm Ib: Safety Run In Phase Ib and Arm II: Investigational Treatment Phase II. These groups correspond to study phases, not randomized alternatives; differences between them cannot be interpreted as treatment effects of one arm versus the other.

The planned treatment sequence included durvalumab with radiation therapy, followed by adjuvant durvalumab monotherapy. The registry describes radiation to gross disease over 36 fractions and adjuvant treatment Q4 week for up to 12 months. The regimen text is truncated in places, so further timing or completion details are not reported in the registry record. The record lists 26 participants enrolled, a start date of 2016-11-16, primary completion on 2019-08-06, and a status of terminated.

Secondary outcomes listed include disease control rate after completion of concurrent durvaRT, median progression-free survival, phase II complete remission, and overall survival. The registry record lists 7 outcome measures, but the outcome results and analysis details are not reported in the registry record. It lists no analyses. A protocol-specific rationale for the sample size, the reason for termination, and details of any interim review 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.

Study Treatment

Reasons for not completing this period:

Follow up

Reasons for not completing this period:

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 Phase Ib: Safety Assessment - Evaluation of DLT (Dose Limiting Toxicity) Rate, measured over Begin W1 and every 2 chemotherapy cycles (2 weeks) thereafter, for up to 2 years or until unacceptable toxicity..

The phase Ib primary endpoint was a dose-limiting toxicity (DLT) rate assessment. A DLT endpoint counts participants who experience a toxicity meeting a prespecified definition during a stated assessment period. It is used in safety evaluation because it focuses attention on treatment-limiting toxicities during exposure, rather than treating all reported events as equivalent. The registry states that the assessment was based on CTCAEv4.0 and that the objective was to assess whether the DLT rate was lower than 33%.

The stated assessment began at W1 and continued every 2 chemotherapy cycles (2 weeks) thereafter, for up to 2 years or until unacceptable toxicity. The registry record does not provide the observed DLT count, the number of participants evaluated for this endpoint, a rate estimate, or an interval estimate. Consequently, the posted record does not establish how many participants met the DLT definition or how precisely any rate was estimated.

In general, a rate is more informative when accompanied by a confidence interval, which describes the range of values compatible with the data under the chosen statistical method. A point estimate alone can appear definitive even when its uncertainty is substantial. Here, the endpoint result and its uncertainty are not reported in the registry record, so the stated target of lower than 33% is an objective, not a posted finding.

The registry also lists other outcomes, including complete remission in phase II, disease control rate, progression-free survival, and overall survival. Those secondary outcomes do not replace the primary phase Ib safety question, and their results are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical methods depend on the question being asked and on the structure of the study. In general, a randomized trial can use random assignment to balance measured and unmeasured characteristics across treatment groups on average. This study was non-randomized and single arm, with sequential phase Ib and phase II groups. As a result, the groups do not form a randomized treatment comparison. Descriptive results can characterize what was recorded among participants, but a difference between phases would not isolate the effect of treatment.

What does a DLT rate measure?

A dose-limiting toxicity rate is a proportion: the numerator is the number of participants meeting the DLT definition, and the denominator is the number assessed under the endpoint rules. The registry identifies CTCAEv4.0 as the basis for the safety assessment and states a target of lower than 33%. It also gives the assessment timeframe, but the DLT count and analysis are not reported in the registry record. Without those observations, the rate cannot be interpreted from the registry entry. A threshold written in an endpoint description is a criterion or objective, not evidence that the observed rate fell on either side of it.

In general, an estimate of a proportion is subject to sampling uncertainty. A confidence interval communicates that uncertainty by showing values compatible with the observed data under a specified method. When the number of observations is limited, intervals can be wide, and a point estimate can be unstable. No DLT estimate or confidence interval is reported in the registry record, so its precision cannot be assessed from the posted information.

Why does the non-randomized design matter?

Without random assignment or a concurrent control group, the study cannot use a between-group contrast to account for differences in prognosis, eligibility, follow-up, or other factors. The sequential phases serve different study purposes: phase Ib is identified as a safety run-in, while phase II is identified as investigational treatment. These phase labels do not make the groups statistically exchangeable. Comparisons between them, if made, would need to account for their design and participant differences; details of any such analysis are not reported in the registry record.

Masking is listed as none. In general, open-label treatment means participants and study personnel are not masked to the treatment assignment. This can matter for outcomes involving judgment, reporting, or decisions about care. The DLT endpoint is described as based on CTCAEv4.0, but the registry record does not provide details about adjudication, independent review, or steps used to standardize assessment across institutions. Those procedures are not reported in the registry record.

How should event counts be read?

Counts of participants with reported events are descriptive. They need a clear denominator, event definition, and observation period to support interpretation. A participant can potentially experience more than one event, so counts of event terms should not automatically be interpreted as counts of distinct participants. The registry lists participants at risk and affected for serious and other adverse events, along with deaths, but details on event definitions, duration of observation, and attribution are not reported in the registry record. The counts should therefore be read as registry summaries, not as a causal comparison.

In general, over-dispersion matters when event data vary more than a model's assumed distribution allows. A model that does not account for that extra variation may produce uncertainty estimates that are too narrow. The registry record does not report a model for the safety counts or enough outcome detail to assess whether over-dispersion was considered. No adjusted estimate or model-based comparison is reported in the registry record.

What can be said about the planning illustrations?

In general, sample-size planning asks how many participants or events would be needed under specified assumptions to detect an effect with a chosen error rate and power. The planning illustrations associated with the record use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is expressed as a fraction of the observed effect. Time-to-event illustrations use total events, while other illustrations use participants per arm. These are planning assumptions, not a description of the study's actual allocation or observed outcomes.

Such illustrations are not observed power and do not establish that the study was adequately powered. This trial was non-randomized and sequential, and the listed phases are not a like-for-like randomized comparison. The protocol's own sample-size justification is not reported in the registry record. An observed effect used in a planning illustration should not be mistaken for a primary endpoint result or evidence of a treatment effect.

Multiplicity arises when several outcomes or comparisons are tested. In general, testing many hypotheses can increase the chance of at least one apparently notable result unless the analysis plan addresses that issue. The registry lists multiple secondary outcomes, but planned testing procedures, hierarchy, and multiplicity adjustments are not reported in the registry record. The registry also does not report how missing observations were handled, which participants entered each endpoint analysis, or whether analyses followed a prespecified statistical 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("Arm Ib: Safety Run In Phase Ib")
n      <- c(6)
events <- c(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  Arm Ib: Safety Run In Phase Ib  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0

11. Multiplicity, Missing Data and Analysis Populations

The registry lists several secondary outcomes: disease control rate after completion of concurrent durvaRT, median progression-free survival, phase II complete remission, and overall survival. It also lists 7 outcome measures in total. When multiple outcomes are assessed, the interpretation of individual statistical findings can depend on whether outcomes were prespecified as primary or secondary, whether tests were planned in a hierarchy, and whether multiplicity was addressed. Those statistical procedures are not reported in the registry record. No analyses are listed, so there are no posted test results to interpret in light of multiplicity.

Missing-data handling is also not reported in the registry record. The record does not specify how participants with incomplete follow-up, unevaluable endpoint data, or treatment discontinuation were handled in each analysis. The analysis populations for the primary and secondary outcomes are not reported in the registry record. Without these details, it is not possible to determine whether the denominators used for particular outcomes differed from enrollment or how incomplete observations may affect estimates.

In general, missingness can affect interpretation when participants with unavailable outcomes differ systematically from participants with observed outcomes. The direction and size of any resulting bias cannot be determined without information about the extent, reasons, and handling of missing data. The record's terminated status does not, by itself, identify the reason for termination or its consequences for data completeness; those details are not reported in the registry record.

The registry record does not report interim analyses, stopping rules, or the protocol-specific statistical analysis plan. These omissions limit assessment of how outcome selection, repeated testing, and participant inclusion were handled. They do not establish that a particular procedure was or was not used outside what is recorded.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: urinary tract infection (33.3%), abdominal pain (16.7%), dehydration (16.7%), esophagitis (16.7%), gastritis (16.7%).

The registry lists serious and other adverse event counts separately for the phase Ib and phase II groups. In phase Ib, 6 participants were listed as at risk for serious adverse events and 4 as affected; 6 were listed as at risk for other adverse events and 6 as affected. The record also lists 4 deaths in this group. In phase II, the corresponding entries are 20 at risk and 8 affected for serious adverse events, 20 at risk and 20 affected for other adverse events, and 8 deaths.

These are counts, not randomized comparisons. The phase Ib and phase II groups belong to sequential study phases and cannot be treated as equivalent groups differing only by treatment. The registry also lists urinary tract infection at 33.3% and abdominal pain, dehydration, esophagitis, gastritis, and hip fracture at 16.7% each among the top serious adverse event terms. The record does not report enough detail to establish the attribution of each event, how event terms were counted, or whether the deaths were treatment-related. These counts should be read as recorded safety information, not as evidence of causation or a comparative risk estimate.

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

The registry record describes a clinical study and its intended safety question, but the primary endpoint result is not reported in the registry record. The stated phase Ib objective was to assess whether the DLT rate was lower than 33%, using CTCAEv4.0. Without a posted DLT count or rate, the record does not show whether the objective was met, how uncertain an estimate would be, or how many participants contributed to that assessment.

The study's non-randomized, single-arm, sequential design also limits what its outcomes can establish. Descriptive observations among treated participants do not provide a randomized estimate of what would have happened under a different treatment. The phase Ib safety run-in and phase II investigational treatment phase are not control and intervention groups. The registry record therefore does not support a causal treatment comparison from differences between those phases.

The posted safety counts and serious adverse event terms describe events recorded for the study groups. They do not establish that treatment caused an event, and the deaths listed in the record are not identified as treatment-related. Details about attribution, follow-up, and analysis populations are not reported in the registry record.

Secondary outcomes including disease control rate, progression-free survival, complete remission, and overall survival are listed, but their results are not reported in the registry record. The record lists no analyses. Accordingly, it does not provide efficacy estimates, comparative effects, or confidence intervals for those outcomes. A planning illustration based on an observed effect is a design calculation, not a trial finding and not observed power. Overall, the registry information supports a description of the study design, endpoint objective, enrollment, and selected safety counts, while leaving the primary result and statistical analyses unreported.

14. Why This Trial Matters Statistically

This study illustrates why the design and the endpoint definition are as important as a number attached to an outcome. The primary question was a safety-rate assessment in phase Ib, with an explicit target of lower than 33%. A target is useful for defining the question, but without the observed DLT data it cannot answer that question. Reporting a numerator, denominator, estimate, and uncertainty would be needed to judge how informative the safety assessment was.

The sequential phase structure also matters statistically. A safety run-in and a later investigational treatment phase have different roles, and they are not randomized comparison groups. Treating their outcomes as though they came from an ordinary controlled trial could lead to misleading conclusions. This distinction is especially important when interpreting event counts or any planning calculations that assume equal allocation between two arms.

The record also demonstrates the difference between a list of outcome measures and a report of outcome analyses. Several secondary outcomes are named, but their results and statistical methods are not reported in the registry record. Without those results and methods, readers cannot assess estimates, uncertainty, multiplicity, or missing-data handling.

Finally, safety summaries require careful interpretation. Counts can describe events recorded during a study, but they do not by themselves identify causes or establish comparative risk. The absence of reported attribution and follow-up details limits what can be inferred from the listed serious events and deaths. These are general statistical considerations that apply to interpretation of single-arm clinical research; they do not substitute for results that are not reported in the registry record.

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 registry identifies the study as terminated but does not report the reason for termination. It records enrollment of 26, but does not report the number evaluated for each endpoint or the analysis populations. The primary DLT result, secondary outcome results, and analyses are not reported in the registry record. This prevents assessment of endpoint estimates, precision, and whether the stated phase Ib safety objective was met.

The non-randomized, open-label, sequential design has no randomized control group. It can describe outcomes in the enrolled groups but does not support a randomized estimate of treatment effect. The phase Ib and phase II groups have different study roles and should not be treated as interchangeable arms. The record does not report protocol-specific details that would clarify eligibility, allocation between study phases, or the statistical approach to any cross-phase comparisons.

Some intervention descriptions end mid-sentence, so further treatment timing and completion details are not reported in the registry record. The record also does not report the protocol's sample-size justification, interim analyses, stopping rules, multiplicity procedures, missing-data methods, or the analysis populations. The listed adverse event counts lack reported details on event attribution and follow-up, and the relationship of the deaths to treatment is not reported in the registry record. These omissions constrain interpretation of both safety and efficacy; they do not establish that the missing procedures or information were absent from the study itself.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Durvalumab And Radiation Therapy Followed by Adjuvant Durvalumab in Patients With Urothelial Cancer (T2-4 N0-2 M0) of the Bladder — NCT02891161.
• Registry record last updated 2024-11-27; status last verified 2024-11.
• Results first posted 2024-11-27.
• 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 NCT02891161, a phase Ib/II, open-label, non-randomized, sequential study of durvalumab with radiation therapy followed by adjuvant durvalumab in bladder urothelial cancer described as T2-4 N0-2 M0. Enrollment was 26. The study status is terminated, with primary completion on 2019-08-06.

The phase Ib primary endpoint was a dose-limiting toxicity rate assessment based on CTCAEv4.0, with an objective of a rate lower than 33%. Safety counts are listed for the phase Ib and phase II groups, along with selected serious adverse event terms. The registry also names disease control rate, progression-free survival, complete remission, and overall survival as secondary outcomes.

The primary endpoint result, secondary outcome results, and statistical analyses are not reported in the registry record. The record does not report the termination reason, protocol-specific sample-size justification, analysis populations, missing-data procedures, or multiplicity methods. The non-randomized, single-arm design does not provide a randomized treatment comparison.