CV301 Combined With PD-1/L1 Blockade in Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for CV301 Combined With PD-1/L1 Blockade in Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer (NCT03628716), a na phase 2 study. The primary outcome is Objective Response Rate (ORR).

2. Clinical Question

3. Trial Design

This was a Phase 2, multicenter, single-arm trial of CV301 in combination with atezolizumab for locally advanced or metastatic urothelial bladder cancer. The registry lists Bavarian Nordic as the sponsor and reports enrollment of 43 participants. The study status is completed. Its recorded start date is 2018-09-18 and its primary completion date is 2020-11-03.

The study included two treatment settings. Cohort 1 addressed first-line treatment of urothelial cancer in patients not eligible for cisplatin-containing chemotherapy. Cohort 2 addressed second-line treatment after standard first-line cisplatin-based chemotherapy. Both cohorts received the same named combination, CV301 plus atezolizumab. The registry lists 19 participants at risk in Cohort 1 and 24 in Cohort 2 for the adverse-event summaries. It does not describe a randomized assignment between the cohorts or a direct treatment comparison between them.

Allocation is listed as not applicable, masking as none, and the model as single group. These features mean that the primary design estimates outcomes among people receiving the combination rather than comparing assigned treatment groups. Cohort differences in prior treatment setting and eligibility make an informal comparison between cohorts especially difficult to interpret as a treatment effect.

The primary endpoint was objective response rate, assessed by investigators using RECIST v1.1, with a timeframe of up to 24 months. Secondary outcomes include progression-free survival, overall survival, duration of response, treatment-emergent adverse events, laboratory toxicity grade shifts, and vital signs. The registry lists 11 outcome measures and no analyses. It does not report the protocol’s sample-size justification, planned statistical analysis details, or the handling of interim assessments.

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: Full Analysis Set subjects with objective response

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: The Full Analysis Set consists of all subjects taking any amount of trial vaccine

6. Primary Endpoint

The registry lists the primary outcome as Objective Response Rate (ORR), measured over up to 24 months.

Objective response rate (ORR) is defined in the registry as the proportion of participants in the Full Analysis Set with a complete response or partial response according to their best overall investigator-assessed RECIST v1.1 evaluation. The timeframe is up to 24 months. In general, ORR is a binary endpoint: each participant is classified as having an objective response or not having one under the specified criteria. The resulting proportion describes the frequency of qualifying responses in the assessed population; it does not by itself describe how long a response lasts or whether a treatment caused the response.

The record describes RECIST v1.1 measurements using the sum of the longest diameters of non-nodal target lesions and the short axis of nodal target lesions. It allows a maximum of 2 target lesions per organ and 5 target lesions overall. A complete response means disappearance of all known disease, confirmed at 4 week, with lymph nodes measuring less than 10 mm in short axis. A partial response requires at least a 30% decrease from baseline measurement, confirmed at 4 week.

ORR is commonly used to summarize tumor shrinkage under defined response criteria. It gives a clinically interpretable count-based summary, but does not capture every aspect of disease course. The registry record does not report the number of complete or partial responses, the ORR estimate, or its uncertainty. Thus, the endpoint definition is available, but the observed primary result is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a binary participant-level classification: objective response or no objective response under the registry’s RECIST v1.1 definition. In general, a binary outcome can be summarized by counting participants in each category and dividing the response count by the analysis population. The registry record gives the definition and identifies the analysis population as the Full Analysis Set, but does not report either the response count or the population size used for the primary calculation. No rate can therefore be stated from the registry record.

What does an objective response measure?

RECIST v1.1 uses specified target-lesion measurements to classify change in disease. As described in the record, the sum of longest diameters for non-nodal target lesions and short-axis measurements for nodal target lesions are used. The record allows up to 2 target lesions per organ and 5 overall. A complete response requires disappearance of all known disease, confirmed at 4 week, and lymph nodes must be less than 10 mm in short axis. A partial response requires a decrease of at least 30% from baseline measurement, confirmed at 4 week. These criteria standardize how response is classified, but investigator assessment remains the stated basis for the endpoint.

In general, the response rate is an estimate based on the participants included in the endpoint analysis. Its precision depends in part on the number of participants assessed and the number meeting the response definition. A confidence interval communicates uncertainty around an estimated response rate; it does not guarantee that the underlying value lies within the interval. The registry does not report an estimate or interval for ORR, so neither the response frequency nor its statistical precision can be assessed from this record.

What does the single-arm design allow?

A single-arm study observes outcomes in one treatment group. It can describe what happened among enrolled participants, but it does not provide a concurrent control group for estimating the difference attributable to treatment. General comparisons with outcomes from other studies can be affected by differences in eligibility, disease setting, follow-up, assessment, and patient mix. No external comparison or comparator outcome is reported in this registry record. Accordingly, the design should be read as descriptive rather than as a randomized test of CV301 plus atezolizumab against another strategy.

The study includes two distinct cohorts with different treatment histories and eligibility settings. In general, subgroup or cohort summaries can help describe variation in outcomes, but direct contrasts need careful interpretation when groups were not randomly assigned and differ by design. The registry gives cohort-specific safety counts, but does not report cohort-specific primary response results or a formal comparison between cohorts.

How should the safety counts be read?

The adverse-event record distinguishes serious adverse events from other adverse events and gives participants at risk and affected participants by cohort. These are counts, not treatment-effect estimates. In general, an adverse event occurring after treatment does not automatically establish that treatment caused it. Assessment of causality would require attribution information and clinical context, neither of which is reported in the registry record for the listed counts. The record also lists deaths, but does not state in these figures whether they were treatment-related.

Over-dispersion is a general concern when count outcomes vary more than a simple statistical model expects. It can make uncertainty estimates too narrow if a model assumes less variability than the data contain. That issue is not a reported analysis of this trial: the primary endpoint is described as a participant count/proportion, and the registry lists no analyses or model details from which to assess over-dispersion.

What can planning calculations establish?

In general, sample-size calculations are planning illustrations based on assumptions, not observed evidence and not observed power. The registry record does not report its own sample-size justification. Any separate planning illustration described for this study uses a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect expressed as a fraction of the observed effect. Time-to-event illustrations use total events; other illustrations use participants per arm. These assumptions do not match the trial’s single-arm allocation, so such illustrations should not be read as the actual design or as observed power. No numerical planning result is reported in the registry record.

Overall, the registry contains endpoint definitions and descriptive design information, but no listed statistical analyses. The planned handling of multiplicity, missing outcomes, interim looks, confidence intervals, and formal hypothesis tests is not reported in the registry record. General statistical methods can explain how such analyses might work, but cannot substitute for the absent trial-specific analysis plan or outcome estimates.

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("CV301 + Atezolizumab (Cohort 1)", "CV301 + Atezolizumab (Cohort 2)")
n      <- c(19, 24)
events <- c(1, 2)
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  CV301 + Atezolizumab (Cohort 1)  19  1  5.3  0.1  26.0  0.9  24.6  1.2  24.9
ARM  CV301 + Atezolizumab (Cohort 2)  24  2  8.3  1.0  27.0  2.3  25.8  2.5  26.0

11. Multiplicity, Missing Data and Analysis Populations

The registry lists ORR as the primary outcome and names several secondary outcomes, including progression-free survival, overall survival, duration of response, treatment-emergent adverse events, laboratory toxicity grade shifts, and vital signs. It reports 11 outcome measures in total. However, the record does not report how these outcomes were ordered for statistical testing, whether particular hypotheses were prespecified, or how multiplicity across endpoints or cohorts was addressed. A multiplicity strategy is not reported in the registry record.

Multiplicity matters in general when several statistical questions are tested: the chance of at least one apparently notable result can increase as the number of tests grows. Interpretation depends on the prespecified testing plan and the role of each outcome. Since the registry lists no analyses and does not describe a testing hierarchy or adjustment procedure, no claim about multiplicity control can be made.

The primary endpoint population is named as the Full Analysis Set, but its definition, size, and inclusion rules are not reported in the registry record. The record does not state how participants without an adequate response assessment were handled, whether missing assessments were classified as nonresponse, or how other missing outcome data were addressed. These choices can affect a binary response estimate and its interpretation.

Interim analyses, stopping criteria, and the detailed statistical analysis plan are also not reported in the registry record. Their absence from the record does not establish what procedures were or were not used outside the registry entry. It limits the ability to assess whether the posted outcomes follow a prespecified analysis strategy.

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: acute kidney injury (15.8%), confusional state (10.5%), abdominal pain (5.3%), large intestinal obstruction (5.3%), dehydration (5.3%).

The adverse-event record separates serious events from other adverse events and presents counts for each cohort. In Cohort 1, 7 of 19 participants at risk are listed with serious adverse events, and 18 of 19 with other adverse events; 11 deaths are listed. In Cohort 2, 5 of 24 are listed with serious adverse events, and 24 of 24 with other adverse events; 15 deaths are listed. These are descriptive counts, not estimates of a causal treatment effect.

The most frequent serious-event terms listed are acute kidney injury at 15.8%, confusional state at 10.5%, abdominal pain at 5.3%, large intestinal obstruction at 5.3%, dehydration at 5.3%, and fluid overload at 5.3%. The registry record does not provide the event-term details needed to determine whether participants could contribute more than one event, how terms were attributed to cohorts, or whether events were judged treatment-related. The percentages should therefore be read as registry-reported descriptive values, not as comparative risks.

Deaths are listed as counts, but the record does not specify in these figures their timing, causes, or relationship to treatment. Because the trial has no concurrent control arm, the counts cannot show whether the combination changed the likelihood of adverse events or death compared with another treatment. Differences between cohorts would also be nonrandomized and should not be interpreted as treatment contrasts.

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

The registry record establishes that a Phase 2, single-arm study of CV301 plus atezolizumab was conducted in locally advanced or metastatic urothelial bladder cancer, with 43 participants enrolled across two treatment settings. It specifies an investigator-assessed RECIST v1.1 objective response endpoint and reports descriptive safety counts. These details define the study question and some of the information collected.

What the record does not establish is the observed primary response result. The number of participants with complete or partial response, the ORR estimate, and its uncertainty are not reported in the registry record. The record also lists no analyses. It is therefore not possible to quantify response frequency, assess precision, or evaluate a formal statistical test from the posted results.

Even if a response estimate were available, a single-arm study would describe outcomes in the treated group rather than provide a randomized estimate of the treatment’s effect relative to a control. The record does not include a concurrent comparator. The two cohorts also address different settings—first-line treatment for patients not eligible for cisplatin-containing chemotherapy and second-line treatment after standard first-line cisplatin-based chemotherapy—so their outcomes would not automatically provide a like-for-like comparison.

The adverse-event counts and listed serious-event terms indicate that safety outcomes were recorded, but they do not establish causation. The listed deaths likewise do not, on their own, show treatment-related mortality. The registry record does not report attribution details for those figures.

In general, a result can be statistically uncertain even when expressed as a simple proportion, particularly when the assessed population is limited or incompletely described. Here, the primary result and its uncertainty are not reported, so no conclusion about the size or precision of an observed response can be drawn from the registry entry. Missing analysis details also prevent assessment of endpoint hierarchy, missing-data handling, or formal inference. The record supports a description of the design and recorded counts, not a conclusion about comparative effectiveness.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of the distinction between an endpoint definition and an endpoint result. The registry gives a detailed definition of objective response, including investigator assessment under RECIST v1.1, but does not report the response count or rate. A clearly defined measure is necessary for interpretation, yet it is not sufficient to establish what was observed. Readers also need the analyzed population, the estimate, and an account of uncertainty.

The single-arm design is another important statistical feature. It can describe outcomes among participants receiving a combination, but does not create a randomized control comparison. This distinction matters when interpreting outcomes in a disease setting where patient eligibility and prior treatment differ. Cohort 1 and Cohort 2 have different clinical contexts, and their results cannot be treated as a direct comparison simply because both received the same named combination.

The record also illustrates why safety counts require careful framing. Counts of participants with serious or other adverse events, listed event terms, and deaths provide descriptive information. Without a concurrent control and treatment-attribution details, these figures do not isolate the contribution of the study treatment. Nor do cohort counts alone support a causal comparison.

Finally, the registry identifies multiple secondary outcomes but does not report the analysis plan, missing-data procedures, or multiplicity approach. In general, those methods affect how outcome estimates and statistical evidence should be interpreted. Their absence from the registry record limits reproducibility and critical appraisal. The available design information is useful, but the missing primary result and analysis details place a firm boundary on statistical conclusions.

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 the lack of a reported primary endpoint result. The registry defines ORR but does not report a response count, rate, confidence interval, or test. It lists no analyses, so the statistical evidence for the primary question cannot be evaluated from the registry record.

The single-arm design has no concurrent control group. Outcomes in the combination arm cannot be separated from influences such as patient selection, natural disease course, or other factors using this design alone. The study’s two cohorts also represent different treatment settings: first-line use for patients not eligible for cisplatin-containing chemotherapy and second-line use after standard first-line cisplatin-based chemotherapy. The record does not provide cohort-specific primary response results.

The registry names the Full Analysis Set but does not define it or give its size. It does not describe how unevaluable participants, missing assessments, or missing outcome data were handled. The methods for multiplicity, interim analyses, and the statistical analysis plan are also not reported in the registry record. This prevents assessment of whether analyses followed prespecified rules.

For safety, the record provides participant counts, event terms, percentages for listed serious events, and deaths. It does not provide enough information in those summaries to establish event causality, timing, or a controlled comparative risk. The listed counts should therefore remain descriptive.

The registry does not report its sample-size justification. Any planning illustration based on assumed allocation and a fraction of an observed effect is not a substitute for the trial’s own design rationale or an observed outcome. No numerical planning estimate or observed-power result is reported in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: CV301 Combined With PD-1/L1 Blockade in Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer — NCT03628716.
• Registry record last updated 2022-04-27; status last verified 2022-03.
• Results first posted 2022-04-27.
• 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 describes NCT03628716 as a completed Phase 2, multicenter, single-arm trial sponsored by Bavarian Nordic. It enrolled 43 participants with locally advanced or metastatic urothelial bladder cancer and evaluated CV301 with atezolizumab. Cohort 1 concerned first-line treatment for patients not eligible for cisplatin-containing chemotherapy; Cohort 2 concerned second-line treatment after standard first-line cisplatin-based chemotherapy.

The primary endpoint was investigator-assessed RECIST v1.1 objective response rate, with assessment up to 24 months. The registry record defines complete and partial response but does not report the primary response count, estimate, or uncertainty. It lists secondary outcomes and descriptive adverse-event counts, but no statistical analyses. The endpoint definition and trial design are available; the primary outcome result, detailed analysis methods, and missing-data procedures are not reported in the registry record.