A Study of Nivolumab Plus Brentuximab Vedotin in Patients Between 5 and 30 Years Old, With Hodgkin's Lymphoma (cHL), Relapsed or Refractory From First Line Treatment: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of Nivolumab Plus Brentuximab Vedotin in Patients Between 5 and 30 Years Old, With Hodgkin's Lymphoma (cHL), Relapsed or Refractory From First Line Treatment (NCT02927769), a non-randomized phase 2 study. The primary outcome is Complete Metabolic Response (CMR) Rate at Any Time Prior to Radiation Therapy by Blinded Independent Centralized Review (BICR) - Cohort 1.

2. Clinical Question

The endpoint was assessed from first dose until complete metabolic response or completion of six cycles of therapy, up to approximately 18 weeks. The registry describes the primary endpoint as prespecified for Cohort 1 only. It does not report the numerical response rate or its confidence interval, so the primary question cannot be answered from the posted results.

The study also included a standard-risk relapse cohort and listed other outcomes, including overall response, progression-free survival, duration of response, event-free survival, and complete metabolic response assessed at other points or by an investigator. These outcomes address different aspects of response and follow-up; they should not be treated as interchangeable with the primary Cohort 1 endpoint.

Because treatment assignment was not randomized, comparisons between the cohorts or treatment pathways would not isolate the effect of one regimen from differences in participant risk, response, or treatment sequence. The study is therefore best read as a response-adapted phase II investigation rather than a randomized comparative trial.

3. Trial Design

This was a phase II, open-label, non-randomized study with a parallel design. It enrolled participants between 5 and 30 years old with relapsed or refractory classic Hodgkin lymphoma after first-line treatment. The registry lists an enrollment of 72 and describes two risk groups: Cohort 1 for low-risk relapse and Cohort 2 for standard-risk relapse. It does not report the criteria used to assign risk categories.

The treatment pathway began with nivolumab plus brentuximab vedotin. Participants described as having a suboptimal response could receive brentuximab vedotin plus bendamustine. This response-adapted sequence means that not all participants necessarily followed the same treatment course. The registry does not provide arm descriptions specifying the detailed regimens, dosing, or rules for moving to the subsequent treatment.

The primary endpoint was the complete metabolic response rate before radiation therapy, assessed by blinded independent centralized review in Cohort 1. The registry identifies the primary population as all treated participants in Cohort 1, while its endpoint definition describes the rate among response-evaluable participants. How those population descriptions were reconciled in the actual analysis is not reported in the registry record. The endpoint timeframe extended from first dose until complete metabolic response or completion of six cycles, up to approximately 18 weeks.

The registry record lists the study as completed, with a start date of 2017-03-28 and a primary completion date of 2024-05-28. It lists 17 outcome measures, including response and time-to-event outcomes. The record does not report the study’s sample-size justification, its detailed statistical analysis plan, or numerical primary endpoint results. Since assignment was non-randomized and masking was absent, interpretation should account for the descriptive, response-adapted nature of the design.

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: All participants entered the Induction phase and received treatment with nivolumab + brentuximab vedotin (N+ Bv) Participants moved into the Intensification phase if they received treatment with brentuximab + bendamustine (Bv + B). Participants moved into the Consolidation Phase if they received radiation therapy (Cohort 1) or high-dose chemotherapy followed by an autologous stem cell transplant (HDCT/ASCT) (Cohort 2).

Induction Phase

Reasons for not completing this period:

Consolidation Phase

Intensification Phase

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All treated participants in Cohort 1. Prespecified to be collected for Cohort 1 only.

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 Complete Metabolic Response (CMR) Rate at Any Time Prior to Radiation Therapy by Blinded Independent Centralized Review (BICR) - Cohort 1, measured over From first dose to complete metabolic response or the completion of six cycles of therapy (up to approximately 18 weeks)..

The primary endpoint was the complete metabolic response rate in Cohort 1 before radiation therapy, assessed by blinded independent centralized review. It was defined as the percentage of response-evaluable participants whose best response was complete metabolic response. The registry’s criteria describe metabolic findings at lymph nodes and other sites, new lesions, and bone marrow. A participant who stopped treatment early because of toxicity without achieving complete metabolic response was still considered evaluable.

A response rate condenses participant-level outcomes into the proportion meeting a defined response criterion. It can provide a focused description of activity over a specified assessment period, but it does not by itself describe how long a response lasts, whether disease later progresses, or the balance of benefits and harms. The registry lists duration of response and progression-free survival separately, reflecting that these are distinct questions.

The endpoint’s population wording merits attention. The registry identifies all treated participants in Cohort 1 as the primary population, but defines the rate using response-evaluable participants. The number included in that denominator and the handling of participants with unavailable assessments are not reported in the registry record. Those details matter because the percentage depends on which participants are counted.

The registry specifies a 90% confidence interval using the Clopper and Pearson method. A confidence interval expresses uncertainty around an estimated response rate; it is not a guarantee that the true rate lies within the interval. Because the numerical estimate and interval are not reported, the precision of the primary endpoint cannot be assessed from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a binary response measure: each evaluable participant either met the complete metabolic response definition or did not. In general, a response rate is estimated by dividing the number meeting the outcome definition by the number included in the analysis denominator. The registry does not report either count for the primary endpoint, so no response rate can be interpreted from this record.

What does the confidence interval describe?

The registry specifies a 90% confidence interval for the primary response rate. In general, a confidence interval conveys sampling uncertainty around an estimate: intervals that are wider indicate less precision, while narrower intervals indicate greater precision under the method’s assumptions. The interval does not express the probability that a particular treatment effect is true, and it does not account automatically for design limitations such as non-random treatment assignment.

The specified method is Clopper and Pearson, an exact method for a binomial proportion. In general, exact methods construct an interval from the binomial distribution rather than relying on a large-sample normal approximation. The method can be conservative, meaning that its actual coverage can exceed the nominal confidence level in some settings. The registry record does not report the resulting interval, so its width and the precision of the primary estimate cannot be assessed.

Why does the denominator matter?

The endpoint definition states that the rate is calculated among response-evaluable participants, while the primary population description says all treated participants in Cohort 1. These descriptions are not identical. In general, excluding participants without an evaluable response assessment can change the denominator and may affect the estimated rate, particularly if missing assessments are related to response or treatment experience. The registry does not explain how this distinction was handled, how many participants were response-evaluable, or how missing assessments were treated.

The description that participants who stopped treatment early for toxicity without a complete metabolic response remained evaluable clarifies one aspect of the endpoint definition. It does not resolve how other circumstances, such as unavailable or incomplete assessments, were handled. Those rules are not reported in the registry record.

What does blinded independent review contribute?

In general, independent centralized review can apply common assessment criteria across participants and reduce reliance on judgments made solely by the treating investigator. Blinding can reduce the influence of knowledge about treatment on outcome assessment. These features concern outcome measurement; they do not make treatment assignment random, remove differences between cohorts, or eliminate all possible sources of bias. The registry identifies blinded independent centralized review for the primary Cohort 1 endpoint, but does not describe its procedures in detail.

How should the study structure affect comparisons?

Randomization, in general, helps balance both measured and unmeasured participant characteristics between treatment groups. This study was non-randomized, and the subsequent treatment depended on response to the initial regimen. Participants receiving brentuximab vedotin plus bendamustine were therefore selected based on their response history. Comparing their outcomes with outcomes among participants who did not receive that regimen would not provide an unconfounded estimate of a treatment effect.

The study is also open-label, so participants and treating clinicians were not masked to treatment. For an outcome assessed by a blinded central reviewer, that review may limit some assessment-related influence, but it does not remove possible influences on care, treatment decisions, or other outcomes. The registry does not report an adjusted comparative analysis, and its record cautions that the arms are not like-for-like controls.

What do planning calculations mean?

In general, a sample-size planning illustration describes how many participants might be needed under stated assumptions to detect a specified effect with a chosen statistical method. It is not the same as the number enrolled, and it is not observed power. A calculation based on an observed effect is especially dependent on that estimate and should not be read as independent confirmation of it. The registry record does not report the trial’s own sample-size justification. Any planning illustration should therefore be understood as a hypothetical calculation under its stated assumptions, not as evidence that the trial was designed around those assumptions or that it had a particular probability of detecting an effect.

The record does not report the statistical analysis plan in enough detail to establish whether analyses were adjusted, how subgroup analyses were handled, or how uncertainty was addressed across multiple outcomes. The listed endpoints include both response proportions and time-to-event outcomes; these require different statistical summaries and should be interpreted according to their own definitions. No numerical analysis for the primary endpoint is reported in the registry record.

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: Relapsed/Refractory Classic Hodgkin Lymp")
n      <- c(28)
events <- c(26)
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: Relapsed/Refractory Classic Hodgkin Lymp  28  26  92.9  76.5  99.1  77.4  98.0  77.2  97.8

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 17 outcome measures, including several response measures and time-to-event outcomes. When a study evaluates multiple outcomes, the chance of obtaining at least one apparently notable result can be affected by how many statistical tests are performed and how results are selected or emphasized. In general, a prespecified hierarchy, adjustment procedure, or clear distinction between primary and exploratory outcomes can help readers interpret this issue. The registry identifies one primary endpoint, but a detailed multiplicity strategy is not reported in the registry record.

The record does not report a detailed statistical analysis plan, including whether secondary outcomes were subject to any multiplicity adjustment, which analyses were confirmatory, or how subgroup comparisons were intended to be interpreted. The presence of multiple outcomes does not itself make an individual estimate invalid, but it affects how much weight should be placed on isolated findings, especially when the analysis plan is unavailable.

Missing-data handling is also not reported. The primary endpoint definition includes an evaluability concept and states that participants stopping early for toxicity without a complete metabolic response were evaluable. The record does not explain the treatment of other unavailable assessments or reconcile the response-evaluable denominator with the stated population of all treated participants in Cohort 1. This matters because different denominator rules can change a response-rate estimate.

The record does not describe interim analyses, stopping rules, or any imputation or sensitivity analyses. Those features should not be assumed. Without the numerical outcome results, denominator details, and analysis plan, readers cannot assess the practical effect of missing data or multiplicity on the primary inference.

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: pyrexia (50.0%), otitis media (16.7%), infusion related reaction (16.7%), pain in extremity (16.7%), acute kidney injury (16.7%).

The registry reports serious adverse event figures separately for the listed cohort and treatment-pathway groups. For Cohort 1 receiving nivolumab plus brentuximab vedotin, 6 of 22 participants at risk were affected by serious adverse events; the group also records 18 other adverse events among 22 at risk and 0 deaths. For the Cohort 1 group that also received brentuximab vedotin plus bendamustine, 3 of 6 were affected by serious adverse events, 6 of 6 had other adverse events, and 0 deaths were recorded.

For Cohort 2 receiving nivolumab plus brentuximab vedotin, 11 of 33 were affected by serious adverse events, 33 of 33 had other adverse events, and 0 deaths were recorded. For the Cohort 2 group that also received brentuximab vedotin plus bendamustine, 4 of 11 were affected by serious adverse events, 11 of 11 had other adverse events, and 1 death was recorded.

The registry lists pyrexia at 50.0% among the top serious event terms, followed by otitis media, infusion related reaction, pain in extremity, acute kidney injury, and urticaria, each at 16.7%. The denominator and event-count basis for these percentages are not reported in the registry record. These summaries should not be treated as comparative treatment risks: the groups differ by cohort and response-adapted treatment, and event timing and exposure details are not given.

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

The registry record establishes what the study set out to evaluate: a response-adapted treatment pathway for young people with relapsed or refractory classic Hodgkin lymphoma after first-line treatment. It identifies complete metabolic response before radiation therapy in Cohort 1 as the primary endpoint and specifies independent centralized review and a confidence-interval method. Those details define the intended question, but they do not supply its answer.

The numerical primary response estimate and its confidence interval are not reported in the registry record. The record therefore cannot show the observed frequency of complete metabolic response or the precision of that estimate. The missing result should not be interpreted as a zero response, an unsuccessful treatment, or evidence of no effect. It means that this record does not contain the outcome information needed to judge the endpoint.

The non-randomized design also limits what can be inferred by comparing participants who followed different treatment pathways. The additional regimen was intended for participants with a suboptimal response, so those receiving it were selected after treatment began. Differences between groups could reflect response history or cohort risk as well as treatment. The study design does not provide a randomized estimate of the relative effect of the regimens.

Likewise, the safety figures are descriptive. They report affected participants and events within the registry’s groupings, but do not establish causation or support a fair comparison between pathways. The registry does not provide detailed exposure time, event timing, or the denominator basis for the listed serious event-term percentages.

The appropriate reading is therefore bounded: the record describes a phase II, open-label, non-randomized study, its response-adapted pathway, and its planned outcomes. It does not report the numerical primary efficacy result or enough analysis detail to assess missing data, multiplicity, or comparative effects. Any broader conclusion about efficacy or comparative safety would go beyond the information reported in the registry record.

14. Why This Trial Matters Statistically

This trial illustrates why an endpoint’s definition and analysis population matter as much as its label. “Complete metabolic response rate” sounds straightforward, but interpretation depends on assessment criteria, who evaluates response, the time window, and who is counted in the denominator. Here the registry specifies blinded independent centralized review and a defined assessment period, while describing the population as all treated participants in Cohort 1 and the rate as applying to response-evaluable participants. The unresolved difference highlights the need for clear reporting of analysis populations.

The design also demonstrates the statistical challenges of response-adapted treatment. A subsequent regimen is given according to response to the initial treatment, so the participants receiving it are not exchangeable with those who do not. Treating the resulting pathways as simple comparison arms would ignore selection into treatment and differences in treatment history. This is a useful distinction between describing outcomes in a clinical pathway and estimating a causal treatment contrast.

The study’s multiple outcomes provide different views of response and follow-up, including response proportions, duration of response, progression-free survival, and event-free survival. In general, each addresses a distinct question, and the interpretation of a set of outcomes depends on prespecification and multiplicity planning. The registry identifies a primary endpoint but does not report the detailed analysis plan or numerical results needed to assess the full evidence.

Finally, the record illustrates that a completed study listing is not equivalent to a complete results report. Design information can clarify what was intended, but without the primary estimate, confidence interval, and denominator details, readers cannot judge the result’s magnitude or precision. Statistical transparency requires both a clear question and sufficient outcome reporting to evaluate the answer.

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 most consequential limitation for interpreting this record is the absence of numerical results for the primary endpoint. Although the endpoint, assessment window, review method, and confidence-interval approach are specified, the response count, rate, and interval are not reported. The record therefore does not permit evaluation of the primary estimate or its precision.

The stated primary population and endpoint denominator are described differently: the population is all treated participants in Cohort 1, while the rate is defined among response-evaluable participants. The registry does not report the denominator used, explain how those definitions align, or describe handling of unavailable assessments beyond the statement about early discontinuation for toxicity without complete metabolic response.

Non-randomized assignment and response-dependent treatment create limits on comparisons. The low-risk and standard-risk cohorts differ by their stated risk category, and receipt of brentuximab vedotin plus bendamustine depends on suboptimal response. Outcomes across these groups cannot be interpreted as an unbiased comparison of treatment effects. Open-label conduct may also influence aspects of care or assessment; blinded central review is specified for the primary endpoint, but does not address every possible source of bias.

The registry does not report the detailed sample-size justification, statistical analysis plan, multiplicity approach, interim analyses, or missing-data sensitivity analyses. It also does not provide detailed dosing, treatment-transition rules, or the denominator basis for the listed serious event-term percentages. These omissions limit assessment of analytic decisions and safety comparisons. The registry’s completed status and enrollment figure do not substitute for the missing outcome estimates.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study of Nivolumab Plus Brentuximab Vedotin in Patients Between 5 and 30 Years Old, With Hodgkin's Lymphoma (cHL), Relapsed or Refractory From First Line Treatment — NCT02927769.
• Registry record last updated 2025-02-10; status last verified 2025-01.
• Results first posted 2025-02-10.
• 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 phase II, open-label, non-randomized study of nivolumab plus brentuximab vedotin, with brentuximab vedotin plus bendamustine for participants with a suboptimal response. The study enrolled participants between 5 and 30 years old with relapsed or refractory classic Hodgkin lymphoma after first-line treatment, across low-risk relapse and standard-risk relapse cohorts.

The primary endpoint was the complete metabolic response rate before radiation therapy in Cohort 1, assessed by blinded independent centralized review. The registry specifies a 90% Clopper and Pearson confidence interval, but does not report the numerical response rate or interval. It lists 17 outcome measures and provides descriptive serious adverse event figures for the treatment-pathway groups.

Because treatment assignment was non-randomized and subsequent treatment depended on response, the pathways are not like-for-like control groups. The registry does not report the detailed analysis plan, primary endpoint denominator, or missing-data and multiplicity procedures. Its design and endpoint can be described, but the primary result’s magnitude and precision cannot be assessed from the registry record.