A Study of Brentuximab Vedotin in Relapsed or Refractory Non-Hodgkin Lymphoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of Brentuximab Vedotin in Relapsed or Refractory Non-Hodgkin Lymphoma (NCT01421667), a non-randomized phase 2 study. The primary outcome is Objective Response Rate (ORR) by Investigator With Brentuximab Vedotin Monotherapy.

2. Clinical Question

The study evaluates brentuximab vedotin in several lymphoma settings rather than addressing one uniform treatment comparison. Part A concerns single-agent treatment in patients with CD30-positive non-Hodgkin lymphoma. Part B evaluates brentuximab vedotin with rituximab in relapsed or refractory DLBCL. Part C further evaluates the relationship between CD30 expression and response in DLBCL. These questions differ in population, treatment, and purpose, so results from one component should not automatically be generalized to another.

The registered primary outcome is investigator-assessed objective response rate for brentuximab vedotin monotherapy. It counts participants whose best response was complete remission or partial remission, using the response criteria described in the registry record. The primary analysis population is limited to treated participants with a baseline disease assessment and at least one post-baseline assessment. The registry record does not report the observed response percentage or its confidence interval, so the primary question cannot be answered from the posted results described in the record.

3. Trial Design

This is a phase 2, open-label, non-randomized study with a parallel model. The registry lists an enrollment of 176 and a status of completed. The recorded study start is 2011-08, and the primary completion date is 2015-06. No masking is listed. These design features describe how the trial was organized; they do not by themselves establish the size or direction of any treatment effect.

The study has distinct components. Part A evaluates brentuximab vedotin as a single agent in patients with CD30-positive non-Hodgkin lymphoma. Part B evaluates brentuximab vedotin in combination with rituximab in patients with relapsed or refractory DLBCL. Part C further evaluates the correlation between CD30 expression and response in DLBCL. The interventions listed in the registry are brentuximab vedotin and rituximab. The arm descriptions do not contain additional details.

The registered primary outcome is objective response rate by investigator with brentuximab vedotin monotherapy, measured as a percentage of participants. Listed secondary outcomes include response and complete remission with the combination, duration of response and complete remission, progression-free survival, CD30-expression correlation, adverse events, and an antibody-drug conjugate concentration measure. The record lists 14 outcome measures but no analyses. This means analyses are not listed in the registry record; it does not establish whether analyses were conducted elsewhere.

Because allocation was non-randomized, the listed groups are not a randomized comparison. Differences between groups could reflect differences in the participants or disease settings as well as treatment. The registry record does not report a protocol-based statistical plan, sample-size justification, interim analyses, or further details of allocation and analysis procedures.

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: Four additional patients enrolled, but withdrew prior to receiving treatment.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All participants who received treatment with brentuximab vedotin monotherapy and had both a baseline and at least one post-baseline disease assessment.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: All participants who received treatment.

6. Primary Endpoint

The registry lists the primary outcome as Objective Response Rate (ORR) by Investigator With Brentuximab Vedotin Monotherapy, measured over Up to approximately 3 years.

The primary endpoint is investigator-assessed objective response rate with brentuximab vedotin monotherapy. It is defined as the percentage of participants whose best response was complete remission or partial remission. The registry describes complete remission as disappearance of all evidence of disease and partial remission as regression of at least 50% of measurable disease with no new sites, according to the stated response criteria.

The endpoint is restricted to participants who received monotherapy and had both a baseline disease assessment and at least one assessment after baseline. It therefore does not automatically use all 176 enrolled participants as its denominator. The registry record gives a timeframe of up to approximately 3 years and specifies a 95% confidence interval as the measure of uncertainty. However, the observed response percentage and confidence interval are not reported in the registry record.

In general, response rate is a binary-outcome summary: each eligible participant is classified according to whether a qualifying response occurred, and the endpoint expresses the share classified as responders. It can provide a direct description of observed tumor response under the assessment rules, but it does not by itself describe how long response lasts or compare treatment with an untreated or randomized control group. Those are separate questions, reflected in some of the listed secondary outcomes.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the response rate represent?

The primary outcome is a binary response measure summarized as a percentage. For each participant in the stated analysis population, the assessment classifies the best observed response as complete remission, partial remission, or another outcome. The response rate is the proportion in the two qualifying response categories. The registry uses investigator assessment and specifies the response criteria, rather than describing an independent central review. The criteria and analysis population define what counts in the measure; they do not disclose the result.

The population is not simply everyone enrolled. It consists of participants treated with brentuximab vedotin monotherapy who had a baseline assessment and at least one post-baseline disease assessment. In general, restricting an analysis this way means that participants without the required assessments are not included in that endpoint denominator. The registry does not report how many participants met these conditions or how many had each response category.

How should the confidence interval be understood?

The registry specifies a 95% confidence interval for the primary response rate. In general, a confidence interval expresses the statistical uncertainty around an estimate. A narrower interval indicates greater precision under the method used; a wider interval indicates less precision. It does not guarantee that the true value lies inside the interval, and it is not a measure of the probability that the treatment has a particular effect. Since neither the estimated response rate nor its interval is reported in the registry record, the precision of the primary estimate cannot be evaluated.

The confidence interval also cannot resolve design limitations. It describes uncertainty in an estimate for the analyzed population, but it does not remove possible bias from outcome assessment, missing assessments, or non-random treatment assignment. In general, precision and validity are different properties: an estimate can be precise while still being affected by systematic limitations.

What does non-randomized allocation mean for interpretation?

In a randomized comparison, allocation is designed to make treatment groups comparable on average with respect to measured and unmeasured characteristics. This study is listed as non-randomized. General statistical reasoning therefore cautions against interpreting differences between its groups as treatment effects without careful consideration of group composition and analysis methods. The record itself says the arms are not a like-for-like control comparison. It does not report a randomized comparator or an adjusted analysis that would establish a comparative effect.

The open-label design means masking is listed as none. In general, knowledge of treatment assignment can influence aspects of assessment or reporting, particularly when outcomes require clinical judgment. The registry’s investigator-assessed response endpoint should therefore be read in the context of the stated open-label design. The record does not describe additional measures intended to reduce assessment bias.

Why do the different outcome types need different methods?

Objective response rate and complete remission rate are binary outcomes: participants either meet the specified outcome definition or do not. Duration of response and progression-free survival are time-to-event outcomes. In general, time-to-event methods account for the fact that follow-up may end before an event is observed for every participant. The registry names Kaplan-Meier analysis for some duration outcomes, but does not report numerical estimates or analysis details for them.

The study also names a correlation between antitumor activity and CD30 expression. A correlation analysis addresses whether measures vary together; it does not establish that one causes the other. The registry record does not state the correlation method, the expression measure, or a numerical result. The listed concentration outcome concerns a drug concentration at the end of infusion in Cycle 1 and is a different type of measure from response or safety.

What can be said about planning illustrations?

General power calculations estimate the sample size that would be needed to detect a specified effect under stated assumptions. The planning illustrations use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is a stated fraction of the observed effect. For time-to-event outcomes, the stated planning approach uses the total number of events; for other outcomes, it expresses participants per arm. These are planning illustrations, not observed power and not evidence about what the trial was designed to detect.

The registry record does not report the trial’s own sample-size justification or statistical plan. The planning assumptions therefore should not be mistaken for the protocol rationale or for proof that the study had adequate power for its outcomes. In general, power depends on assumptions about the effect, outcome variability or event rate, analysis, and design. A planning calculation cannot substitute for a reported result and its uncertainty.

Over-dispersion is a general issue for count data when observed variability exceeds what a simple model assumes. It can make standard errors too small if the model does not allow for that extra variability. The primary endpoint is a response percentage, not a count-rate endpoint, and the registry record does not identify an over-dispersion analysis. It would not be appropriate to infer that such a method was used.

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("CD30+ T-Cell NHL, BV", "CD30+ Other B-Cell NHL, BV", "CD30+ DLBCL, BV", "CD30u DLBCL, BV")
n      <- c(34, 19, 48, 52)
events <- c(14, 5, 21, 16)
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  CD30+ T-Cell NHL, BV  34  14  41.2  24.6  59.3  26.4  57.8  26.3  57.9
ARM  CD30+ Other B-Cell NHL, BV  19  5  26.3  9.1  51.2  11.8  48.8  11.9  49.1
ARM  CD30+ DLBCL, BV  48  21  43.8  29.5  58.8  30.7  57.7  30.7  57.8
ARM  CD30u DLBCL, BV  52  16  30.8  18.7  45.1  19.9  44.3  19.9  44.3

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 14 outcome measures, including response, complete remission, duration outcomes, progression-free survival, CD30-expression correlation, adverse events, and a drug concentration measure. When a study evaluates multiple outcomes, general statistical practice considers whether the analysis plan addresses multiplicity, because testing many questions can increase the chance of an apparently notable result arising by chance. The registry record does not report a multiplicity strategy, hierarchy of endpoints, or adjustment method. No adjustment should be assumed.

The registry identifies the primary response population as treated monotherapy participants with both a baseline and at least one post-baseline disease assessment. That definition makes assessment availability part of the analysis population. The record does not report the number excluded for lack of an assessment, the amount or pattern of missing data, or methods for handling missing outcomes. It is therefore not possible to judge whether missing assessments could have affected the response estimate.

The enrollment is 176, but that figure should not be substituted for the primary endpoint denominator. The primary analysis has additional eligibility requirements, and the record does not report the number meeting them. Nor does it describe analysis populations for all secondary outcomes. The listed number of analyses is 0, meaning analysis-level results are not listed in the registry record; it does not establish that no analyses were conducted.

In general, missing-data assumptions and multiplicity decisions affect how confidently results can be interpreted. The registry record does not report those details, and it does not provide the numerical primary endpoint result. These gaps prevent evaluation of the analysis population, robustness to missing assessments, or the handling of the many listed outcomes.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

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: diffuse large b-cell lymphoma (11.3%), pyrexia (8.7%), pneumonia (7.8%), escherichia urinary tract infection (6.2%), febrile neutropenia (6.2%).

The registry reports adverse-event counts for three groups: CD30+ NHL (T-Cell and B-Cell), BV; CD30u DLBCL, BV; and CD30+ DLBCL, BV+R. For the first group, 49 of 103 participants were affected by serious events, and 96 of 103 were affected by other events. For the second, the corresponding counts are 22 of 53 and 48 of 53. For the third, they are 3 of 16 and 15 of 16. These are descriptive counts within the listed groups, not randomized comparisons.

The listed serious-event terms include diffuse large B-cell lymphoma at 11.3%, pyrexia at 8.7%, pneumonia at 7.8%, Escherichia urinary tract infection at 6.2%, febrile neutropenia at 6.2%, and hyponatremia at 6.2%. The registry record does not give additional detail in the registry record about the denominator or overlap for these term percentages. A participant may have more than one event, so the listed terms should not be treated as mutually exclusive categories.

The groups differ in size and treatment setting, and the record does not establish that events were caused by treatment. Death counts are not reported in the registry record. These summaries describe the posted safety information; they do not provide a like-for-like estimate of comparative safety.

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

The record establishes that a phase 2 study evaluated brentuximab vedotin in non-Hodgkin lymphoma, including monotherapy in CD30-positive disease and a combination with rituximab in a DLBCL component. It also specifies an investigator-assessed monotherapy response endpoint, the qualifying response categories, and the population intended for that endpoint. These registry entries clarify the question the study set out to address.

The record does not report the primary response percentage or its 95% confidence interval. It therefore does not show the observed frequency of complete or partial remission in the primary analysis population or the precision of that estimate. The absence of the result in the registry record cannot be interpreted as evidence that a response did or did not occur. It means that the primary outcome cannot be quantified from the posted record.

Nor does the record support a direct causal comparison between monotherapy and combination therapy. The study is non-randomized, and the registry cautions that its arms are not a like-for-like control comparison. The components concern different settings, and no comparative estimate or adjustment method is reported. The posted adverse-event counts can describe the listed groups, but do not establish comparative risk or causation.

More generally, an endpoint definition, completed status, and enrollment figure do not replace outcome results. The study’s registered secondary questions may be relevant to response duration, progression, safety, or CD30 expression, but numerical results for them are not reported in the registry record. Interpretation should therefore remain limited to the study design, outcome definitions, and descriptive safety figures actually recorded.

14. Why This Trial Matters Statistically

This study is statistically notable for asking several related but distinct questions within one phase 2, non-randomized program. It separates monotherapy in CD30-positive non-Hodgkin lymphoma from a combination-treatment component in relapsed or refractory DLBCL and a further evaluation of CD30 expression and response. Keeping those populations and questions distinct is essential: the study does not represent one homogeneous group receiving one common regimen.

The primary endpoint illustrates why careful definition of analysis populations matters. The outcome is an investigator-assessed response percentage, but the eligible population requires treatment and both baseline and post-baseline assessment. Enrollment alone does not tell a reader how many participants contributed to that endpoint. The registry record gives the population rule but not the resulting denominator or response estimate.

The design also illustrates the distinction between descriptive and comparative evidence. A non-randomized study can describe outcomes observed in its treatment groups, but differences across groups cannot automatically be attributed to treatment when allocation is not randomized and the groups are not like-for-like controls. This matters particularly when the study includes different lymphoma settings and both single-agent and combination regimens.

Finally, a registry can identify a broad outcome program without reporting the estimates needed for statistical interpretation. Here, the listed outcomes include response, time-to-event measures, correlation, safety, and concentration. The registry record’s lack of analysis-level results leaves the primary response and its precision unavailable. Recognizing that distinction helps prevent design details and endpoint names from being mistaken for evidence about the outcomes.

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 main trial-specific limitation for interpreting efficacy is that the registry record does not report the primary objective response rate or its 95% confidence interval. It also does not report the numerical results for the listed secondary efficacy outcomes. The endpoint is defined, but the number of participants assessed and their response classifications are not stated in the record.

The study is non-randomized and open-label, with no masking listed. Its arms are explicitly not like-for-like control groups. Consequently, the design does not support a straightforward randomized treatment comparison, and investigator assessment may be influenced by the open-label setting. The registry record does not report adjustment methods or other details that would permit assessment of potential group differences.

The record does not report the statistical analysis plan, the trial’s sample-size justification, interim analyses, multiplicity handling, or missing-data methods. It also does not report how many participants met the primary endpoint’s assessment requirements. These omissions limit assessment of analysis choices, outcome precision, and the possible impact of missing assessments.

The posted safety information is descriptive and spans groups of different sizes and settings. It does not establish causality or a comparable risk contrast. Death counts are not reported in the registry record. The registry lists 14 outcome measures but 0 analyses, so analysis-level outcome estimates are not available from the record. These limitations concern what can be interpreted from the registry record; they do not establish what may have been reported elsewhere.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study of Brentuximab Vedotin in Relapsed or Refractory Non-Hodgkin Lymphoma — NCT01421667.
• Registry record last updated 2016-11-28; status last verified 2015-06.
• Results first posted 2016-10-13.
• 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

NCT01421667 is a completed phase 2, open-label, non-randomized, parallel study of brentuximab vedotin in relapsed or refractory non-Hodgkin lymphoma, with an enrollment of 176. The recorded study start is 2011-08 and primary completion is 2015-06. Study components address brentuximab vedotin monotherapy, brentuximab vedotin plus rituximab in DLBCL, and CD30 expression in relation to response.

The primary outcome is investigator-assessed objective response rate with monotherapy among treated participants with baseline and post-baseline disease assessments. The registry describes the response criteria and specifies a 95% confidence interval, but does not report the numerical primary result. Safety counts and selected serious-event percentages are listed for three groups. The registry record does not report analysis-level results, the statistical plan, missing-data methods, or the trial’s sample-size justification.