Brentuximab Vedotin and Chemotherapy in CD30+ PMBL, Diffuse Large B-Cell, and Grey Zone Lymphoma Patients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Brentuximab Vedotin and Chemotherapy in CD30+ PMBL, Diffuse Large B-Cell, and Grey Zone Lymphoma Patients (NCT01994850), a na phase 1, phase 2 study. The primary outcome is Number of Subjects With Dose-limiting Toxicities.

2. Clinical Question

The registry record describes a study of brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin and prednisone (R-CHP) as front-line treatment for people with CD30-positive primary mediastinal large B-cell lymphoma, diffuse large B-cell lymphoma, or grey zone lymphoma. Its central early-phase question was whether the brentuximab vedotin dose used in the Phase I cohort produced dose-limiting toxicity during Cycle 1. This safety assessment was intended to inform use of the dose in the Phase II cohort; the record states that Phase I participants were included in the efficacy analysis after no DLTs were observed.

The posted primary outcome is a count of participants with dose-limiting toxicities during 21 days (Cycle 1). The registry defines a DLT as a new grade 3 or 4 non-hematologic toxicity during Cycle 1 that requires a dose delay of >14 days from the planned start of Cycle 2. The Phase I cohort began at 1.8 mg/kg; the record says de-escalation to 1.2 mg/kg would occur if at least 2 of 6 participants at the initial dose level experienced a DLT. The registry reports no DLTs among the 6 Phase I participants assessed.

This was not a randomized comparison. There was no concurrent control group against which to estimate the effect of adding brentuximab vedotin to chemotherapy, and the record does not report a comparative treatment-effect estimate. The central question supported by the posted primary outcome is therefore narrow: whether a DLT meeting the registry definition was observed during the specified first-cycle assessment in the Phase I cohort. The registry record does not report a primary efficacy result in the registry record for this analysis.

3. Trial Design

The registry classifies this as a Phase I/II, multicenter, single-arm, non-randomized, open-label study. The recorded enrollment is 32. The study is marked completed, with a start date of 2013-11 and a primary completion date of 2017-08. The sponsor is Abramson Cancer Center at Penn Medicine. Allocation is listed as not applicable, consistent with the absence of randomized treatment groups.

The intervention combined brentuximab vedotin with rituximab, cyclophosphamide, doxorubicin and prednisone. The described regimen was six 21-day cycles. For Cycle 1, the rituximab dose was divided between Days 1 and 2 for rituximab-naive participants to prevent severe infusion reactions. The available arm description ends before giving further administration details, so the registry record does not report those details in the information available for this analysis.

The Phase I portion assessed DLTs in the first cycle. The initial planned brentuximab vedotin dose for that cohort was 1.8 mg/kg. According to the record, de-escalation to 1.2 mg/kg was to occur if at least 2 of 6 participants at the initial dose level experienced a DLT. The record reports that no DLTs were observed among the 6 Phase I participants. It also states that those participants were included in the efficacy analysis because they received the same 1.8 mg/kg dose as the Phase II participants.

There is no randomized control group, and masking is listed as none. The study can describe outcomes observed among participants receiving the combination, but its design cannot separate the contribution of brentuximab vedotin from the contribution of the chemotherapy regimen or other influences. The registry record does not report a statistical analysis plan, interim analyses, or a sample-size justification. The posted record lists 2 outcome measures and 0 analyses.

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: A total of 6 subjects were evaluated for dose limiting toxicities during Phase I. Since no DLTs were observed, the Phase I subjects were included in the efficacy analysis as they received the same dose of brentuximab vedotin 1.8 mg/kg as the Phase II subjects.

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 Number of Subjects With Dose-limiting Toxicities, measured over 21 days (Cycle 1).

The primary endpoint is the number of participants with dose-limiting toxicities during 21 days (Cycle 1). It is a count endpoint, rather than a time-to-event or continuous measurement. The registry defines a DLT as a new grade 3 or 4 non-hematologic toxicity arising during Cycle 1 that requires a dose delay of >14 days from the planned Day 1 of Cycle 2.

In an early-phase study, a DLT endpoint is used to characterize treatment tolerability during a specified initial exposure period and to guide decisions about dose levels. The record describes an initial brentuximab vedotin dose of 1.8 mg/kg in a Phase I cohort of 6 participants, with planned de-escalation to 1.2 mg/kg if at least 2 of 6 had a DLT. This makes the endpoint a rule-based safety measure: only toxicities meeting the stated severity, type, timing and dose-delay criteria count as DLTs.

The registry reports no DLTs among the 6 Phase I participants assessed. That result applies to the endpoint definition and observation window; it does not mean that no other toxicity occurred. The separate adverse-event record lists serious and other adverse events. DLTs are not interchangeable with all adverse events because an event must satisfy the specific DLT criteria to count toward this primary endpoint. The registry record does not report further endpoint details, such as how incomplete Cycle 1 observation would have been handled.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record describes a Phase I/II study with a single treatment group and no masking. The primary outcome is a participant count, not an estimate comparing randomized groups. The methods used to analyze that endpoint are not reported in the registry record beyond the stated DLT definition and dose-de-escalation rule.

What does a participant count convey?

A count states how many participants met an outcome definition. It is straightforward to interpret descriptively, but its meaning depends on both the definition and the number of participants observed. In this study, the reported count is no DLTs among the 6 Phase I participants evaluated. The endpoint is not a count of every adverse event; it counts only events satisfying the registry’s DLT criteria during Cycle 1.

General statistical explanation: a count from a cohort is an observed result, not a guarantee about the underlying risk in other participants. A confidence interval, when reported, communicates the range of values reasonably compatible with the data under a statistical model. The registry record does not report a confidence interval for the DLT outcome. No interval should be treated as a registry result unless it is explicitly reported.

Why does the endpoint definition matter?

The DLT definition combines several requirements: the toxicity must be new, non-hematologic, grade 3 or 4, occur during Cycle 1 and require a dose delay of >14 days from the planned Day 1 of Cycle 2. A toxicity outside any of those conditions would not qualify under this definition, even though it could still be clinically important or appear in the adverse-event record. This is why a DLT count and a broader adverse-event summary answer different questions.

The definition also fixes the observation window. The primary outcome concerns 21 days (Cycle 1), not the full duration of the six-cycle regimen or follow-up after treatment. A result about that period should not be extended to later cycles without corresponding data. The registry record does not report the timing or completeness of follow-up for participants who may not have completed the planned observation window.

What can a single-group design estimate?

General statistical explanation: a single-group study can describe outcomes among people receiving a regimen. It does not include the concurrent untreated or alternative-treatment group needed for a direct randomized comparison. Without such a comparator, differences from an external expectation can reflect patient selection, disease characteristics, supportive care, measurement, or other influences, as well as treatment.

Here, allocation is listed as not applicable, masking as none, and the study model as single group. Consequently, the posted results cannot isolate the effect of brentuximab vedotin from the accompanying R-CHP regimen. No comparative treatment estimate or randomized analysis is reported in the registry record.

How should uncertainty be understood?

General statistical explanation: estimates based on a limited sample are uncertain, and uncertainty is usually made visible through an interval estimate or a model-based analysis. A point observation alone does not show how precisely the underlying event frequency has been estimated. The record reports the DLT count but does not report an interval estimate, hypothesis test, or analysis model for it. The result is therefore best read as a descriptive count rather than a precise estimate of a population rate.

The registry record lists 0 analyses. It does not report a prespecified statistical analysis plan, methods for handling missing outcome observations, or an approach to multiplicity. Those omissions limit what can be said about inferential procedures. They do not change the descriptive DLT count, but they prevent a fuller assessment of how outcomes were selected, analyzed and interpreted.

What do planning illustrations represent?

General statistical explanation: sample-size calculations can illustrate how many participants might be needed to detect an assumed effect under stated modeling choices. They are planning exercises, not evidence that a study achieved a particular probability of detecting an effect. The listed illustration assumptions are a two-sided significance level of 0.05, equal allocation between two arms and a normal approximation, with the target effect expressed as a fraction of the observed effect. These assumptions describe an illustration and are not reported as the trial’s own design or statistical plan.

Those hypothetical assumptions do not match the registry’s single-group design, which has no two-arm allocation. The registry record does not report that the trial was designed using those assumptions, nor does it report a sample-size justification. Any planning illustration should therefore be kept separate from the observed clinical results and should not be interpreted as observed power.

Finally, the record’s statement that Phase I participants were included in the efficacy analysis because they received the same dose as Phase II participants does not provide details of an efficacy analysis. The outcome measures include 2, but the registry record lists 0 analyses in the registry record for this interpretation. The efficacy analysis methods and results are not 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("Phase I/II")
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  Phase I/II  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 record lists 2 outcome measures, but the registry entries available for this analysis identify a primary DLT endpoint and do not describe the other outcome measure in detail. The record lists 0 analyses. It does not report a multiplicity adjustment, a hierarchy of outcomes, or a plan for controlling the chance of false-positive findings across multiple outcomes. It is therefore not possible to determine from the registry record whether multiplicity was addressed in the study’s analyses.

Missing-data methods are not reported in the registry record. The DLT outcome is defined for the Cycle 1 period, but the available information does not state how participants with incomplete observation, early discontinuation, or unavailable toxicity assessments were handled. The reported result is no DLTs among the 6 Phase I participants evaluated; the record does not provide additional detail about outcome availability or missingness.

The record states that Phase I participants were included in the efficacy analysis because they received the same 1.8 mg/kg brentuximab vedotin dose as Phase II participants. It does not describe eligibility rules for the efficacy analysis, an intention-to-treat or per-protocol population, or how deviations from treatment were handled. Those analysis-population details are not reported in the registry record.

Without a reported analysis plan, missing-data approach and population definition, readers cannot assess whether the posted outcomes reflect a prespecified analysis or how incomplete data might affect interpretation. The descriptive DLT count remains the reported result, but these methodological details are unavailable.

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: febrile neutropenia (19.4%), fever (3.2%), left ventricular systolic dysfunction (3.2%), abdominal infection (3.2%), gum infection (3.2%).

The registry lists 31 participants at risk for serious adverse events, with 12 affected, and 31 at risk for other adverse events, with 29 affected. It also lists 2 deaths. These are separate entries in the posted safety record; the registry information does not state whether the deaths were attributed to treatment or provide further context about their timing or causes. The counts should not be combined with the primary DLT count, which concerns a narrower event definition and the Cycle 1 assessment.

The listed serious adverse-event terms and percentages are febrile neutropenia, 19.4%; fever, 3.2%; left ventricular systolic dysfunction, 3.2%; abdominal infection, 3.2%; gum infection, 3.2%; and urinary tract infection, 3.2%. These term-level percentages are presented as recorded, without recalculating them. The record information does not specify additional details about event severity, duration, recurrence, attribution, or overlap among participants.

Serious adverse-event summaries describe reported safety events; they do not establish that a treatment caused an event. The single-group design also means these figures cannot be compared with a concurrent control group. Their interpretation is limited to the recorded study group and the definitions used in the registry.

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

The primary result establishes that no DLT meeting the registry definition was observed among the 6 Phase I participants assessed during Cycle 1. The definition applies to a particular type and grade of toxicity that requires a dose delay of >14 days. The finding is useful as a description of the early-cycle safety experience under that rule and observation period.

It does not establish that the regimen produced no adverse effects. The registry separately lists serious and other adverse events, and the DLT endpoint does not include every event that may occur during treatment. The posted safety figures include 12 participants affected by serious adverse events among 31 at risk, 29 affected by other adverse events among 31 at risk, and 2 deaths. The registry information does not establish causal attribution for these events or deaths.

The result also does not establish the frequency of DLTs in a larger or different population. The primary DLT observation comes from the Phase I cohort, and the registry record does not report an uncertainty interval. The result should not be treated as proof that the underlying risk is zero or that later treatment cycles have the same safety experience.

Nor does this study provide a randomized estimate of comparative benefit or harm. It used a single group receiving brentuximab vedotin with R-CHP, with no concurrent control. Outcomes cannot be attributed specifically to brentuximab vedotin or compared fairly with another regimen using this design alone. The available registry information does not report an efficacy result, so it cannot establish whether the combination changed disease outcomes.

The supported conclusion is limited: the registry reports no Cycle 1 DLTs in the assessed Phase I cohort, alongside separate adverse-event summaries for the study group. The endpoint definition, cohort size, observation window, absence of a comparator and lack of reported inferential methods all matter when deciding how broadly to interpret that observation.

14. Why This Trial Matters Statistically

This study illustrates how early-phase clinical research can use a tightly defined toxicity endpoint to guide dose decisions. The DLT rule specifies which toxicities count, when they must occur and what treatment consequence qualifies them. That specificity makes the endpoint interpretable as a decision-oriented safety measure, while also making clear that it is not a complete summary of all harms.

The registry’s report of no DLTs among the 6 Phase I participants illustrates the difference between an observed count and a population-level conclusion. A zero observed count is still an observation from a limited cohort. Without an uncertainty interval or additional modeling, it should not be converted into a claim that the underlying event risk is absent. The record provides the count but does not report a statistical interval or test.

The trial also highlights the limits of single-group evidence. A combination regimen may be studied in an early-phase setting to describe its use and safety, but without a concurrent comparator the design cannot estimate the treatment contrast that a randomized trial would target. Because brentuximab vedotin was administered with R-CHP, the effect of one component cannot be isolated from the combination in these data.

Finally, the registry record distinguishes the primary DLT outcome from its broader adverse-event reporting. A DLT definition is not interchangeable with serious adverse-event counts, other adverse-event counts, or deaths. Keeping these measures separate is essential for clear statistical interpretation. The available record is informative about what was observed and how the primary outcome was defined, while leaving efficacy, comparative effects, analysis methods and several safety details unreported.

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 important design limitation is the absence of a concurrent comparator. The trial is single-group, non-randomized and open-label, so the posted outcomes cannot establish comparative treatment effects or separate the contribution of brentuximab vedotin from R-CHP. The design also does not support a like-for-like comparison with another regimen.

The primary endpoint is limited to DLTs during 21 days (Cycle 1), using a specific definition based on toxicity type, grade and dose delay. It does not capture all adverse events or describe safety over the full six-cycle regimen. The registry record does not report how incomplete Cycle 1 observation was handled, or whether any participants had missing endpoint data.

The DLT finding comes from 6 Phase I participants. The registry reports no DLTs in that cohort but does not report an uncertainty interval or an inferential analysis. The posted count therefore has limited precision as an estimate of experience beyond the assessed cohort.

Other important details are not reported in the registry record, including a statistical analysis plan, a sample-size justification, multiplicity methods, missing-data methods and detailed definitions of analysis populations. Although the record states that Phase I participants were included in the efficacy analysis, the available information does not describe the efficacy results or analysis methods. The serious adverse-event entries also lack further context about attribution, timing and overlap among participants.

These limitations mean the record supports a narrow descriptive reading of the DLT and adverse-event information, rather than a broad conclusion about comparative efficacy or safety.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Brentuximab Vedotin and Chemotherapy in CD30+ PMBL, Diffuse Large B-Cell, and Grey Zone Lymphoma Patients — NCT01994850.
• Registry record last updated 2021-01-05; status last verified 2020-12.
• Results first posted 2019-09-17.
• 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 a completed Phase I/II, multicenter, single-arm, non-randomized, open-label study of brentuximab vedotin combined with R-CHP for CD30-positive primary mediastinal large B-cell lymphoma, diffuse large B-cell lymphoma and grey zone lymphoma. Recorded enrollment was 32. The study ran from 2013-11 to a primary completion date of 2017-08.

The primary outcome was the number of participants with DLTs during 21 days (Cycle 1). The registry reports no DLTs among the 6 Phase I participants evaluated. It separately lists serious and other adverse-event counts and terms. There is no concurrent comparator, and the record lists 0 analyses. Efficacy results, detailed analysis methods, missing-data procedures and a sample-size justification are not reported in the registry record.