Ublituximab Followed by Response-driven Addition of Umbralisib for Treatment-naive Follicular or Marginal Zone Lymphoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Ublituximab Followed by Response-driven Addition of Umbralisib for Treatment-naive Follicular or Marginal Zone Lymphoma (NCT04508647), a non-randomized phase 2 study. The primary outcome is Number of Participants With Complete Response Rate (CR) at up to 12 Months Post MONO - Monotherapy: Ublituximab or Combotherapy: Ublituximab + Umbralisib..

2. Clinical Question

Statistically, the central question is whether complete responses were observed under this initial-treatment strategy and how precisely their frequency can be estimated. The registry’s outcome is a participant count, not a time-to-event measure or a continuous measurement. Its description encompasses participants in the monotherapy or combination-treatment paths, but does not report results by path. Since the treatment path depends on response, differences between the listed groups cannot be interpreted as if treatment assignment were randomized. The record does not report a prespecified statistical comparison between the groups.

3. Trial Design

This is an open-label Phase II interventional study with non-randomized allocation and a parallel model. The registry lists follicular lymphoma and marginal zone lymphoma as the conditions under study. Its stated purpose is to assess the efficacy and safety of ublituximab as initial therapy, with umbralisib added for suboptimal response. The study status is completed, and enrollment was 4.

The planned treatment strategy begins with ublituximab monotherapy. The registry describes 900mg IV weekly for 4 doses, followed by an end-of-treatment assessment 8 weeks after the last single-agent dose. Participants with less than a complete response were to receive a combination of ublituximab and umbralisib for a total of 12 cycles. The registry gives some details of the combination schedule but its description ends before the umbralisib dosing instruction is complete; the full regimen is not reported in the registry record.

This response-driven structure is important for interpretation. The treatment path is linked to response after initial therapy rather than assigned randomly at the outset. Outcomes among participants who continue with ublituximab alone and those who add umbralisib can therefore reflect their different response status as well as any treatment differences. The record does not report a randomized control group or a like-for-like comparison of these paths.

The registry lists a primary complete-response outcome and an overall-response-rate secondary outcome. It lists 3 outcome measures and 0 analyses. A detailed statistical analysis plan, including the intended handling of the response-driven treatment path, is not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Cycle 1: Baseline to 8 Weeks

Cycle 2: 8 Weeks to 12 Months

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 Participants With Complete Response Rate (CR) at up to 12 Months Post MONO - Monotherapy: Ublituximab or Combotherapy: Ublituximab + Umbralisib., measured over up to 12 months post induction.

The primary endpoint is the number of participants with a complete response at up to 12 months post induction. The registry describes complete response as a Lugano score of 3 or less, assessed by PET-CT using the Lugano-Deauville criteria. The accompanying description specifies that none of the lymphoma lesions had FDG avidity greater than liver uptake.

A complete-response endpoint represents a categorical outcome: each participant is classified according to whether the stated response definition was met. Reporting a count makes clear how many participants met that definition, while an estimated response proportion and its uncertainty would help readers understand the precision of the result. The registry record does not report the complete-response count, an estimated proportion, or a confidence interval.

General: response endpoints are used to describe whether disease findings meet a prespecified clinical and imaging definition at an assessment time. PET-CT criteria provide a structured basis for classification, but interpretation still depends on applying the stated criteria consistently. The registry identifies the assessment method and threshold; details of blinded image review, adjudication, or handling of indeterminate assessments are not reported in the registry record.

The primary outcome title refers to up to 12 months post MONO, while the timeframe states up to 12 months post induction. The record does not further explain this wording or specify a more detailed assessment schedule.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the primary outcome count?

The primary outcome is a count of participants who met the complete-response definition at up to 12 months post induction. Each participant is classified as meeting or not meeting the endpoint definition. The registry specifies PET-CT assessment using the Lugano-Deauville criteria and a Lugano score of 3 or less. Its description also states that none of the lymphoma lesions had FDG avidity greater than liver uptake.

General: a count is the numerator of a response summary. To interpret it as a response rate, readers also need the relevant denominator: the number of participants included in that endpoint analysis. A rate is often more informative than a count when comparing groups of different sizes, but both the denominator and the analysis population must be clear. The registry record does not report the primary response count, denominator used for the primary analysis, or a response-rate estimate.

What does a confidence interval add?

General: a confidence interval expresses the uncertainty around an estimated quantity, such as a response rate. It reflects the range of values reasonably compatible with the data under the statistical method used. A narrow interval indicates greater precision than a wide interval; it does not remove possible bias in the study design or measurement. The registry record does not report a confidence interval for the primary outcome.

For a small study, estimates can be imprecise because each participant’s outcome has considerable influence on the overall summary. Here, enrollment was 4. The registry does not provide a primary outcome estimate, so its precision cannot be assessed from the posted results.

Why does the allocation method matter?

The study is non-randomized. General: random assignment helps balance measured and unmeasured participant characteristics across comparison groups, on average. Without randomization, groups can differ for reasons related to prognosis, eligibility, clinician decisions, or other factors. Statistical adjustment can sometimes address measured differences, but cannot ensure that all sources of confounding have been removed.

This study also uses a response-driven treatment path. Participants who had less than a complete response after ublituximab were to receive additional treatment with umbralisib and ublituximab. Their membership in the combination path thus depends on an earlier response. Comparing outcomes across the listed treatment paths would mix the effects of treatment with the selection rule that directed participants to each path. The registry cautions that the arms are not a like-for-like control comparison and reports no analyses.

What do the planning illustrations represent?

General: sample-size calculations explore how many participants might be needed to detect a specified effect under stated assumptions. Such calculations depend on assumptions about the effect, variability or event frequency, significance level, allocation, and statistical method. A calculation based on an observed effect is a planning illustration, not a result from a new experiment. It does not show the probability that the completed trial detected an effect and should not be called observed power.

The registry describes its planning assumptions as a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation. It says the effect to detect is a stated fraction of the observed effect. These are planning assumptions, not a reported protocol design or justification. The registry record does not report the trial’s own sample-size justification or statistical plan. The planning illustrations cannot replace the unreported primary outcome estimate and its uncertainty.

Why can over-dispersion matter?

General: over-dispersion occurs when observed variability is greater than a statistical model assumes. If a model does not account for that extra variability, uncertainty may be understated and tests may be too optimistic. The primary endpoint is a binary participant outcome, and the registry does not report a model-based analysis or a dispersion measure. Over-dispersion is therefore a general statistical consideration rather than a reported feature of this trial.

What can be inferred from the listed analyses?

The registry lists 3 outcome measures and 0 analyses. It does not report a statistical test, adjustment method, model, confidence interval, or analysis population for the primary outcome. Without these details and the outcome data, readers cannot evaluate the analytic choices or reproduce a treatment-effect estimate from 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("Ublituximab Only", "Ublituximab First, Then Ublituximab and Umbralisib")
n      <- c(2, 2)
events <- c(2, 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  Ublituximab Only  2  2  100.0  15.8  100.0  34.2  100.0  29.2  99.2
ARM  Ublituximab First, Then Ublituximab and Umbralisib  2  2  100.0  15.8  100.0  34.2  100.0  29.2  99.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 3 outcome measures, including complete response as the primary outcome and overall response rate as a secondary outcome. It reports 0 analyses. A multiplicity adjustment or a plan for interpreting several outcomes is not reported in the registry record. General: when researchers test multiple outcomes or comparisons, the chance of at least one apparently unusual result can increase. Prespecifying a primary outcome and an approach to secondary outcomes can help readers distinguish confirmatory questions from exploratory ones. The registry identifies the primary outcome, but does not report a detailed statistical plan for multiplicity.

The registry record does not report how missing or unevaluable PET-CT assessments were handled, whether participants without an assessment were counted as non-responders, or whether any imputation method was used. It also does not report the analysis population for the primary outcome, such as whether all enrolled participants or only those with an evaluable assessment were included. These choices can affect the interpretation of a response count and rate.

The treatment path is response-driven, but the registry does not explain the analysis approach for comparing participants who remained on ublituximab alone with those who received the combination. Because those paths arise from post-treatment response, a simple comparison would not isolate the effect of adding umbralisib. No adjusted analysis or causal method is reported in the registry record. These omissions limit assessment of both endpoint completeness and comparative 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 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry’s adverse-event summary lists 2 participants at risk for serious adverse events in each group and 0 affected by serious adverse events in each group. It lists 2 participants at risk for other adverse events and 2 affected in each group. The summary lists 0 deaths in each group, and no serious adverse-event terms are listed.

These are counts, not estimates of risk that can be precisely generalized beyond the participants represented. The registry does not define the “other” adverse-event category in the posted summary, and the listed event terms do not identify which events occurred. The figures should therefore be read as a brief registry count rather than a complete description of event types, severity, timing, or duration.

General: safety summaries depend on consistent event definitions, observation periods, and reporting procedures. A count of participants affected does not describe the number of events if participants can experience more than one event. The registry record does not report event-level details, exposure-adjusted rates, or a fuller narrative of safety findings. The absence of listed serious events in this small record should not be treated as evidence that a treatment is safe or unsafe.

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

The record describes a completed, open-label Phase II study of a response-driven treatment strategy for treatment-naive follicular or marginal zone lymphoma. It specifies ublituximab as initial therapy and addition of umbralisib for participants with less than a complete response. It also defines complete response using PET-CT and the Lugano-Deauville criteria. These details clarify the clinical question and outcome definition.

The record does not report the primary complete-response count, an estimated response rate, or uncertainty around the result. It therefore does not establish the observed frequency or precision of complete response. The listed overall-response-rate outcome also has no reported result. The registry’s 0 analyses means no statistical analyses are posted in this record; it does not supply a basis for a treatment-effect estimate.

Even if results were available for each treatment path, the non-randomized design and response-driven assignment would limit direct comparison. Participants receiving the combination were selected after their response to initial ublituximab. A difference between paths could arise from this selection process as well as from treatment. The registry cautions that the arms are not a like-for-like control comparison.

General: a small, early-phase study can describe feasibility, observed outcomes, and safety experience in the enrolled participants, while leaving substantial uncertainty about broader effects. The enrollment of 4 makes that limitation especially relevant, but the absent endpoint results prevent even a numerical description of the response experience in this record. The statistical interpretation should therefore remain focused on what the registry documents: the design, response-based treatment approach, endpoint definition, and limited safety counts, alongside substantial gaps in posted outcome and analysis information.

14. Why This Trial Matters Statistically

This trial is statistically notable because treatment assignment follows response to initial therapy. That design asks about a treatment strategy rather than a clean randomized contrast between two treatments. Participants who receive the combination are selected because they had less than a complete response to ublituximab. This makes the distinction between describing outcomes and estimating a causal treatment effect especially important.

The study also illustrates why endpoint definitions and analysis populations matter. The registry gives a specific PET-CT response definition, but does not report the complete-response count, denominator, or handling of missing assessments. Without those elements, readers cannot evaluate either the magnitude or precision of the primary outcome.

Enrollment was 4, while the primary outcome is a participant count. In a study of this size, estimates would be highly sensitive to individual outcomes, and uncertainty would be central to interpretation. Yet the registry does not report an outcome estimate or confidence interval. The posted safety figures are similarly counts from a limited enrollment and lack event-level detail.

The registry’s planning assumptions also distinguish hypothetical sample-size calculations from trial design and observed evidence. Calculations based on an observed effect may illustrate future planning, but do not establish the study’s design intent or demonstrate statistical power. The registry does not report its own sample-size justification or full analysis plan.

These features make the record useful for understanding how a response-adapted strategy was structured, while underscoring why design, reporting, and uncertainty must be considered before interpreting treatment comparisons.

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 statistical interpretation is that the registry does not report the primary outcome result. The complete-response definition is available, but the corresponding count, denominator, response estimate, and confidence interval are not reported in the registry record. Secondary outcome results are also not reported.

Enrollment was 4, limiting the amount of information available for estimating outcomes or describing less common events. The record does not provide a detailed account of participant flow, evaluable assessments, withdrawals, or missing data. The handling of missing or indeterminate PET-CT results is not reported in the registry record.

The non-randomized, open-label design limits causal interpretation. In particular, the combination path was determined by response to initial ublituximab, so comparisons between treatment paths would be subject to selection by response. The registry explicitly notes that the groups are not a like-for-like control comparison. Blinding of outcome assessment is not reported in the registry record.

The registry lists 0 analyses and does not report a full statistical analysis plan, multiplicity approach, sample-size justification, or analysis population. The combination-treatment description is incomplete, and the record does not explain the difference in wording between the primary outcome title and timeframe. Safety information is limited to group counts; detailed event terms and a fuller account of adverse-event ascertainment are not reported in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Ublituximab Followed by Response-driven Addition of Umbralisib for Treatment-naive Follicular or Marginal Zone Lymphoma — NCT04508647.
• Registry record last updated 2024-03-21; status last verified 2024-03.
• Results first posted 2023-11-09.
• 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, open-label Phase II study of ublituximab as initial therapy for treatment-naive follicular or marginal zone lymphoma, with umbralisib added for suboptimal response. Allocation was non-randomized, and the study used a parallel model. Enrollment was 4.

The primary outcome was the number of participants with complete response at up to 12 months post induction, defined using PET-CT and the Lugano-Deauville criteria. An overall-response-rate outcome is listed as secondary. The registry does not report primary or secondary outcome results and lists 0 analyses.

The adverse-event summary reports 0 serious events and 0 deaths in each group, with 2 participants affected by other adverse events in each group. Because the treatment paths were response-driven and not randomized, they do not form a like-for-like control comparison. The record supplies design and endpoint details but not the results and analysis information needed for a quantitative assessment of efficacy.