A Study Evaluating the Safety, Efficacy and Pharmacokinetics of Venetoclax Combined With Chemotherapy in Participants With B-Cell Non-Hodgkin's Lymphoma (NHL) and DLBCL: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study Evaluating the Safety, Efficacy and Pharmacokinetics of Venetoclax Combined With Chemotherapy in Participants With B-Cell Non-Hodgkin's Lymphoma (NHL) and DLBCL (NCT02055820), a randomized phase 1, phase 2 study. The primary outcome is Safety: Number of Participants With Dose-Limiting Toxicities (DLTs).

2. Clinical Question

3. Trial Design

This was a multicenter, open-label, parallel-group phase Ib/II study of venetoclax combined with CHOP and either rituximab or obinutuzumab. The registry records randomized allocation and no masking. The study enrolled 267 participants overall. It began on 2013-11-17, reached primary completion on 2017-06-28, and is recorded as completed. The trial addressed B-cell non-Hodgkin's lymphoma, including DLBCL.

The study had a dose-finding phase Ib stage followed by a phase II expansion stage. During phase Ib, participants were randomized to venetoclax plus R-CHOP or venetoclax plus G-CHOP, and venetoclax doses were explored in each combination. The stated purpose of dose finding was to determine the maximum tolerated dose for each combination. The posted primary safety outcome specifically reports the dose-finding participants.

In the phase II portion, venetoclax plus R-CHOP was given on a non-continuous dosing schedule selected following phase Ib safety and tolerability observations. The registry says the G-CHOP arm was not expanded in phase II in first-line DLBCL after the sponsor reported that the primary endpoint of investigator-assessed PFS in the separate Goya study was not met. That context explains the described study development; it is not a result of the present trial.

Both combinations used CHOP, with rituximab or obinutuzumab as the antibody component. The registry describes six cycles of CHOP and eight cycles of venetoclax with the relevant antibody, with each cycle lasting 21 days. The posted record does not give a detailed account of allocation procedures, concealment, or the statistical plan. The trial's open-label status means participants and investigators were not masked to treatment assignment.

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: The data reported for participant flow is based on safety population, which includes all participants who received at least one dose of study medication.

Only the first 6 of 10 groups are shown.

Phase I: Dose-Finding

Reasons for not completing this period:

Phase II: Expansion

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety population: All participants who enrolled in the study and received any amount of venetoclax or R-CHOP/G-CHOP were included in the safety population for safety analyses. Here, participants in the Dose Finding phase were analyzed.

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.

Only the first 6 of 11 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Safety: Number of Participants With Dose-Limiting Toxicities (DLTs), measured over Start of venetoclax administration (Cycle 1 Day 4 or 3 days after first CHOP dose) up to end of Cycle 2 (cycle length = 21 days).

The primary endpoint was the number of participants with dose-limiting toxicities, or DLTs. It was a safety endpoint used in the dose-finding phase to identify adverse events considered sufficiently serious and plausibly related to the combined treatment to affect decisions about venetoclax dose escalation. Counting participants with an event gives a direct summary of how often the endpoint occurred in each dose arm; it does not capture every detail of severity, duration, or clinical course.

DLTs were defined using NCI CTCAE v4.0. In general, the definition included Grade 3 or higher adverse events with a reasonable possibility of being related to combined venetoclax plus R-CHOP or G-CHOP, unless the investigator attributed the event to a clearly identifiable alternative cause. The definition also specified that Grade 3 or 4 neutropenia or thrombocytopenia identified on Day 1 of Cycle 2 or 3 and resulting in a dose delay counted as DLTs. B-cell decrease, lymphopenia, and leukopenia caused by lymphopenia were excluded as expected outcomes of treatment.

The observation period began at venetoclax administration, on Cycle 1 Day 4 or three days after the first CHOP dose, and continued through the end of Cycle 2. The cycle length was 21 days. This early-window endpoint is suited to dose escalation because it focuses on specified toxicities during initial treatment. It is not a measure of longer-term safety, disease control, or survival.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary at the participant level: each participant either met the DLT definition during the stated observation period or did not. The registry reports the number of participants with DLTs in each dose arm. For an outcome of this kind, the count gives the event frequency observed in that group. Interpreting it requires attention to the group size and to the endpoint definition; the same count can convey different levels of precision in groups of different sizes.

What does a confidence interval express?

In general, a confidence interval describes the uncertainty around an estimated quantity under a specified statistical method. For event proportions, intervals can show how imprecise an estimate may be when event counts or group sizes are limited. They do not guarantee that the true value lies within a particular realized interval, and they do not remove uncertainty caused by design limitations or measurement choices. No confidence intervals are reported for the primary DLT results in the registry record.

Why are direct arm comparisons limited?

The phase Ib arms explored dose levels within two drug combinations, and the group sizes shown for the primary endpoint are small. As a general statistical matter, estimates based on few participants can be unstable: a single event can materially affect the apparent event frequency. A difference in observed counts between arms is not, by itself, evidence of a statistically reliable difference. The registry record does not report a formal comparison test, an adjusted effect estimate, or a confidence interval for differences between arms.

Randomization is recorded for the overall study, and phase I participants were randomized between the R-CHOP and G-CHOP combinations. However, the registry does not provide enough detail to assess the randomization procedure or to determine whether dose-level comparisons were randomized in a way that supports causal conclusions. The study was open-label, and the DLT definition incorporates investigator attribution regarding relation to treatment and alternative causes. These features matter when interpreting safety-event classification.

What does the DLT definition contribute?

An endpoint definition makes clear which events count toward the primary outcome and when they are considered. Here, the definition refers to NCI CTCAE v4.0 severity grading, a reasonable possibility of relation to the combined treatment, and specified alternative causes. It also includes particular hematologic events associated with dose delays and excludes selected changes described as expected treatment outcomes. This helps distinguish a DLT from the broader set of adverse events, but leaves the event classification dependent in part on clinical assessment.

The observation window is restricted to early treatment, beginning with venetoclax administration at Cycle 1 Day 4 or three days after the first CHOP dose and ending at the end of Cycle 2. This is a design choice suited to early dose-finding decisions. It cannot summarize later toxicities or establish the longer-term safety profile. The registry record does not report the number of participants with missing DLT assessments or how missing endpoint data were handled.

How should planning illustrations be understood?

General sample-size calculations describe how many participants might be needed under stated assumptions to detect an effect of a chosen size with a chosen statistical approach. Such calculations are planning illustrations, not observed trial outcomes, and do not show the probability that this completed study found a real effect. The planning information associated with these results uses a two-sided significance level of 0.05, equal allocation, and a normal approximation, with effects expressed as fractions of the observed effect. It is not reported as the original study's design justification. Any illustrated sample sizes should therefore not be treated as the trial's actual enrollment targets, as observed power, or as evidence that a treatment effect exists.

For binary outcomes, the normal approximation is a general method that can be less dependable when event counts are sparse. Other methods for sparse binary data may be considered in a full statistical analysis, but the registry record does not identify a particular method for comparing DLTs. It also does not report adjustment for baseline factors, an interim-analysis plan, a multiplicity strategy, or a prespecified hypothesis test for this endpoint.

What do recalculations mean?

When an analysis is labelled recalculated, it represents a simple unadjusted calculation from posted summary information, rather than the sponsor's full analysis. If a discrepancy is identified, the sponsor's own analysis takes precedence. For the primary endpoint information described in the registry record, no recalculated treatment comparison is available: the posted result is a set of arm-specific event counts and values are missing or not estimable for a two-arm binary comparison. This absence should not be filled by creating a comparison from the counts.

Statistical interpretation also depends on the analysis population. The record defines the safety population as participants who enrolled and received any amount of venetoclax or R-CHOP/G-CHOP, and says that participants in the dose-finding phase were analyzed for the primary endpoint. The posted counts should be understood in that context rather than assumed to represent every enrolled participant or the phase II population.

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("Venetoclax 200 mg + R-CHOP", "Venetoclax 400 mg + R-CHOP", "Venetoclax 600 mg + R-CHOP", "Venetoclax 800mg + R-CHOP", "Venetoclax 200mg + G-CHOP", "Venetoclax 400mg + G-CHOP")
n      <- c(7, 3, 8, 6, 7, 7)
events <- c(1, 0, 1, 0, 2, 1)
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  Venetoclax 200 mg + R-CHOP  7  1  14.3  0.4  57.9  2.6  51.3  3.2  52.7
ARM  Venetoclax 400 mg + R-CHOP  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Venetoclax 600 mg + R-CHOP  8  1  12.5  0.3  52.7  2.2  47.1  2.8  48.2
ARM  Venetoclax 800mg + R-CHOP  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Venetoclax 200mg + G-CHOP  7  2  28.6  3.7  71.0  8.2  64.1  8.5  65.1
ARM  Venetoclax 400mg + G-CHOP  7  1  14.3  0.4  57.9  2.6  51.3  3.2  52.7

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 22 outcome measures, reports 19 posted secondary outcomes, and records 0 analyses. The secondary outcomes include pharmacokinetic measures such as venetoclax and prednisone AUC, Tmax, and Cmax, venetoclax Cmin, and rituximab Cmax. With multiple outcomes, there is a general statistical issue of multiplicity: when many hypotheses are tested, the chance of at least one apparently notable result can increase unless the analysis plan addresses that issue. The registry record does not report a multiplicity adjustment, a hierarchy among outcomes, or a detailed strategy for interpreting multiple tests.

The posted primary outcome is a count of participants with DLTs in the dose-finding phase. The record defines the safety population as enrolled participants who received any amount of venetoclax or R-CHOP/G-CHOP, and specifies that the dose-finding participants were analyzed for this primary safety endpoint. The record does not provide a separate account of missing observations, exclusions after enrollment, or the handling of participants without a complete DLT assessment. Missing-data handling is therefore not reported in the registry record.

The study includes phase Ib dose finding and a phase II expansion, and the registry describes the R-CHOP phase II schedule as informed by phase Ib safety and tolerability. It does not report a complete statistical analysis plan, interim-analysis procedures, a sample-size justification, or a prespecified multiplicity approach. These omissions limit assessment of how outcome selection, dose decisions, and missing information were handled analytically. They do not justify assuming that a particular procedure was or was not used outside what the registry states.

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 0.05% 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 (42.9%), anaemia (33.3%), thrombocytopenia (33.3%), atrial fibrillation (33.3%), cardiomyopathy (33.3%).

The safety summaries report serious adverse events, other adverse events, and deaths by group. These are separate measures. A serious adverse event is not necessarily a DLT: the primary DLT endpoint used its own severity, attribution, alternative-cause, and observation-period criteria. The record gives group-specific counts for participants at risk and participants affected, but the summaries should not be treated as a direct randomized comparison unless a suitable analysis is reported.

For example, the phase II venetoclax 800 mg + R-CHOP group records 116 of 208 participants with serious adverse events, 204 of 208 with other adverse events, and 33 deaths. These figures describe the registry's group summaries; they do not establish that every event was caused by treatment, or that the counts are comparable across groups with differing doses, phases, or follow-up. The record does not give adverse-event observation windows in the information.

The most frequently listed serious-event terms include febrile neutropenia at 42.9%, and anaemia, thrombocytopenia, atrial fibrillation, cardiomyopathy, and vomiting at 33.3% each. These are reported percentages for terms, not substitutes for the overall serious-event counts. The record does not specify in this summary the precise denominator or event-term counting method behind those percentages. No causal conclusions should be drawn from the term list alone.

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

The results provide descriptive early safety information from a phase Ib dose-finding study of venetoclax combined with R-CHOP or G-CHOP. They show how many participants in each listed dose arm met the registry's DLT criteria during the observation period through the end of Cycle 2. This is relevant to understanding the study's dose-finding purpose and the safety outcome used during that stage.

They do not establish that one venetoclax dose or antibody combination is safer than another. The groups are small, the report presents counts rather than a formal comparative estimate, and the registry does not provide confidence intervals or a statistical test for the arm differences. Nor do the counts establish that treatment caused every recorded event, since DLT classification used investigator attribution and considered alternative causes.

The primary endpoint does not measure tumor response, progression-free survival, or overall survival. Therefore, the DLT results cannot show whether treatment controlled lymphoma or improved any clinical outcome. The record's account of the separate Goya study is background to the decision not to expand the G-CHOP arm in first-line DLBCL; it should not be presented as a result from this trial.

The serious and other adverse-event summaries offer additional safety descriptions, but they are not interchangeable with the DLT endpoint. Their counts and term percentages require their own definitions and denominators, and the record does not provide all of the detail needed for independent comparisons. Overall, the posted results support a narrow reading: observed early safety events in the dose-finding arms, within a particular treatment context and endpoint definition. Broader claims about comparative safety or efficacy are not supported by these counts alone.

14. Why This Trial Matters Statistically

Dose-finding studies address a different statistical question from trials designed primarily to estimate treatment efficacy. Their central task is to characterize tolerability across dose levels sufficiently to guide subsequent development. The primary endpoint operationalizes that task through a prespecified-in-description set of toxicity criteria and an early observation window. Keeping that purpose in view helps prevent the event counts from being mistaken for evidence of treatment benefit.

The study also illustrates how a treatment combination can create interpretive complexity. Venetoclax was combined with CHOP and one of two antibody therapies, and the dose-finding arms covered several venetoclax dose levels. Any apparent variation in DLT counts occurs in groups that differ by both dose and combination, while the registry does not report formal comparative estimates. Separating descriptive patterns from causal conclusions is especially important in this setting.

Another statistical issue is the distinction between an endpoint-specific safety count and broader adverse-event reporting. DLTs were defined using severity, attribution, alternative causes, and timing. Serious adverse events and other adverse events are reported separately. Reading these outcomes as if they were a single measure would obscure their distinct definitions and could overstate what the primary endpoint tells us.

Finally, the registry makes clear that trial interpretation depends on the phase and analysis population. The primary endpoint concerns dose-finding participants, while the overall trial also included a phase II expansion. The results should therefore be understood as evidence from a particular stage of development, not as a standalone randomized efficacy comparison. The limitations of the posted statistical detail are part of the interpretation, rather than a reason to infer unreported methods or conclusions.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The primary endpoint is based on a small number of participants within each dose-finding arm. As a general consequence, arm-specific event counts can be imprecise, and the registry does not provide confidence intervals that would quantify that uncertainty. It also does not report a formal statistical comparison between the arms. The counts should therefore remain descriptive.

The study was open-label. The DLT definition included an investigator judgment about whether an event had a reasonable possibility of being related to combined treatment and whether another clearly identifiable cause applied. This clinical assessment is part of the endpoint definition, but open-label assessment can be relevant when considering the possibility of differences in event recognition or attribution. The registry record does not describe procedures used to limit such effects.

The endpoint covered the period from venetoclax initiation through the end of Cycle 2, so it does not characterize later-onset toxicities. The registry does not report missing DLT assessments or their handling. The primary results apply to the stated safety population and dose-finding participants; they should not be generalized automatically to the entire enrolled population, the phase II expansion, or other treatment settings.

The posted record does not provide the full statistical plan, dose-escalation rules, sample-size justification, multiplicity strategy, interim-analysis details, or a complete account of endpoint assessment. It also does not provide enough information in these results to evaluate the denominators and follow-up underlying every adverse-event percentage. These limitations constrain causal and comparative interpretation, even though the record gives clear descriptive counts for the primary outcome.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study Evaluating the Safety, Efficacy and Pharmacokinetics of Venetoclax Combined With Chemotherapy in Participants With B-Cell Non-Hodgkin's Lymphoma (NHL) and DLBCL — NCT02055820.
• Registry record last updated 2020-06-11; status last verified 2020-05.
• Results first posted 2018-12-20.
• 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

NCT02055820 is a completed, multicenter, open-label phase Ib/II study recorded as randomized and parallel. It evaluated venetoclax with CHOP and rituximab or obinutuzumab in participants with B-cell non-Hodgkin's lymphoma, including DLBCL. Overall enrollment was 267. The trial began on 2013-11-17 and reached primary completion on 2017-06-28.

The study used phase Ib dose finding followed by a phase II expansion. The primary safety endpoint was the number of participants with DLTs during the early treatment observation period. The posted primary findings are dose-arm event counts for phase Ib; the registry does not report a formal statistical comparison of those arms. The record also includes serious and other adverse-event summaries and lists pharmacokinetic secondary outcomes.

Interpretation is limited by small dose-finding groups, the open-label design, the early endpoint window, and the absence of reported confidence intervals, a formal comparative analysis, and details of missing-data and multiplicity procedures. The results describe observed safety outcomes; they do not establish comparative efficacy.