A Study of Obinutuzumab, Polatuzumab Vedotin, and Lenalidomide in Relapsed or Refractory Follicular Lymphoma (FL) and Rituximab in Combination With Polatuzumab Vedotin and Lenalidomide in Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of Obinutuzumab, Polatuzumab Vedotin, and Lenalidomide in Relapsed or Refractory Follicular Lymphoma (FL) and Rituximab in Combination With Polatuzumab Vedotin and Lenalidomide in Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL) (NCT02600897), a non-randomized phase 1, phase 2 study. The primary outcome is Percentage of Participants With Dose-Limiting Toxicities (DLTs).

2. Clinical Question

The study also described efficacy and pharmacokinetics as objectives. Its brief summary says that post-induction treatment depended on response at end of induction (EOI): participants with FL achieving complete response (CR), partial response (PR), or stable disease (SD) could receive obinutuzumab with lenalidomide; participants with DLBCL achieving CR or PR could receive rituximab with lenalidomide. Those response-based treatment pathways do not make the primary endpoint an efficacy comparison. The central statistical question for the primary endpoint is whether the dose-escalation cohorts had observed DLTs under the study regimens, but the registry record contains no posted primary-outcome analysis with which to answer it.

3. Trial Design

This was a Phase Ib/II, non-randomized, unmasked, parallel study sponsored by Hoffmann-La Roche. The registry lists enrollment of 114 and a completed status. The recorded start date is 2016-03-24 and the primary completion date is 2021-12-15. The conditions were relapsed or refractory FL and relapsed or refractory DLBCL.

The study organized participants into disease-specific dose-escalation and expansion cohorts. In FL, obinutuzumab was combined with polatuzumab vedotin and lenalidomide. The dose-escalation description says polatuzumab vedotin and lenalidomide doses were escalated with a fixed obinutuzumab dose to identify recommended Phase 2 doses. In DLBCL, rituximab was combined with polatuzumab vedotin and lenalidomide; the dose-escalation description says lenalidomide doses were escalated to identify its recommended Phase 2 dose. The expansion cohorts used regimens described separately for FL and DLBCL.

The brief summary describes induction followed by response-dependent post-induction treatment. For FL, the stated post-induction eligibility included CR, PR, or SD at EOI. For DLBCL, it included CR or PR at EOI. The arm descriptions specify 6 months of induction in the dose-escalation cohorts and give distinct maintenance or consolidation descriptions for the expansion cohorts. These design features mean that disease, regimen, dose, and treatment stage vary across groups.

Because allocation was not randomized and masking was absent, the cohorts do not provide a like-for-like controlled comparison. The design is suited to describing dose escalation and outcomes in the specified cohorts, but between-cohort contrasts can reflect differences in disease and regimen as well as dose. A detailed protocol, statistical analysis plan, and sample-size justification are 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.

Before assignment: Participants were enrolled in Phase Ib and Phase II study to receive polatuzumab vedotin (pola) in combination with lenalidomide (L) \& fixed doses of rituximab (R)/obinutuzumab(G). Of the 114 enrolled participants, 113 participants received at least one dose of the study drug and their intended treatment. One participant withdrew consent prior to receiving any study treatment.

Only the first 6 of 9 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The safety-evaluable population included all participants who received at least one dose of any component of the combination.

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: The ITT population included all participants enrolled in the study.

Only the first 6 of 10 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Dose-Limiting Toxicities (DLTs), measured over Day 1 of Cycle 1 to Day 1 of Cycle 2 (1 cycle = 28 days) in dose-escalation phase.

The primary endpoint is the percentage of participants with dose-limiting toxicities (DLTs) during dose escalation. The assessment window runs from Day 1 of Cycle 1 to Day 1 of Cycle 2, with one cycle defined as 28 days. A DLT was a toxicity during the first treatment cycle that the investigator assessed as related to study treatment and that met at least one of the listed criteria.

The criteria include an adverse event of any grade causing a delay of > 14 days in starting the next treatment cycle; Grade 3 or 4 non-hematologic adverse events, with exceptions; specified liver-test changes, including an increase in hepatic transaminase > 3 x baseline together with direct bilirubin > 2 x the upper limits of normal (ULN), subject to the stated exclusions; and hematologic adverse events meeting protocol-specified criteria. Assessment was according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0).

A DLT endpoint is used in dose escalation to describe treatment-limiting toxicity under the study’s defined rules. It is not a complete account of every adverse event, nor does the label alone establish that every event was caused by treatment. The record defines the safety-evaluable population as participants who received at least one dose of any combination component. It says endpoint percentages were rounded to the first decimal point, but reports no primary endpoint percentage or analysis.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a percentage endpoint represent?

For a binary outcome, each participant is classified according to whether the defined event occurred within the stated assessment rules. The percentage is the number meeting the outcome divided by the relevant analysis population, expressed as a proportion on a percentage scale. That estimate depends on the event definition, the denominator, and how participants with incomplete assessment are handled. In this trial, the primary endpoint is DLT percentage, and the stated safety-evaluable population includes participants who received at least one dose of any component of the combination. The registry record does not post the primary outcome count, denominator by cohort, or calculated percentage.

Why does the endpoint window matter?

The primary endpoint is restricted to the dose-escalation phase and the window from Day 1 of Cycle 1 to Day 1 of Cycle 2. A participant’s classification for this endpoint is therefore tied to events in that first-cycle assessment period and to the protocol’s DLT criteria. This is different from counting all adverse events over the entire study. The DLT definition also requires investigator assessment of relation to study treatment and contains specified clinical and laboratory criteria. General statistical point: a well-defined time window and event rule make a binary endpoint more reproducible, but they also limit what the endpoint captures.

How should precision be assessed?

General statistical explanation: an estimate is more informative when accompanied by a measure of uncertainty, such as a confidence interval. A confidence interval describes a range of values compatible with the data under the stated method; it is not a guarantee that the underlying value lies within that range. For percentages based on small cohorts, uncertainty can be substantial, even when the displayed percentage appears exact. The registry record does not report a primary DLT estimate or confidence interval, and no precision claim can be made for that endpoint from the posted information.

What do the secondary outcome methods indicate?

The outcome list specifies CR and objective response at EOI, with assessments by investigator or IRC and imaging based on PET-CT or CT scans alone. These are distinct assessment approaches. General statistical explanation: different reviewers or imaging criteria can produce different classifications, so it is important to retain the named reviewer and method when interpreting response estimates. The registry record lists these outcomes but does not report their analyses. It does not establish that one assessment approach was the prespecified primary analysis or that discrepancies between reviewers were resolved in a particular way.

What does non-randomized allocation mean for comparisons?

General statistical explanation: random allocation helps balance measured and unmeasured characteristics between treatment groups on average. In a non-randomized study, group membership may align with disease type, dose cohort, or study stage. The present cohorts intentionally differ in disease and drug combination, and dose-escalation groups vary by dose. Consequently, a raw comparison of their outcome percentages would not isolate a treatment effect. The registry states that allocation was non-randomized and that the study was unmasked; the record does not describe an adjusted comparative analysis.

How should the planning illustration be understood?

The registry’s planning assumptions describe an illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The intended effect is a stated fraction of the observed effect. For time-to-event outcomes, the assumptions describe a total event count using the Schoenfeld approach; other outcomes use participants per arm. These are planning conventions, not trial results or observed power. No numerical planning estimates or observed effect for this illustration are reported in the registry information. The assumed equal allocation also does not change the actual study design: the trial itself is non-randomized and has disease- and regimen-specific cohorts.

What can be inferred from the safety summaries?

General statistical explanation: event counts and percentages describe what was recorded in a defined group and period. Their interpretation depends on the denominator, follow-up, exposure, and event definitions. A group-level count does not by itself show why an event occurred or whether a regimen caused it. The adverse-event information lists counts of participants at risk and affected for serious and other adverse events, as well as deaths, by cohort. The record does not provide exposure-adjusted analyses or enough detail in these summaries to attribute events to treatment. The descriptive data should therefore remain separate from causal or comparative claims.

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("Dose-escalation Phase: 1.4 mg Pola + 10 mg L + 100", "Dose-escalation Phase: 1.8 mg Pola + 10 mg L + 100", "Dose-escalation Phase: 1.4 mg Pola + 15 mg L + 100", "Dose-escalation Phase: 1.4 mg Pola + 20 mg L + 100", "Dose-escalation Phase: 1.8 mg Pola + 10 mg L + 375", "Dose-escalation Phase: 1.8 mg Pola + 15 mg L + 375")
n      <- c(3, 4, 3, 6, 3, 5)
events <- c(0, 2, 0, 0, 0, 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  Dose-escalation Phase: 1.4 mg Pola + 10 mg L + 100  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Dose-escalation Phase: 1.8 mg Pola + 10 mg L + 100  4  2  50.0  6.8  93.2  15.0  85.0  14.7  85.3
ARM  Dose-escalation Phase: 1.4 mg Pola + 15 mg L + 100  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Dose-escalation Phase: 1.4 mg Pola + 20 mg L + 100  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Dose-escalation Phase: 1.8 mg Pola + 10 mg L + 375  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Dose-escalation Phase: 1.8 mg Pola + 15 mg L + 375  5  0  0.0  0.0  52.2  0.0  43.4  0.4  45.9

11. Multiplicity, Missing Data and Analysis Populations

The registry lists multiple secondary response outcomes. They include CR or objective response at EOI, with different combinations of reviewer and imaging method: investigator or IRC assessment, PET-CT scans, and CT scans alone. Multiple endpoints and assessment approaches raise a general statistical issue: when many hypotheses are tested, the chance of at least one apparently notable result can increase unless the analysis plan addresses multiplicity. The registry record does not report a multiplicity adjustment, a testing hierarchy, or a prespecified strategy for interpreting these outcomes. It also posts no analyses for the listed outcomes.

Missing-data handling for the primary or secondary endpoints is not reported in the registry record. The endpoint descriptions do not state how participants with missing assessments, early discontinuation, or unevaluable imaging were classified. Without those rules and the corresponding denominators, it is not possible to assess the potential effect of missing outcome information on reported percentages.

The primary endpoint defines a safety-evaluable population as participants who received at least one dose of any component of the combination. That is the population definition stated for the endpoint, but a primary analysis result and its cohort-specific denominator are not reported. The registry record does not describe an intention-to-treat population or other analysis populations for efficacy outcomes. It also does not report a statistical analysis plan, covariate-adjusted methods, or interim analyses. These omissions should be read as information not reported in the registry record, rather than evidence that a particular method was or was not used outside the posted information.

12. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: febrile neutropenia (33.3%), acute coronary syndrome (33.3%), colitis (33.3%), diarrhoea (33.3%), pyrexia (33.3%).

The adverse-event summaries give cohort-level counts for serious adverse events, other adverse events, and deaths. For serious adverse events, the listed affected and at-risk counts are: FL dose-escalation, 1.4 mg Pola + 10 mg L + 1000 mg G, 3 and 3; FL dose-escalation, 1.8 mg Pola + 10 mg L + 1000 mg G, 2 and 4; FL dose-escalation, 1.4 mg Pola + 15 mg L + 1000 mg G, 2 and 3; FL dose-escalation, 1.4 mg Pola + 20 mg L + 1000 mg G, 3 and 6; DLBCL dose-escalation, 1.8 mg Pola + 10 mg L + 375 mg R, 0 and 3; DLBCL dose-escalation, 1.8 mg Pola + 15 mg L + 375 mg R, 0 and 5; DLBCL dose-escalation, 1.8 mg Pola + 20 mg L + 375 mg R, 4 and 10; FL expansion, 1.4 mg Pola + 20 mg L + 1000 mg G, 26 and 40; DLBCL expansion, 1.8 mg Pola + 20 mg L + 375 mg R, 19 and 39.

The record also lists FEBRILE NEUTROPENIA, ACUTE CORONARY SYNDROME, COLITIS, DIARRHOEA, PYREXIA, and SEPTIC SHOCK at 33.3% each among its top serious terms. The term-specific denominators are not reported in the registry record. Death counts are reported by cohort, but their causes and attribution are not given in this information. These descriptive summaries do not establish that an event was caused by study treatment, and comparisons across these different cohorts are not randomized comparisons.

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

The record establishes that this was a completed, non-randomized Phase Ib/II study of combination regimens for participants with relapsed or refractory FL or DLBCL. Its primary endpoint was defined as the percentage with DLTs during the first-cycle dose-escalation assessment window. That definition makes clear what the primary safety question was intended to measure, but the registry record does not report a primary-outcome analysis. There is therefore no posted DLT estimate from which to judge the observed frequency or its precision.

The available adverse-event figures provide descriptive counts by cohort. They can be read as the numbers recorded as affected among the listed at-risk participants for serious and other adverse events, alongside death counts. They cannot, on their own, establish causation, compare treatment effects, or tell whether the observed differences arose from regimen, disease, dose, follow-up, or other factors. The study was not randomized, and the cohorts differ by disease, combination, dose, and stage.

The listed response outcomes indicate that CR and objective response were also of interest, with assessments using different reviewers and imaging methods. They are outcome definitions, not evidence that a particular response rate was observed. The registry record reports no outcome analyses for these measures in the information summarized.

Thus, the record supports an understanding of the study’s structure, the primary DLT definition, and the categories of safety information posted. It does not support a quantitative conclusion about the primary endpoint, efficacy, comparative safety, or the balance of benefits and harms. Such conclusions would require reported outcome analyses, denominators, uncertainty estimates, and relevant analysis details.

14. Why This Trial Matters Statistically

This study is statistically informative as an example of a design in which dose escalation and expansion occur in disease-specific cohorts rather than through randomized treatment allocation. The distinction matters: the purpose and interpretation of dose-escalation information differ from those of a controlled treatment comparison. Here, the FL and DLBCL cohorts receive different antibody combinations, and dose levels vary across dose-escalation groups. The posted cohort figures must therefore be interpreted in their design context rather than treated as direct head-to-head evidence.

The primary endpoint is also a useful illustration of how a safety outcome depends on precise operational rules. The registry defines DLTs using an early assessment window, investigator attribution, and specified clinical, laboratory, and hematologic criteria. Those details help distinguish the primary endpoint from a general count of all adverse events. At the same time, without a posted primary analysis, a clear endpoint definition alone does not tell readers what was observed or how precisely it was estimated.

The record lists response outcomes assessed by investigators and an IRC using PET-CT or CT scans alone. Keeping reviewer and imaging method attached to each outcome is important because endpoint classification depends on those choices. The record lists numerous outcomes but does not report how multiplicity was addressed or provide analyses for them.

Finally, the distinction between descriptive safety information and inferential evidence is central. Cohort counts can describe what was recorded, but the non-randomized structure and absence of posted primary results limit comparative interpretation. Statistical reporting is most useful when event counts are accompanied by denominators, uncertainty, analysis populations, missing-data rules, and a prespecified analysis approach. Several of those details are not reported in the registry record.

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 central limitation for interpreting the primary endpoint is that the registry record reports its definition but no primary-outcome analysis. It does not give an observed DLT percentage, a cohort-specific result, or an uncertainty interval. The record’s enrollment figure does not establish the number evaluated for this endpoint in each cohort, and the endpoint population definition does not supply those denominators.

The study is non-randomized and unmasked. Its cohorts differ by disease, antibody, dose, and study stage, so their outcomes are not directly comparable as if they were randomized arms. The record does not report adjusted comparisons that might address differences between groups. Nor does the adverse-event summary establish event attribution, event timing, or exposure-adjusted rates.

The listed secondary outcomes use different reviewers and imaging methods, but analyses are not reported. Multiplicity handling and missing-data rules are not reported in the registry record. A statistical analysis plan, interim analysis details, and sample-size justification are also not reported. These gaps limit assessment of how endpoint results would have been selected, calculated, or interpreted.

The adverse-event terms are listed with percentages, but their denominators are not reported in the registry record. Death counts are presented by cohort without causes or treatment attribution in this information. These limitations mean the figures should be treated as descriptive records, not standalone evidence of causal safety effects or comparative efficacy.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study of Obinutuzumab, Polatuzumab Vedotin, and Lenalidomide in Relapsed or Refractory Follicular Lymphoma (FL) and Rituximab in Combination With Polatuzumab Vedotin and Lenalidomide in Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL) — NCT02600897.
• Registry record last updated 2023-12-26; status last verified 2023-12.
• Results first posted 2023-12-26.
• 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

NCT02600897 is a completed, non-randomized, unmasked, parallel Phase Ib/II study sponsored by Hoffmann-La Roche. It enrolled 114 participants and addressed relapsed or refractory FL and DLBCL. FL cohorts evaluated obinutuzumab with polatuzumab vedotin and lenalidomide; DLBCL cohorts evaluated rituximab with polatuzumab vedotin and lenalidomide. The study included dose-escalation and expansion cohorts.

The primary endpoint was the percentage of participants with DLTs during the dose-escalation first-cycle window. The safety-evaluable population was defined as participants receiving at least one dose of any combination component. The registry record lists 20 outcome measures and 0 analyses, and does not report a primary DLT result. It includes cohort-level adverse-event counts and lists secondary response outcomes, but the information does not support randomized comparisons or causal conclusions.