Lenalidomide Combined With Vorinostat/Gemcitabine/Busulfan/Melphalan With Autologous Stem-Cell Transplantation in Diffuse Large B-Cell Lymphoma of the ABC Subtype: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Lenalidomide Combined With Vorinostat/Gemcitabine/Busulfan/Melphalan With Autologous Stem-Cell Transplantation in Diffuse Large B-Cell Lymphoma of the ABC Subtype (NCT02589145), a na phase 1, phase 2 study. The primary outcome is Maximum Tolerated Dose (MTD).

2. Clinical Question

3. Trial Design

This was a phase 1 and phase 2, single-group, open-label study sponsored by M.D. Anderson Cancer Center. The registry lists an enrollment of 8 and a status of terminated. The study began on 2016-06-22, and its primary completion date is listed as 2019-04-08. These design and status details describe the registry entry; they do not explain why the study was terminated beyond the stated low accrual for the primary endpoint.

The study was intended to identify a maximum tolerated dose of lenalidomide when combined with vorinostat, gemcitabine, busulfan and melphalan, with autologous stem-cell transplantation. The summary also describes treatment with or without rituximab. Dose levels were selected adaptively for successive cohorts, with a minimum cohort size of 2 patients. The record does not give the actual lenalidomide doses or a complete treatment schedule in the arm description.

There was no randomized allocation or masking, and no separate comparator group is described. Accordingly, the dose-level groups are descriptive cohorts within a dose-finding study, not like-for-like control arms. The record lists overall survival, complete remission rate, overall remission rate, toxicity profile and pharmacodynamic studies among the secondary outcomes. It lists 7 outcome measures in total, but 0 analyses are posted. Statistical methods beyond the primary endpoint’s dose-limiting toxicity definition and adaptive cohort description are not reported in the registry record.

Low accrual is central to interpreting the study: the registry explicitly states that the maximum tolerated dose could not be determined. The posted information therefore does not establish a selected dose as the maximum tolerated dose, and the listed secondary outcomes cannot be used to make claims about treatment effects.

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

Analysis population for the primary outcome, as defined in the registry: Due to low accrual, MTD could not be determined for this outcome.

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: Patients age 15-65 with ABC (determined by immunohistochemistry using the Hans algorithm) Diffuse Large B-cell Lymphoma (DLBCL) with primary refractory disease.

6. Primary Endpoint

The registry lists the primary outcome as Maximum Tolerated Dose (MTD), measured over Enrollment up to day 30 post transplant for each dosing cohort.

The primary endpoint was the maximum tolerated dose of lenalidomide in combination with vorinostat, gemcitabine, busulfan and melphalan with autologous stem-cell transplantation. The registry says the endpoint covered enrollment through day 30 post transplant for each dosing cohort. It defined dose-limiting toxicity as any Grade 4 or 5 nonhematologic, noninfectious toxicity, or any grade 3 mucositis or skin toxicity lasting > 5 days at peak severity. Toxicity scoring followed the National Cancer Institute Common Toxicity Criteria, version 4.

In general, dose-finding studies use a maximum tolerated dose endpoint to guide dose selection by relating dose levels to a prespecified definition of unacceptable toxicity. The endpoint is not itself a measure of comparative efficacy. Its interpretation depends on the toxicity definition, observation period and dose-assignment approach; these details determine which events count toward dose limitation and when they are assessed.

Here, the registry says dose levels were chosen adaptively for successive cohorts, with a minimum size of 2 patients. It also states that low accrual meant the maximum tolerated dose could not be determined. No estimated maximum tolerated dose or associated uncertainty interval is reported in the registry record. The listed secondary measures include remission and survival outcomes, but their numerical results are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a dose-finding study, but does not report a complete statistical analysis plan. The distinction matters: the endpoint definition and cohort approach are available, while the statistical procedures used to summarize or analyze the data are not reported in the registry record. The explanations below separate those posted design details from general statistical context.

What does the maximum tolerated dose endpoint mean?

In general, a maximum tolerated dose is a dose selected under a study’s rules for dose-limiting toxicity. It is not a universal property of a drug that can be interpreted without its toxicity definition, assessment period and participant population. In this study, the registry defined dose-limiting toxicity as any Grade 4 or 5 nonhematologic, noninfectious toxicity, or grade 3 mucositis or skin toxicity lasting > 5 days at peak severity. It states that toxicity was scored using the National Cancer Institute Common Toxicity Criteria, version 4.

The observation window was enrollment through day 30 post transplant for each dosing cohort. In general, a defined window makes clear which period contributes to the endpoint, but it does not capture toxicity outside that period unless the study separately reports it. The registry does not describe additional endpoint rules, such as how incomplete toxicity assessments were handled, so these details cannot be inferred.

How did dose assignment work?

The registry says lenalidomide doses were chosen adaptively for successive cohorts, each with a minimum size of 2 patients. In general, adaptive dose finding means later dose choices depend on information from earlier participants or cohorts. This differs from assigning every participant to a fixed dose in a randomized comparison. The record does not report the full dose-escalation or dose-decision algorithm, the actual dose amounts, or any interim decision rules. Those elements are not reported in the registry record.

The minimum cohort size is a design detail, not a guarantee that each dose has enough observations to estimate toxicity precisely. With an enrollment of 8 and a statement that low accrual prevented determination of the maximum tolerated dose, the primary objective remained unresolved. No confidence interval or other uncertainty estimate for an MTD is reported.

What does the single-group design allow?

The study is listed as single-group, with allocation not applicable and no masking. In general, a single-group dose-finding study can describe observed outcomes at the doses used, but it cannot provide a randomized comparison with a control group. Open-label conduct means the registry does not describe masking of participants or study personnel. The record does not report procedures intended to limit assessment or reporting bias beyond the endpoint’s toxicity criteria.

General statistical principle: a confidence interval expresses uncertainty around an estimate under the assumptions of the method used. No confidence interval for the primary endpoint or secondary outcomes is reported in the registry record. Because there is no posted analysis for these outcomes, readers cannot assess the precision of any estimated clinical outcome effect from the registry entry.

What can be said about analysis methods?

The registry lists 7 outcome measures and 0 analyses. It identifies the primary endpoint and gives its toxicity definition, but does not report a statistical analysis plan, model, estimation method, or analysis population. It also does not report an interim-analysis plan or a sample-size justification. These items should not be reconstructed from the phase labels or the adaptive-cohort description.

The sample-size illustrations elsewhere on the page are planning illustrations, not observed power and not the trial’s own design justification. The stated illustration assumptions use a two-sided significance level of 0.05, equal allocation between two arms and a normal approximation, with the effect expressed as a stated fraction of the observed effect. In general, such calculations describe hypothetical future planning under their assumptions; they do not change the design of this single-group study or establish the probability that this trial detected an effect.

General statistical principle: small samples usually leave substantial uncertainty around event rates and make estimates sensitive to individual observations. That principle is relevant when interpreting the small dose-level cohorts, but no new estimate of uncertainty can be calculated from the registry summary. The posted record’s clearest inferential statement remains that low accrual prevented determination of the maximum tolerated dose.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists several secondary outcomes, including overall survival, complete remission rate, overall remission rate, toxicity profile and pharmacodynamic studies. It reports 7 outcome measures in total and 0 analyses. The primary endpoint is identified as maximum tolerated dose, but the record does not report how the secondary outcomes were prioritized for analysis or whether any were exploratory.

Multiplicity arises in general when researchers conduct several statistical tests or examine multiple outcomes: even when each test uses a prespecified error threshold, the chance of at least one apparently notable result can increase across tests. A multiplicity adjustment or a hierarchy of outcomes can address some of that issue, but the approach used is not reported in the registry record. With no posted analyses, there are no reported p-values or outcome estimates to interpret for multiplicity.

Missing-data methods, analysis populations and rules for handling incomplete follow-up are not reported in the registry record. The record does not say how participants with missing outcome assessments would be included, how censoring was handled for overall survival, or whether analyses used all enrolled participants or a subset. These are not details that can be inferred from the endpoint names.

The registry reports low accrual as the reason the maximum tolerated dose could not be determined. It does not report whether accrual-related decisions affected other outcome assessments or whether any interim analyses were conducted. Accordingly, the posted record does not support conclusions about the planned handling of missing data, multiplicity, analysis populations or interim monitoring.

11. 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: ileus (25.0%), mucositis (25.0%), elevated bilirubin (25.0%), hypernatremia (25.0%).

The adverse-event summary separates participants by lenalidomide dose level. At dose level 1, 4 participants were at risk for serious adverse events and 1 was affected; at dose level 2, 2 were at risk and 0 were affected; at dose level 3, 2 were at risk and 0 were affected. The other-adverse-event counts show 4 of 4 affected at dose level 1, 2 of 2 at dose level 2 and 2 of 2 at dose level 3. The death counts are 1, 1 and 0, respectively, across those same dose levels.

The registry’s listed top serious adverse-event terms are ileus, mucositis, elevated bilirubin and hypernatremia, each shown as 25.0%. The record does not provide enough detail to connect each listed term to a particular dose-level cohort or to interpret the percentages as comparative risks. These summaries are descriptive. In general, an adverse event recorded during a study is not by itself proof that the study treatment caused it.

The groups are small and there is no randomized control group. Differences in these counts should not be interpreted as evidence that one dose level is safer than another. The registry does not report further details about event timing, severity distributions beyond the listed serious-event counts, attribution, or missing safety assessments.

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

The posted result does not establish a maximum tolerated dose. The registry explicitly attributes this to low accrual. That means the primary dose-finding question remained unanswered in the posted record; it does not mean that the study identified a dose and then found it unacceptable, nor does it establish that every tested dose was intolerable.

The trial was designed to examine a complex regimen involving lenalidomide, vorinostat, gemcitabine, busulfan and melphalan with autologous stem-cell transplantation, and the summary says treatment could be given with or without rituximab. The registry lists other interventions as well. Because the record describes a single-group study and does not provide a randomized control comparison, outcomes cannot be attributed to one component of the regimen by comparing treatment groups.

The registry lists survival and remission outcomes, along with toxicity and pharmacodynamic measures, but posts 0 analyses. Numerical results for those secondary measures are not reported in the registry record. It is therefore not possible from this entry to assess estimated outcome differences, statistical uncertainty, or how analyses were conducted. The listed adverse-event counts offer descriptive information, not a controlled estimate of risk or treatment effect.

In general, a study’s stated aims, measured outcomes and posted results are distinct. An aim to learn about effectiveness does not itself demonstrate effectiveness, just as a toxicity endpoint does not provide a complete account of clinical benefit. Here, the most supportable interpretation is narrow: the study’s MTD endpoint could not be determined because of low accrual, and the registry entry does not include analyses that resolve the listed secondary questions.

These findings should not be stretched into a conclusion about what a larger study would show. The registry record provides no basis for projecting results to other populations or treatment settings. It also does not report the additional methods and data needed to evaluate such generalization.

13. Why This Trial Matters Statistically

This trial illustrates how a statistical objective can remain unresolved even when a study has a clearly defined endpoint. The registry specifies a maximum tolerated dose question, gives a dose-limiting toxicity definition and describes adaptive cohorts. It then reports that low accrual prevented determination of the MTD. The endpoint’s definition is useful, but it cannot substitute for enough information to reach the planned dose-selection conclusion.

The design also highlights the difference between dose-level cohorts and a controlled comparison. A single-group dose-finding study can collect safety observations across doses, but the cohorts are not randomized control arms. That distinction is important when reading the adverse-event summaries: the counts describe what was recorded in those groups and do not isolate a causal effect of dose or of any one regimen component.

There is also a gap between the outcomes listed and the analyses posted. The record names survival, remission, toxicity and pharmacodynamic outcomes, but reports 0 analyses. Without estimates and methods, readers cannot judge the precision of secondary results or their relationship to the primary endpoint. This is an example of why registry outcome listings alone are not equivalent to a full results analysis.

Finally, the study makes clear why design assumptions should be kept separate from retrospective planning illustrations. A hypothetical sample-size calculation cannot turn an under-accrued, single-group study into a randomized comparison or establish observed power. The statistical reading must follow the actual design and posted results: here, the central result is that the dose-finding objective was not determined.

14. 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 stated in the registry is low accrual, which meant the maximum tolerated dose could not be determined. The enrollment listed is 8, and the adverse-event summaries divide participants among three dose levels, leaving small descriptive groups. Such counts offer limited information about how frequently uncommon events might occur, and they cannot provide a robust dose comparison.

The study has no separate control group and is not described as randomized or masked. Therefore, the posted information cannot support a controlled estimate of treatment effect. The regimen includes multiple drugs and autologous stem-cell transplantation, and the summary says treatment could be given with or without rituximab. The record does not provide enough detail to separate the contribution of any individual component.

The primary endpoint result is reported only as not determined because of low accrual. The registry does not report an MTD estimate, an uncertainty interval, or detailed dose-decision results. Although secondary outcomes are listed, 0 analyses are posted. Numerical estimates and analysis methods for those outcomes are not reported in the registry record.

Other important details are also unavailable in the registry record: the complete protocol and statistical plan, sample-size justification, interim-analysis procedures, analysis populations, missing-data methods, and fuller treatment and outcome-assessment details. The arm description is incomplete. These gaps limit evaluation of the conduct and interpretation of the study; they should not be filled by assuming standard methods or unstated protocol choices.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Lenalidomide Combined With Vorinostat/Gemcitabine/Busulfan/Melphalan With Autologous Stem-Cell Transplantation in Diffuse Large B-Cell Lymphoma of the ABC Subtype — NCT02589145.
• Registry record last updated 2019-12-13; status last verified 2019-11.
• Results first posted 2019-12-13.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

The registry describes a phase 1 and phase 2, single-group, open-label study of lenalidomide with vorinostat, gemcitabine, busulfan and melphalan and autologous stem-cell transplantation for diffuse large B-cell lymphoma of the ABC subtype. The study summary says treatment was with or without rituximab. Enrollment is listed as 8, and status as terminated.

The primary endpoint was maximum tolerated dose, assessed through day 30 post transplant for each cohort using a stated dose-limiting toxicity definition. The registry says dose selection was adaptive, with a minimum cohort size of 2 patients, but low accrual meant the MTD could not be determined. The record lists 7 outcome measures and 0 analyses. Numerical secondary outcome analyses and several statistical methods are not reported in the registry record.