Phase 1 Trial of Siplizumab and Dose-Adjusted EPOCH-Rituximab in T- and NK-Cell Lymphomas: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase 1 Trial of Siplizumab and Dose-Adjusted EPOCH-Rituximab in T- and NK-Cell Lymphomas (NCT01445535), a na phase 1 study. The primary outcome is Number of Participants With Serious and Non-serious Adverse Events.

2. Clinical Question

This is a phase 1 study of a combination regimen in T- and NK-cell lymphomas. The clinical question is chiefly about safety across the dose cohorts, in the context of the registry’s specified adverse-event endpoint. The registry also lists response to therapy, overall progression-free survival and overall survival as secondary outcomes, but their results are not reported in the registry record.

Siplizumab is described as an antibody that attaches to the CD2 protein found in these tumor types. The registry summary gives a rationale for studying the combination, but that rationale is not itself evidence of benefit. The posted safety counts can describe how frequently participants were recorded as having events in each cohort; they do not establish whether the regimen is better than another treatment or whether any event was caused by a particular study drug.

3. Trial Design

This was a phase 1 trial with a sequential model. The registry lists enrollment of 15 and describes four dose cohorts: 3.4 mg/kg, 4.8 mg/kg, 8.5 mg/kg and 15 mg/kg. The treatment combined siplizumab with EPOCH chemotherapy and rituximab, administered every 21 days according to the arm description. The record does not describe a randomized allocation or masking; allocation is listed as not applicable and masking as none.

The record identifies adults with T-cell and NK-cell lymphomas who had never received chemotherapy as the intended population. The conditions listed include T-cell peripheral lymphoma, gamma delta hepatosplenic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma and NK T-cell lymphoma. The study was sponsored by the National Cancer Institute. The listed start date is 2009-01-13, primary completion date is 2011-04-01, and status is completed.

The groups are dose cohorts, not randomized treatment arms. Their event counts therefore describe participants treated at different dose levels in this study; they do not provide a controlled estimate of the effect of siplizumab or the combination. Differences between cohorts could reflect dose, participant characteristics, timing or other factors, and the registry record does not report an adjusted analysis that separates these possibilities.

The primary endpoint was the number of participants with serious and non-serious adverse events. The timeframe ran from signing treatment consent until 30 days after removal from study treatment or until off study, whichever came first; the registry describes this as approximately 22 weeks. The registry lists response to therapy, overall progression-free survival and overall survival as secondary outcomes. Results for those outcomes are not reported in the registry record, so the posted data do not support an assessment of antitumor outcomes.

The registry record does not report the dose-escalation rules, eligibility details beyond the summary description, or a full statistical analysis plan. The sequential design and the dose cohorts are reported, but details about how dose decisions were made are not.

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:

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 Serious and Non-serious Adverse Events, measured over Date treatment consent signed until 30 days after removal from study treatment or until off study, whichever comes first, approximately 22 weeks..

The primary endpoint counts participants with serious and non-serious adverse events assessed using CTCAE v3.0. A participant count is a safety summary: it indicates how many people in a cohort were recorded as experiencing the specified event category during the stated observation period. It is not a count of every separate event episode, and it does not by itself describe how severe, long-lasting or treatment-related an event was.

The registry defines a serious adverse event by consequences such as death, a life-threatening experience, hospitalization, disruption of normal life functions, a congenital anomaly or an important medical event that may require intervention to prevent one of those outcomes. A non-serious adverse event is described as any untoward medical occurrence. These categories distinguish seriousness under the registry’s definition; they do not establish causation.

In general, safety endpoints are important in early-phase studies because they describe adverse events observed while a regimen is being evaluated. Counts can help readers understand the recorded safety experience in the studied cohorts. They are less informative about comparative risk without a suitable control group and clear information about event attribution, exposure and follow-up.

The stated observation window begins at treatment consent and ends at 30 days after removal from study treatment or at off-study status, whichever comes first. The registry characterizes the period as approximately 22 weeks. The primary endpoint therefore reflects events recorded within that specified window, rather than a lifetime or indefinite assessment.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a phase 1 sequential study with dose cohorts. This matters for statistical interpretation: the groups are organized by dose, not by randomized assignment to a study treatment and a control. The posted cohort counts are useful descriptions of the observed safety experience at those dose levels, but they are not a randomized comparison of treatment strategies. The registry record does not report the rules used to move between dose levels or a statistical plan for comparing cohorts.

What does a participant count measure?

The primary endpoint is the number of participants with serious and non-serious adverse events during the specified observation period. A participant-level count records whether participants were affected in the relevant category. It does not necessarily count each event occurrence separately, and it does not describe how long an event lasted. The record separately provides cohort counts of participants at risk and participants affected, which allows the posted results to be read within each cohort.

In general, counts are often easier to interpret when the denominator is clear. A count of affected participants alone does not convey the size of the group observed. Here, the cohort-level at-risk counts are reported alongside affected-participant counts. However, the serious-event term percentages are not accompanied by a stated denominator or calculation basis in the registry record, so they require additional caution.

Why is a sequential phase 1 design different from a randomized trial?

In general, randomization helps balance measured and unmeasured characteristics across comparison groups, on average. A sequential dose-cohort design serves a different purpose: observations are organized across dose levels, and the groups are not intended to function as concurrent randomized controls. The registry explicitly notes that this is not a randomized comparison and that the groups are not a like-for-like control comparison. An apparent difference between cohort counts cannot therefore be attributed to dose alone from these data.

The cohort sizes are small, making each observed participant especially influential in the descriptive results. In general, estimates based on small groups are uncertain and can change considerably with additional observations. Confidence intervals can communicate this uncertainty, but no confidence intervals are reported in the registry record for the posted event counts.

What can significance testing establish?

In general, a statistical test evaluates how compatible data are with a specified null hypothesis under its assumptions. A p-value is not the probability that a treatment works, nor does it measure the size or clinical importance of an effect. The registry record reports zero analyses and does not report p-values, confidence intervals, or a hypothesis-testing plan for the primary endpoint. No statistical-significance claim can be made from the posted counts alone.

The record also does not report adjusted analyses. In a nonrandomized comparison, adjustment may sometimes address measured differences, but it cannot guarantee removal of confounding, and it cannot substitute for the missing details about participant characteristics and analysis methods. The posted results should remain descriptive.

How should planning illustrations be read?

In general, sample-size calculations describe how many participants might be needed under specified assumptions to detect a chosen effect with a chosen statistical procedure. They are planning illustrations, not observed results and not evidence that a study had a particular probability of detecting an effect. The registry’s stated illustration assumptions are a two-sided significance level of 0.05, equal allocation between two arms and a normal approximation, with the effect defined as a stated fraction of the observed effect. The registry specifies that time-to-event illustrations use total events and other illustrations use participants per arm.

Those assumptions do not describe the actual sequential dose-cohort design, which has no randomized two-arm comparison. Any such illustration should not be mistaken for the trial’s own sample-size justification or for observed power. The registry record does not report a sample-size justification for the trial, and it does not report interim analyses or a prespecified statistical analysis plan.

What does over-dispersion mean in general?

For count outcomes, a simple statistical model may assume a particular relationship between the average count and its variability. Over-dispersion means the observed variability is greater than that model expects. In general, ignoring over-dispersion can make uncertainty appear smaller than it is. This trial’s primary endpoint is a participant count in small cohorts, and the registry record does not report a count model or an over-dispersion assessment. A model-based interpretation should not be inferred from the descriptive counts.

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("Cohort 1 - 3.4 mg/kg", "Cohort 2 - 4.8 mg/kg", "Cohort 3 - 8.5 mg/kg", "Cohort 4 - 15 mg/kg")
n      <- c(3, 3, 3, 6)
events <- c(3, 3, 3, 5)
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  Cohort 1 - 3.4 mg/kg  3  3  100.0  29.2  100.0  43.9  100.0  39.8  99.4
ARM  Cohort 2 - 4.8 mg/kg  3  3  100.0  29.2  100.0  43.9  100.0  39.8  99.4
ARM  Cohort 3 - 8.5 mg/kg  3  3  100.0  29.2  100.0  43.9  100.0  39.8  99.4
ARM  Cohort 4 - 15 mg/kg  6  5  83.3  35.9  99.6  43.6  97.0  42.1  96.3

11. Multiplicity, Missing Data and Analysis Populations

The registry lists several outcomes: the primary count of participants with serious and non-serious adverse events, and secondary outcomes for response to therapy, overall progression-free survival and overall survival. Reporting multiple outcomes can raise a multiplicity issue when formal tests are conducted, because repeated testing can increase the chance of at least one apparently notable result. In general, a statistical plan may address this through a testing hierarchy or another adjustment, but the registry record does not report such a plan. The listed secondary outcomes have no results reported in the registry record.

The registry record reports zero analyses. It does not describe which analysis populations were used, how participants who did not complete treatment were handled, or how missing outcome data were addressed. It also does not report whether outcomes were analyzed by dose cohort, by treatment received, or under another population definition. These details matter because the results can depend on who is included and how unavailable measurements are treated.

In general, missing data can reduce precision and can introduce bias if the reasons for missingness are related to outcomes. No missing-data method or amount of missing outcome data is reported in the registry record. This is particularly relevant to outcomes such as response and survival, for which follow-up and event definitions affect the analysis, but no such analysis details are reported.

The safety endpoint has a stated observation window, but the record does not explain how incomplete observation within that window was handled. The registry also does not report a multiplicity adjustment, an interim-analysis plan or a complete statistical analysis plan. These omissions limit assessment of whether all planned analyses and outcomes are represented by the posted results.

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 (66.7%), fever (in the absence of neutropenia, where neutropenia is defined as anc <1.0 x 10e9/l) (33.3%), infection (33.3%), fracture (16.7%).

The serious adverse-event counts are 0 of 3 participants in the 3.4 mg/kg cohort, 2 of 3 in the 4.8 mg/kg cohort, 2 of 3 in the 8.5 mg/kg cohort and 1 of 6 in the 15 mg/kg cohort. The non-serious adverse-event counts are 3 of 3, 3 of 3, 3 of 3 and 5 of 6, respectively. These counts refer to participants, not necessarily to the number of separate event episodes.

The registry lists febrile neutropenia at 66.7%, fever in the absence of neutropenia at 33.3%, infection at 33.3% and fracture at 16.7% among the serious-event terms. The denominator and calculation basis for these percentages are not reported in the registry record. The registry’s fever definition includes absence of neutropenia, with neutropenia defined as ANC <1.0 x 10e9/L.

These safety results describe events recorded within the specified follow-up window. They do not establish that the study drugs caused an event. The death counts are also reported, but their causes and relationship to treatment are not specified in these figures. Cohort sizes are small, and the cohorts are not randomized controls, so the counts should not be used as a comparative estimate of risk.

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

The posted results provide a description of serious and non-serious adverse events recorded across four dose cohorts in a phase 1 study. They show that serious adverse events were recorded in some cohorts and that non-serious adverse events were recorded in most or all listed participants. The registry also reports serious-event terms and deaths by cohort. These observations are relevant to understanding the safety experience recorded during the study’s defined follow-up period.

They do not show that any event was caused by siplizumab or another component of the combination. They do not establish whether a higher dose caused more or fewer events, because cohort membership was not randomized and the record does not report an adjusted comparison. They also do not establish comparative safety against another regimen, since no randomized control group is reported.

The registry names response to therapy, overall progression-free survival and overall survival as secondary outcomes, but their results are not reported in the registry record. Thus, the posted data do not establish the regimen’s antitumor activity or its effect on survival. The study’s stated rationale and the biological description of siplizumab are context, not results.

In general, a clinical study’s findings apply most directly to the participants and conditions observed in that study. The small dose cohorts and the missing detail about event attribution, analysis populations and missing data limit how confidently these counts can be generalized. The registry record also does not report confidence intervals or formal analyses that would quantify uncertainty around the event counts.

The most defensible reading is descriptive: these are the recorded participant counts and event terms for this study. They are not a causal comparison, a precise estimate of risk in a wider population, or evidence of efficacy. The record’s completed status does not resolve these interpretive limitations or substitute for the outcomes and analysis details that are not reported.

14. Why This Trial Matters Statistically

This study illustrates a common statistical challenge in early-phase clinical research: safety information can be important even when the design is not suited to estimate comparative treatment effects. The registry’s primary endpoint is a participant count for serious and non-serious adverse events, which aligns with a descriptive account of what was observed during treatment and follow-up.

The dose cohorts also show why the design must be kept in view when reading results. A sequential study is not a randomized trial with a control group. Cohort counts can be examined separately, but comparisons across dose levels may reflect differences beyond dose. Treating those cohorts as if they were exchangeable would overstate what the data can establish.

Small cohorts make uncertainty visible in a practical way: each participant contributes substantially to a group’s reported count. This is why descriptive counts should be interpreted alongside their denominators and not treated as precise estimates. The posted serious-event percentages also lack a stated denominator and calculation basis, making their interpretation more limited than the cohort-level participant counts.

The record’s separation of primary safety outcomes from secondary response and survival outcomes is also important. Naming an outcome does not mean its result is available, and safety counts cannot stand in for efficacy analyses. The secondary outcome results, formal analyses and analysis populations are not reported in the registry record.

Overall, the statistical value of the record lies in documenting the observed safety counts and the design context, while making clear where inference stops. It is a useful example of why design, denominators, follow-up and analysis reporting all matter when interpreting clinical trial results.

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 study is a phase 1 sequential trial with dose cohorts and no randomized control group. As the registry notes, the groups are not a like-for-like control comparison. This prevents a controlled estimate of the effect of the treatment combination and limits causal interpretation of differences between cohorts.

The cohorts are small: the registry lists 3, 3, 3 and 6 participants at risk across the dose groups. Counts from groups of this size are imprecise as descriptions of broader populations. The record does not report confidence intervals for the posted event counts, so their statistical uncertainty is not quantified.

The registry’s serious-event terms are accompanied by percentages, but their denominators and calculation basis are not reported. It is therefore unclear from the record how to relate those percentages to cohort-level counts or whether participants could be represented under multiple terms. The death counts are reported without a cause-specific explanation or treatment-attribution information in these figures.

The registry record does not report a full statistical analysis plan, a sample-size justification, analysis populations, a missing-data approach, or an interim-analysis plan. Although secondary outcomes are listed, their results are not reported in the registry record. The endpoint description supplies a follow-up timeframe, but the record does not explain how incomplete observation within that window was handled.

The population description is also limited in the registry summary. It identifies adults with specified lymphoma types who had never received chemotherapy, but further participant characteristics and subgroup details are not reported in the registry record. These limitations restrict assessment of generalizability and make the posted safety counts best read as descriptive observations from this study.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Phase 1 Trial of Siplizumab and Dose-Adjusted EPOCH-Rituximab in T- and NK-Cell Lymphomas — NCT01445535.
• Registry record last updated 2021-11-03; status last verified 2021-10.
• Results first posted 2020-08-18.
• 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

NCT01445535 is a completed phase 1 trial of siplizumab with DA-EPOCH-R in T- and NK-cell lymphomas. The registry lists a sequential design, no masking, enrollment of 15, and four dose cohorts: 3.4 mg/kg, 4.8 mg/kg, 8.5 mg/kg and 15 mg/kg. Treatment was described as being given every 21 days.

The primary endpoint was the number of participants with serious and non-serious adverse events assessed using CTCAE v3.0. The stated timeframe was from treatment consent until 30 days after removal from study treatment or until off study, whichever came first, approximately 22 weeks. The posted results include cohort-level safety counts and selected serious-event terms. Death counts are also listed by cohort.

Response to therapy, overall progression-free survival and overall survival are listed as secondary outcomes, but their results are not reported in the registry record. The record does not report a randomized control group or a complete statistical analysis plan. The safety findings are therefore descriptive and do not provide a controlled estimate of treatment effect.