Biological Therapy in Treating Patients at High-Risk or With Lymphoma, Lymphoproliferative Disease, or Malignancies: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Biological Therapy in Treating Patients at High-Risk or With Lymphoma, Lymphoproliferative Disease, or Malignancies (NCT00002663), a non-randomized phase 1, phase 2 study. The primary outcome is Objective Response Rate (ORR).

2. Clinical Question

3. Trial Design

This is a phase I/II, nonrandomized, parallel-group study registered as NCT00002663. Its stated purpose was to study side effects and dose of biological therapy for patients at high risk of, or with, EBV-associated lymphoma or lymphoproliferative disease. The registry lists an enrollment of 58 and a completed status. The recorded start is 1995-03, and primary completion is recorded as 2019-07.

The treatment is EBV-directed cellular therapy. The intervention listing identifies Epstein-Barr virus-specific cytotoxic T lymphocytes, or EBV-CTLs. The arm descriptions also identify tabelecleucel, abbreviated tab-cel, and include groups receiving one or the other treatment. Those groups differ by clinical setting, including EBV-positive disease after hematopoietic cell transplant or solid organ transplant, viremia, acquired immunodeficiency-associated disease, leiomyosarcoma, nasopharyngeal carcinoma, primary immunodeficiency-associated disease, and lymphoma. The registry descriptions specify intravenous treatment in several arms, but the descriptions are not complete for every listed group.

Allocation is nonrandomized and masking is listed as none. The parallel model indicates that treatment groups are considered alongside one another rather than participants crossing through treatments in sequence. However, the groups represent different conditions and treatment histories; they should not be read as interchangeable arms in a randomized comparison. The registry record does not report a randomized allocation process, a blinded assessment process, or a conventional untreated control group.

The primary outcome is objective response rate, assessed from Day 1 through 251.1 months after the Day 1 dose. The record also lists six outcome measures, including overall survival, survival rate at 12 months, follow-up time, time to response, and clinical benefit rate. Numerical results for these outcomes are not reported in the registry record. The record lists zero analyses, so the stated outcome definitions do not by themselves establish what numerical estimates or inferential analyses were performed.

Although the record is categorized as phase I/II, a detailed phase-specific design, dose-escalation scheme, or phase-specific analysis is not reported in the registry record. The sample-size justification and the planned approach to interim analyses are also not reported in the registry record. These omissions limit the ability to reconstruct the study's original statistical design from the registry summary alone.

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: A total of 58 participants were treated. However, 1 participant was analyzed in 2 different arms due to treatment. This participant was counted in only 1 arm for Participant Flow results and was counted in each arm for Outcome Measures.

Only the first 6 of 10 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full analysis set included all participants who received at least one dose of study treatment (tabelecleucel or EBV-CTLs). Results from arms with \<= 3 participants (as shown in the participant flow) are excluded due to the low numbers of participants; these low numbers pose a risk for participant re-identification in these rare indications of this single center study.

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: Full analysis set included all participants who received at least one dose of study treatment (tabelecleucel or EBV-CTLs). Results from arms with \<= 3 participants (as shown in the participant flow) are being excluded due to the low numbers of participants; these low numbers pose a risk for participant re-identification in these rare indications of this single center study.

6. Primary Endpoint

The registry lists the primary outcome as Objective Response Rate (ORR), measured over From Day 1 through 251.1 months after Day 1 dose.

The primary endpoint is objective response rate (ORR), expressed as the percentage of participants whose best overall response was complete remission or response (CR) or partial remission or response (PR), based on investigator assessment. In general, a response-rate endpoint reduces each participant's observed disease course to a response category and then summarizes the proportion meeting the specified response definition. It can describe antitumor or disease response without implying that the treatment caused the response.

For participants with clinically or radiologically evident EBV lymphoproliferative disease or malignancy, the registry defines CR as complete resolution of clinical and radiologic evidence, with biopsy confirmation when indicated. The response must last at least 3 weeks following completion of a cycle of tabelecleucel. PR is a 50 % or greater reduction in the size of all lymphomatous lesions, measured by CT or MRI, maintained for at least 3 weeks following completion of a cycle of tabelecleucel.

For participants without clinically or radiologically evident tumors but with increasing EBV DNA, CR is clearance of EBV without later development of EBV-positive lymphoproliferative disease. PR is at least a 10-fold decrease in EBV DNA levels. These different rules reflect distinct ways of assessing disease in participants with measurable tumors and those monitored through EBV DNA.

The registry specifies a 95% confidence interval for the endpoint. A confidence interval conveys uncertainty around an estimated response percentage; it does not describe the range of individual participant outcomes. The numerical ORR estimate, its interval, and the response counts are not reported in the registry record, so the endpoint's observed magnitude and precision cannot be assessed from the record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

A response rate is a binary-outcome summary: each participant is classified according to whether the defined response criterion was met, and the proportion meeting it is then estimated. In general, the result depends on both the response definition and the analysis population. Here, the registry defines ORR as the percentage with best overall response of CR or PR, but the numerical estimate is not reported in the registry record. Thus, the method can be explained, but its observed result cannot be reconstructed.

What does the confidence interval describe?

The registry lists a 95% confidence interval for ORR. In general, a confidence interval describes the uncertainty of an estimate under the statistical method used. A narrower interval indicates greater precision under that method, while a wider interval indicates less precision. It is not a range containing a specified percentage of individual responses, and it does not by itself establish that a treatment caused the observed outcome. Since neither the estimate nor the interval is reported in the registry record, the precision of this endpoint cannot be evaluated.

Why does the response definition matter?

CR and PR are not defined identically for all participants in this study. For those with evident disease, the endpoint relies on resolution or reduction of lesions, assessed clinically or radiologically, with the registry specifying CT or MRI measurements for PR. For participants without evident tumors but with increasing EBV DNA, response is based on clearance or reduction in EBV DNA. In general, endpoint rules need to be applied consistently because differences in measurement or assessment can influence classification. The registry record does not report operational details such as assessment schedules beyond the stated endpoint timeframe, independent review, or procedures for resolving uncertain classifications.

The definitions also require response to persist for at least 3 weeks after completion of a cycle of tabelecleucel in the stated tumor response criteria. This condition distinguishes a response that meets the duration rule from a change that does not. The record does not report how incomplete follow-up or discontinuation before confirmation was handled. It also does not report whether the same duration rule was applied to EBV DNA response classifications.

What does nonrandomized allocation imply?

In general, randomization helps balance measured and unmeasured prognostic factors between treatment groups, on average. In a nonrandomized study, treatment selection and clinical group membership can be associated with prognosis, prior treatment, or disease characteristics. As a result, an observed difference between groups may reflect those differences as well as treatment. This concern is especially relevant because the registry lists groups defined by distinct diseases and treatment histories. The record does not identify a randomized comparator or report a comparative statistical analysis that would address these differences.

Masking is listed as none. In general, knowledge of treatment assignment can influence subjective outcome assessment or reporting, particularly when outcome classification requires investigator judgment. The registry's outcome definition is investigator-assessed, but the record does not report further safeguards such as independent blinded review. This does not establish that assessments were biased; it identifies a possible source of measurement uncertainty that cannot be assessed from the registry summary.

What is known about the analysis population?

The registry describes the full analysis set as all participants who received at least one dose of study treatment, either tabelecleucel or EBV-CTLs. It also states that ORR results from arms with 3 or fewer participants were excluded because low numbers posed a risk for participant r. The final phrase is incomplete in the registry description. The record does not report the exact ORR denominator, the number of evaluable participants, or the reasons participants may have been omitted from outcome assessment. Therefore, enrollment should not be treated as the denominator for the ORR.

Missing outcome data can affect a binary response estimate if participants without an assessable response are handled differently from participants with an observed response. In general, analysts may define rules for missing or unevaluable outcomes, conduct sensitivity analyses, or describe missingness by group. Such handling can change the interpretation of a response proportion. The missing-data rules and any sensitivity analyses are not reported in the registry record.

How should sample-size illustrations be read?

In general, a sample-size calculation illustrates how many observations might be needed under specified assumptions; it is not evidence about the results of the completed study. The planning assumptions described for the illustrations use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect expressed as a stated fraction of the observed effect. These are planning conditions, not a report of observed power. The registry record does not report the study's own sample-size justification, and the numerical ORR result needed to anchor an observed-effect illustration is not reported in the registry record.

Over-dispersion is a general issue when outcome variability exceeds what a simple statistical model assumes; if ignored, uncertainty can be understated. The registry information does not identify an over-dispersion model or say that one was needed for this binary endpoint. No such analysis should be inferred from the endpoint definition alone.

Finally, the registry lists zero analyses. That entry does not provide an estimate, hypothesis test, or model specification. Statistical methods beyond the endpoint's 95% confidence interval are not reported in the registry record. General descriptions of confidence intervals, nonrandomized comparisons, and missing-data concerns explain how such analyses are usually interpreted, but they are not claims about methods actually used in this trial.

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("EBV+ PTLD-HCT R/R Rituximab (Tab-cel Only)", "EBV+ PTLD-SOT R/R Rituximab + Chemo (Tab-cel Only)", "EBV+ LMS (Tab-cel Only)", "EBV+ PTLD-HCT R/R Rituximab (EBV-CTLs Only)", "EBV+ Viremia (EBV-CTLs Only)")
n      <- c(11, 4, 5, 23, 7)
events <- c(7, 2, 0, 10, 4)
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  EBV+ PTLD-HCT R/R Rituximab (Tab-cel Only)  11  7  63.6  30.8  89.1  35.4  84.8  34.9  84.8
ARM  EBV+ PTLD-SOT R/R Rituximab + Chemo (Tab-cel Only)  4  2  50.0  6.8  93.2  15.0  85.0  14.7  85.3
ARM  EBV+ LMS (Tab-cel Only)  5  0  0.0  0.0  52.2  0.0  43.4  0.4  45.9
ARM  EBV+ PTLD-HCT R/R Rituximab (EBV-CTLs Only)  23  10  43.5  23.2  65.5  25.6  63.2  25.6  63.4
ARM  EBV+ Viremia (EBV-CTLs Only)  7  4  57.1  18.4  90.1  25.0  84.2  24.5  84.3

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary endpoint and secondary outcomes that include overall survival, survival rate at 12 months, follow-up time, time to response, and clinical benefit rate. It reports six outcome measures, but the numerical estimates for the listed outcomes are not reported in the registry record. The record lists zero analyses. It therefore does not show which outcomes were analyzed, whether all planned outcomes were reported, or how estimates were calculated.

Multiplicity arises in general when several outcomes, comparisons, or analyses are examined. If many statistical tests are conducted, the chance of at least one apparently notable result can increase unless the analysis plan accounts for it. The registry record does not report a multiplicity adjustment, a hierarchy among secondary outcomes, or a prespecified testing strategy. It would be inappropriate to assume that a particular correction was or was not used in the underlying study based only on the available record.

The outcome population is described as a full analysis set including participants who received at least one dose of treatment. The record also says that results from arms with 3 or fewer participants were excluded from ORR results. It does not report the number of participants actually contributing to the ORR estimate, the number with unevaluable response, or the treatment of participants with missing assessments.

In general, missingness matters when the availability of an outcome is related to participants' prognosis or observed course. Excluding participants with missing assessments can make a response proportion differ from one based on all treated participants, depending on the reasons for missingness and the analysis rule. The registry does not report missing-data assumptions, imputation methods, sensitivity analyses, or outcome-specific denominators. Accordingly, the completeness and robustness of the endpoint analysis cannot be assessed from the registry record.

The sample-size justification, interim-analysis plan, and full statistical analysis plan are not reported in the registry record. The record does describe planning illustrations based on specified assumptions, but those illustrations are not a substitute for a trial-specific design justification or evidence of observed power.

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

Serious events with the highest arm-level rate: pyrexia (22.4%), device related infection (13.8%), hypoxia (8.6%), infection (6.9%), febrile neutropenia (5.2%).

The registry lists 58 participants at risk for the overall serious adverse event summary and 40 affected. It also lists 32 deaths. These are separate recorded figures; the registry information does not establish that every death was caused by treatment or clarify the relationship between the deaths and serious adverse events. The record does not report timing, causes, or individual clinical context for these counts.

Several serious adverse event terms are listed with percentages: pyrexia, 22.4%; device related infection, 13.8%; hypoxia, 8.6%; infection, 6.9%; febrile neutropenia, 5.2%; and abdominal pain, 5.2%. These figures describe the percentages recorded for the listed terms. The registry summary does not provide term-specific counts or clearly state the denominator and counting rules for each percentage, so the percentages should not be converted into counts or compared as if their denominators were fully documented.

In general, a serious adverse event is a safety classification, not a judgment that treatment caused the event. A listed event may occur during a study without being attributable to the intervention. The registry information does not provide event-by-event causality assessments, severity grades, duration, or exposure-adjusted rates. The figures therefore describe reported safety events but do not, by themselves, establish their cause or allow a complete comparison of risks between treatment groups.

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

The record establishes that a completed phase I/II study evaluated EBV-directed cellular therapy in a range of patients with EBV-associated disease or elevated risk. It identifies objective response rate as the primary endpoint and gives definitions for complete and partial response across participants with evident tumors and those monitored through EBV DNA. It also records an overall enrollment of 58 and reports aggregate serious adverse event and death figures.

What it does not establish from the registry information is the magnitude of the observed ORR. The response percentage, response counts, and 95% confidence interval are not reported in the registry record. The listed outcome definition is not a result, and the completed status does not fill in the missing endpoint estimate. The secondary outcome results are also not reported in the registry record.

The nonrandomized design means that the listed treatment groups should not be interpreted as randomized alternatives. Groups vary by disease setting and treatment history, and the record does not report a comparative analysis adjusting for those differences. Therefore, the record cannot establish a causal treatment effect or a reliable relative ranking of the listed groups.

The safety summary records serious events and deaths, but does not report enough information to attribute events to treatment or to interpret them as comparative risks. The figures can be read as safety events recorded in the overall study population, not as proof that the intervention caused those events. The registry does not provide the event-level context needed to characterize timing, attribution, or differences across groups.

In general, a clinical response rate can be informative about observed disease response under a specified definition. Its meaning depends on assessment procedures, follow-up, the population analyzed, and how missing data are handled. Those details are incompletely reported in the registry record. The defensible conclusion is therefore descriptive: the record defines an endpoint and describes a study population and safety summary, while leaving the primary numerical response result and important analysis details unreported.

14. Why This Trial Matters Statistically

This study illustrates why a clearly defined endpoint is essential but not sufficient for statistical interpretation. The registry provides detailed response criteria for participants with measurable disease and for those monitored through EBV DNA. That distinction makes the endpoint applicable across varied clinical presentations, while also raising questions about how assessments were harmonized and how different measurement routes were combined. The registry record does not report those operational details.

The trial also shows the interpretive limits of a nonrandomized, multi-group design. Its clinical groups span transplant-related disease, viremia, and several forms of EBV-associated disease. Such breadth may be relevant to describing the settings studied, but it complicates direct comparisons because clinical characteristics and treatment histories differ. The registry explicitly does not describe a like-for-like randomized control comparison.

From a statistical reporting perspective, the absence of a numerical ORR estimate and confidence interval is consequential. Without them, readers cannot assess the response proportion or its precision, even though the endpoint is defined. The record's description of a full analysis set and exclusion of arms with 3 or fewer participants further highlights the need to report denominators and analysis populations alongside outcome estimates.

Safety figures also require context. Aggregate counts and listed percentages can identify events recorded during the study, but they do not by themselves establish causality or comparative risk. Reporting event attribution, timing, and denominator details would be necessary for a fuller safety interpretation.

Overall, the record is useful for understanding the study's broad design, clinical scope, and intended outcome, while demonstrating how much statistical interpretation depends on transparent results and methods reporting. It does not support conclusions about the magnitude or cause of treatment response.

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 limitation for statistical interpretation is that the numerical ORR result is not reported in the registry record. The record gives the endpoint definition and specifies a 95% confidence interval, but the estimate, interval, and response counts are absent. The listed secondary outcomes likewise have no numerical results in the registry information, and the record lists zero analyses.

The study is nonrandomized and includes treatment groups defined by differing disease settings and histories. These groups are not a like-for-like control comparison. The registry does not report adjusted comparisons, group-level prognostic information, or a randomized control group, so treatment effects cannot be isolated from potential differences among participants.

The registry describes the full analysis set as participants who received at least one dose. It also states that ORR results from arms with 3 or fewer participants were excluded, with a rationale that is incomplete in the record. The ORR denominator, number of evaluable participants, arm-specific enrollment, and reasons for any exclusions are not reported in the registry record. Missing-data rules and sensitivity analyses are also not reported.

The endpoint uses different response criteria for participants with evident tumors and those assessed through EBV DNA. The registry does not report assessment standardization, independent review, handling of uncertain assessments, or how differences in assessment routes were considered analytically. Masking is listed as none, and further safeguards against assessment-related bias are not described.

The serious adverse event summary gives overall figures and selected percentages, but does not report event-level causality, timing, term-specific counts, or clear term-specific denominators. Deaths are listed without further context. The sample-size justification, interim-analysis plan, and full statistical analysis plan are not reported in the registry record. These limitations constrain both efficacy and safety interpretation.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Biological Therapy in Treating Patients at High-Risk or With Lymphoma, Lymphoproliferative Disease, or Malignancies — NCT00002663.
• Registry record last updated 2023-02-13; status last verified 2023-01.
• Results first posted 2023-02-13.
• 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.

19. Record Summary

NCT00002663 is a completed phase I/II, nonrandomized, parallel-group study of EBV-directed cellular therapy. The registry records enrollment of 58, with a start date of 1995-03 and primary completion in 2019-07. Treatment descriptions include EBV-CTLs and tabelecleucel in groups defined by disease setting and clinical history. Masking is listed as none.

The primary endpoint is investigator-assessed ORR, defined using complete or partial response criteria tailored to participants with evident disease or increasing EBV DNA without evident tumors. The stated timeframe runs from Day 1 through 251.1 months after the Day 1 dose. The numerical ORR result and 95% confidence interval are not reported in the registry record. The record lists six outcome measures and zero analyses.

The overall safety summary lists 58 participants at risk, 40 affected by serious adverse events, and 32 deaths, along with selected serious adverse event percentages. Event attribution and additional context are not reported in the registry record. The study's nonrandomized groups do not provide a like-for-like control comparison.