Fenretinide and Rituximab in Treating Patients With B-Cell Non-Hodgkin Lymphoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Fenretinide and Rituximab in Treating Patients With B-Cell Non-Hodgkin Lymphoma (NCT00288067), a na phase 1, phase 2 study. The primary outcome is Response Rates of B-Non-Hodgkin Lymphoma to the Combination of Rituximab and Fenretinide (Phase II).

2. Clinical Question

3. Trial Design

This was a Phase I-II study of fenretinide plus rituximab, sponsored by the National Cancer Institute (NCI). The registry lists the study as single-group, with allocation recorded as not applicable and masking as none. These features mean that the design does not provide a concurrent control group for estimating how outcomes would have differed under another treatment. The registry enrollment is 32.

The study had a dose and safety component as well as a response component. The record states that no subjects in Phase I met the DLT criterion, and that Phase II was conducted at 900mg/m2. The criteria used to define a DLT and the detailed dose-escalation approach are not reported in the registry record. The registry describes fenretinide alone in the Phase I schedule and the combination schedule in Phase II.

In Phase I, fenretinide was administered by mouth twice daily on days 1-5, with weekly treatment planned for at least 4 weeks in the absence of disease progression or unacceptable toxicity. In Phase II, fenretinide was administered by mouth twice daily on days 1-5 in weeks 1-8, and rituximab was administered intravenously once weekly in weeks 5-8. The Phase II arm description ends mid-sentence in the registry record, so any subsequent treatment details are not reported there.

The primary outcome concerns response in Phase II, with partial response or better counted as a response. The record indicates stratification by rituximab-naïve and rituximab pre-treated status, with different target response rates for these groups. The study began in 2005-10, had a primary completion date of 2013-07, and is listed as terminated. The reason for termination is 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.

Overall Study

Analysis population for the primary outcome, as defined in the registry: 7 participants were analyzed in the Rituximab Naive arm and 16 participants were analyzed in the Rituximab Pre Treated Arm.

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 Response Rates of B-Non-Hodgkin Lymphoma to the Combination of Rituximab and Fenretinide (Phase II), measured over Up to 7 years.

The primary outcome is the number of participants with B-cell non-Hodgkin lymphoma who achieved a response of partial response or better. Response is a categorical outcome: each participant is classified according to whether the stated response threshold was met. The registry gives the timeframe as up to 7 years, but does not report the response counts or the assessment schedule used to determine response.

A response outcome is used to describe antitumor activity in terms of whether participants meet a prespecified disease-response criterion. It can be useful in an early-phase study because it provides a direct summary of observed responses in the treated group. It is not, by itself, a comparison of treatment effects against an untreated or alternative-treatment group. In a single-group study, the result can describe what was observed among enrolled participants, but it cannot isolate the effect of the combination from other explanations.

The registry states that the target response rates were 30% for rituximab-naïve patients and 10% for rituximab pre-treated patients. The reported endpoint description defines a response as partial response or better, but the actual number responding in either stratum is not reported in the registry record. The record also notes that 4 subjects were not evaluable for disease response, including 2 in Phase I and 2 in Phase II. The handling of those participants in the endpoint analysis is not reported.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a single-group Phase I-II trial and identifies a binary primary outcome: whether a participant achieved partial response or better. The outcome is expressed as a number of participants, rather than as a continuous measurement. The record gives the response timeframe as up to 7 years and describes separate target response rates for patients who were rituximab-naïve and those who were rituximab pre-treated.

What does a single-group response analysis estimate?

General statistical explanation: In a single-group study, a response analysis usually describes the proportion of the analyzed participants who meet the response definition. That proportion is a summary of the observed group. It does not estimate a randomized treatment contrast because there is no concurrent comparison group. Even when a response proportion is compared with a target, the target is not a control group observed under the same study conditions.

The registry record does not report the observed response counts, the analysis denominators, or a response proportion. It therefore does not allow the estimate to be reconstructed or its uncertainty to be evaluated. It also does not report the statistical test or estimation procedure used for the primary outcome.

Why is a confidence interval useful?

General statistical explanation: A confidence interval communicates uncertainty around an estimate. For a response proportion, it describes a range of values compatible with the observed data under the method used. It can help distinguish a relatively precise estimate from one that is uncertain. An interval does not guarantee that the true value lies within its bounds, and it does not correct for design limitations such as the absence of a control group.

No confidence interval or other measure of precision for the response outcome is reported in the registry record. The absence of a reported interval means that readers cannot assess how much uncertainty surrounds the planned comparison with the target rates. The record also lists 4 subjects as not evaluable for response, but does not state how these subjects were incorporated into any analysis.

What role does stratification play?

The primary outcome description says the trial was stratified by rituximab-naïve and rituximab pre-treated status. The stated targets differ between these groups: 30% and 10%, respectively. Stratification can be used to organize analyses or enrollment around a characteristic thought relevant to the outcome. In this study, prior rituximab treatment is the characteristic named in the registry record.

However, the record does not provide the numbers in each stratum, the response counts by stratum, or a statistical method for comparing observed responses with the respective targets. It does not report whether a combined response summary was also planned or how such a summary would account for the different targets. Those details are not reported in the registry record, so the intended analysis cannot be fully reconstructed.

How should the Phase I result be read?

The registry states that no subjects in Phase I met the DLT criterion and that Phase II was conducted at 900mg/m2. In general, a dose-limiting toxicity rule is used in early-phase research to guide dose evaluation. The rule's definition, observation period, and decision method are not reported in the registry record. No further inference about dose selection should be made from the brief statement alone.

Phase I and Phase II address different aspects of the study. The registry's description associates Phase I with dose and side-effect evaluation and Phase II with response. The Phase II response outcome cannot be inferred from the statement about DLTs in Phase I. The record does not report a statistical model for combining data across phases, and the posted primary outcome is specifically described as a Phase II response measure.

Why can over-dispersion matter?

General statistical explanation: Some statistical models assume that observed outcomes vary according to a specified probability distribution. Over-dispersion occurs when actual variability is greater than that assumption allows. If it is ignored, standard errors and confidence intervals can be too small, making results appear more precise than they are. The registry record does not report a model for the response endpoint or indicate whether over-dispersion was assessed. This concept therefore explains a general issue in statistical modeling; it is not a reported feature or finding of this trial.

The registry lists no analyses. It does not report a statistical analysis plan, a sample-size justification, interim analyses, adjustment for multiple comparisons, or the handling of missing response data. The planning illustrations associated with the posted results are not the trial's own design justification. Any such illustration is a planning calculation under its stated assumptions, not observed power and not a substitute for the missing response estimate. No further statistical method should be attributed to the investigators from the information in the registry record.

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("Fenretinide and Rituximab (Rituximab Naive)", "Fenretinide and Rituximab (Rituximab Pre Treated)")
n      <- c(7, 16)
events <- c(4, 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  Fenretinide and Rituximab (Rituximab Naive)  7  4  57.1  18.4  90.1  25.0  84.2  24.5  84.3
ARM  Fenretinide and Rituximab (Rituximab Pre Treated)  16  0  0.0  0.0  20.6  0.0  19.4  0.1  19.5

11. Multiplicity, Missing Data and Analysis Populations

The registry identifies a primary response outcome and two outcome measures overall, but does not describe a multiplicity strategy. It does not report whether statistical testing was planned across outcomes, phases, disease groups, or the rituximab-naïve and pre-treated strata. The record gives separate response targets for the two prior-treatment strata, but does not state whether these were intended as separate formal hypotheses or how any multiple testing would be handled. The statistical plan is not reported in the registry record.

Missingness is relevant because the primary outcome description says 4 subjects were not evaluable for disease response. The record specifies that 2 were in Phase I and 2 were in Phase II. It does not explain why those participants were not evaluable, how evaluability was determined, or whether the reasons differed by phase or treatment history. It also does not report whether non-evaluable participants were excluded, counted as nonresponders, or handled by another approach.

The analysis populations are not reported in the registry record. In particular, the record does not identify the population used for the Phase II response outcome or give analysis denominators within the rituximab-history strata. This prevents assessment of whether the analysis followed all enrolled participants, only those evaluable for response, or another defined group.

These omissions matter because response proportions depend on both the number of observed responses and the denominator used. Different approaches to non-evaluable participants can produce different summaries. Without the analysis population, missing-data approach, response counts, and multiplicity plan, the posted information cannot establish how robust any response estimate would be to those analytical choices.

12. Safety Results

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

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: allergic reaction (3.1%), hypotension (3.1%), rash maculo-papular (3.1%), infections and infestations - other, specify, infection with grade 3 or 4 neutrophils (anc <1.0 x 10 (3.1%), acute coronary syndrome (3.1%).

The registry lists a group titled Fenretinide and Rituximab, with 32 participants at risk for serious adverse events and 6 participants affected. It separately lists 32 participants at risk for other adverse events and 32 affected. These are counts reported in the registry record; they should not be read as evidence about whether an event was caused by the treatment.

The serious adverse event terms listed are Allergic Reaction, Hypotension, Rash Maculo-papular, an infection term whose description includes Grade 3 or 4 neutrophils (ANC <1.0 x 10, Acute Coronary Syndrome, and Wound Infection. Each term is listed as 3.1%. The infection description is incomplete in the registry record. The listed percentages are presented as recorded and do not establish that each term represents a different participant or that the terms account for all serious adverse events.

The registry does not report deaths in the serious adverse event group. It also does not provide event-level detail, timing, duration, severity beyond the text of the listed terms, or a causal assessment for each event. The meaning of the separate other-adverse-event count is not further detailed in the record. Safety counts should therefore be interpreted as descriptive reporting, not as a comparative estimate against another treatment.

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

The registry record establishes that a single-group Phase I-II study evaluated fenretinide with rituximab and that the primary Phase II outcome was the number of participants achieving partial response or better. It also reports the target response rates used for rituximab-naïve and rituximab pre-treated patients, and notes that 4 subjects were not evaluable for response. These details describe the study question and some aspects of the analysis context.

The record does not report the actual response counts, the response analysis denominators, or estimates of precision. It therefore does not show the magnitude of the observed response result or how uncertain that result was. The targets cannot substitute for the observed results. Without response data, no conclusion can be drawn from the posted record about whether the observed response rates met or differed from those targets.

The study also lacks a concurrent control group. A response observed in a single group cannot establish the effect of the combination relative to another treatment, or distinguish treatment effects from other influences on observed outcomes. The registry does not report a comparative estimate. The trial's single-group design is especially important when interpreting response as evidence about treatment effect rather than as a description of outcomes among participants.

The Phase I statement that no subjects met the DLT criterion and that Phase II proceeded at 900mg/m2 describes the study's dose progression as recorded. It does not establish the Phase II response result or provide a complete account of the safety profile. Serious adverse event counts are listed, but causality and comparative safety are not reported.

In sum, the record supports a limited account of the design, planned response endpoint, and some safety counts. It does not support a quantitative assessment of the primary response outcome or a comparative claim about treatment effects. The reason the study was terminated is not reported, so its status should not be interpreted as evidence for any particular efficacy or safety conclusion.

14. Why This Trial Matters Statistically

This study raises several statistical issues common to early-phase clinical research. It combines a Phase I dose and safety component with a Phase II response question, but the registry record provides only limited detail about the decision process connecting those phases. It reports that no subjects met the DLT criterion in Phase I and that Phase II was conducted at 900mg/m2, while leaving the DLT definition and dose-selection method unreported.

The response target differs according to prior rituximab treatment: 30% for rituximab-naïve patients and 10% for rituximab pre-treated patients. This makes the definition of the analysis populations and the reporting of stratum-specific results important. The registry record describes stratification but does not give stratum sizes, response counts, or the statistical plan for interpreting results against the targets.

The single-group design also illustrates the distinction between describing an outcome and estimating a comparative treatment effect. A response count can summarize what happened among participants, but without a concurrent comparator it cannot directly quantify how outcomes would differ under another treatment. This distinction matters when a study's objective is framed in terms of how well a combination works.

Finally, the 4 subjects not evaluable for response underscore the importance of transparent analysis populations and missing-data rules. The registry does not state how those subjects were handled, and it does not report the response result itself. These gaps prevent readers from assessing either the response estimate or its precision. The trial is therefore statistically informative as an example of why outcome definitions, denominators, missing-data handling, and analysis plans need to accompany planned targets.

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 is that the registry record does not report the observed response counts, despite identifying response as the primary Phase II outcome. It also omits the response denominators and any estimate of precision. As a result, the primary efficacy result cannot be interpreted quantitatively from the posted record.

The design is single-group, without a concurrent control. There is no randomized comparison or like-for-like control group from which to estimate a difference in response. The study's response targets are not substitutes for an observed control group. In addition, the registry does not report how the two prior-rituximab strata were populated or analyzed.

The record notes 4 subjects were not evaluable for disease response, including 2 in Phase I and 2 in Phase II, but does not report the reasons, analysis handling, or analysis population. It does not state whether the primary endpoint was assessed consistently across participants or how response was adjudicated. These details are not reported in the registry record.

Several methodological details are also absent: the DLT definition, the statistical analysis plan, sample-size justification, interim analyses, missing-data methods, and multiplicity handling. The Phase II treatment description is truncated after its final sentence begins, leaving any subsequent regimen details unreported in the registry record. The record does not give a reason for the terminated status.

Safety interpretation is constrained by the limited event detail. The registry reports serious adverse event counts and listed terms, but not causal attribution, event-level information, or comparative safety data. The infection term is incomplete as written in the record. Taken together, these limitations mean the record supports a description of the study structure and selected reported counts, but not a complete efficacy or safety assessment.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Fenretinide and Rituximab in Treating Patients With B-Cell Non-Hodgkin Lymphoma — NCT00288067.
• Registry record last updated 2014-10-06; status last verified 2014-01.
• Results first posted 2014-10-06.
• 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

NCT00288067 is a National Cancer Institute (NCI) Phase I-II single-group study of fenretinide and rituximab in patients with B-cell lymphoma. The registry lists enrollment of 32, no masking, a start date of 2005-10, primary completion in 2013-07, and terminated status.

The primary Phase II outcome is the number of participants achieving partial response or better, with a timeframe of up to 7 years. The registry states target response rates of 30% among rituximab-naïve patients and 10% among rituximab pre-treated patients. It reports that 4 subjects were not evaluable for disease response, but does not report the observed response counts or analysis denominators.

The registry reports no Phase I subjects met the DLT criterion and that Phase II was conducted at 900mg/m2. Serious adverse events are reported for 6 participants among 32 at risk; the reason for termination, statistical analysis plan, and response analysis details are not reported in the registry record.