Cyclophosphamide, Fludarabine, and High-Dose Interleukin-2 in Treating Patients With Metastatic Melanoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Cyclophosphamide, Fludarabine, and High-Dose Interleukin-2 in Treating Patients With Metastatic Melanoma (NCT00085423), a na phase 2 study. The primary outcome is Number of partiCIPANTS WITH OBJECTIVE RESPONSE AS MEASURED BY RECIST.

2. Clinical Question

In plain terms, the study concerns response after a combined treatment regimen in patients with metastatic melanoma. Its design can describe outcomes among treated participants, but it cannot by itself separate the effect of the regimen from other explanations for an observed outcome. Without a comparator group, the registry record does not support a direct estimate of how outcomes would differ under another treatment or under no treatment.

The registry record identifies the study as phase II and lists Dartmouth-Hitchcock Medical Center as sponsor. It records the study as completed. These design and status details provide context for interpreting the question; they do not fill in the missing primary response result. Details such as the eligibility criteria and the treatment schedule are not reported in the registry record.

3. Trial Design

This was a phase II, single-group trial, with allocation listed as not applicable and masking listed as none. The registry record describes a completed study sponsored by Dartmouth-Hitchcock Medical Center. Enrollment was 20. The recorded start was 2004-02, and primary completion was 2008-12.

The study evaluated a regimen described as cyclophosphamide, fludarabine, and high-dose interleukin-2 in patients with metastatic melanoma. The interventions list also includes sargramostim, while the arm description refers to GM-CSF. The registry record does not provide detailed dosing, timing, or sequence information in the registry record for this analysis. The listed arm is “IL-2, CTX, fludarabine, GM-CSF.”

A single-group design records outcomes in participants receiving the regimen, without a concurrent randomized comparator. Accordingly, the response result, if reported, would be a description of the treated group rather than a treatment-versus-control effect. Differences between this group and an external population could reflect differences in participants, care, assessment, or follow-up, as well as treatment; the registry record does not establish a basis for disentangling those influences.

The primary outcome is objective response at 12 weeks, assessed by physical examination and radiologic testing using RECIST criteria. The listed secondary outcomes concern lymphocyte recovery measured by blood count and time to progression measured by RECIST. The registry record lists 3 outcome measures but reports 0 analyses in the record information used. That does not establish whether analyses were conducted elsewhere.

The registry record does not report the study’s sample-size justification, any interim analyses, or the statistical analysis plan. It also does not provide details sufficient to determine how all participants were followed or included in each outcome analysis. These omissions matter when interpreting the precision and completeness of any results.

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:

Analysis population for the primary outcome, as defined in the registry: Response was determined by physical examination and radiologic testing. Percent of the total number of patients treated was calculated.

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 OBJECTIVE RESPONSE AS MEASURED BY RECIST, measured over Response at 12 weeks.

The primary endpoint is the number of participants with an objective response at 12 weeks. The registry description says response was assessed by physical examination and radiologic testing using RECIST criteria. RECIST is a standardized approach to classifying tumor response from imaging, with the assessment also incorporating physical examination. The registry record says the percentage of the total number of patients treated was calculated.

As a general statistical concept, a binary response endpoint classifies each assessed participant into a response category, such as response or no recorded response, according to the specified criteria. A count indicates how many participants met the definition; a percentage relates that count to a stated denominator. The endpoint’s meaning therefore depends on a consistent response definition, assessment schedule, and denominator. The registry record identifies the response definition and the 12-week timeframe, but does not provide the response count or calculated percentage.

Objective response is used in cancer studies to describe tumor shrinkage meeting prespecified criteria. It is an outcome of tumor assessment, not by itself a complete account of overall clinical benefit, durability, symptoms, or harms. The listed secondary outcome of time to progression addresses a different question about when progression occurs; lymphocyte recovery is another distinct outcome. Results for those outcomes are not reported in the registry record information.

Because this study has no comparator group, the endpoint can describe response among treated participants but cannot establish a comparative treatment effect. Interpretation also depends on whether all participants were assessed at the stated time and how missing or unevaluable assessments were handled. Those details are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The statistical methods relevant to this study begin with the design. It is classified as a single-group trial, with allocation listed as not applicable and masking listed as none. In general, a single-group study can estimate or describe outcomes among people who receive the study regimen. It does not create a randomized treatment contrast. Without a randomized comparator, observed outcomes cannot by themselves show what would have happened to the same participants under another treatment.

What does a binary endpoint represent?

The primary outcome is a count of participants with objective response at 12 weeks. This is a binary-type endpoint: each participant’s assessment is classified according to whether it meets the response definition. The registry record specifies physical examination and radiologic testing using RECIST criteria. It also says a percentage of the total number of patients treated was calculated. A count and a percentage answer related but distinct descriptive questions: the count gives the number classified as responding, while the percentage expresses that count relative to a denominator.

As a general principle, that denominator needs careful attention. It may be all treated participants, all participants assessed, or another analysis population, depending on the stated method. The registry record’s description refers to the total treated population, but it does not report the response count, percentage, or treatment of missing and unevaluable assessments. The safety denominator is not automatically interchangeable with the endpoint denominator.

How should uncertainty be understood?

A confidence interval is a statistical range intended to express uncertainty around an estimate under a specified method and assumptions. For a response frequency, the interval would help show how much uncertainty remains around the observed proportion, particularly when the number of observations is limited. It does not guarantee that the true value lies in the interval, and it does not account for every possible source of bias. No confidence interval for the primary endpoint is reported in the registry record.

In general, a p-value summarizes how compatible data are with a specified null hypothesis under a statistical model. It is not the probability that a treatment works, nor does it establish clinical importance. Because the registry record lists 0 analyses and gives no primary endpoint estimate, there is no reported primary-outcome p-value to interpret. The registry record does not specify whether a hypothesis test was planned or how it would have been conducted.

What does the single-group structure imply?

Comparative methods estimate a contrast between groups. Here, no randomized comparison group is recorded, so a treatment-versus-control contrast cannot be obtained from the trial design. External comparisons, if made elsewhere, would need to address differences in populations, follow-up, measurement, and care. Such details are not reported in the registry record. The study’s reported results, when available, should therefore be read as outcomes observed in the study group rather than proof of a causal effect.

The absence of masking is another design feature. In general, awareness of treatment or study status can influence subjective decisions or assessments. Imaging-based criteria may offer a standardized framework, but the record does not describe assessment procedures, independent review, or safeguards against assessment bias. It would be inappropriate to assume any such procedures were or were not used beyond the recorded masking status.

How do the planning illustrations differ from trial results?

The stated sample-size assumptions describe planning illustrations computed from an observed effect, not the trial’s own design. They use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is a stated fraction of the observed effect. These conditions differ from the recorded single-group trial design. In general, such illustrations ask how a hypothetical study might be sized under chosen assumptions. They are not observed power, do not show that the trial had adequate power, and should not be presented as a design feature of this study. The registry record does not report the trial’s sample-size justification.

For general planning, a smaller target effect typically requires more information to detect reliably than a larger target effect, all else being equal. This is a general statistical relationship, not a result calculated for this trial. The posted illustration values are not stated in the registry entries used for this explanatory text and should not be inferred. The illustrations also do not change the interpretation of the missing primary result.

Why can event counts differ from rates?

A count records the number of participants or events meeting a definition. A rate or proportion requires a denominator and a clear definition of the unit being counted. In safety reporting, the number of people with at least one event can differ from the number of events if a person experiences multiple events. The safety details list participants at risk and participants affected for serious and other adverse events, but do not specify additional event-level detail. The anemia term is recorded as 44.4%; its context should be understood as a registry-reported term rather than as a treatment comparison.

Over-dispersion is a general concern when event data vary more than a simple statistical model expects. In that situation, a model assuming less variability can make uncertainty appear too small. The record does not provide an event-count model or enough detail to determine whether over-dispersion was assessed. This is a general methodological consideration, not a claim about an analysis performed in this trial.

Finally, the registry record lists 3 outcome measures and 0 analyses in the information used. A count of listed outcomes is not itself evidence of multiplicity adjustment, and the absence of recorded analyses does not establish what analyses were conducted elsewhere. The statistical analysis plan, interim analyses, missing-data methods, and multiplicity procedures are not reported 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("Group 1")
n      <- c(18)
events <- c(3)
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  Group 1  18  3  16.7  3.6  41.4  5.8  39.2  6.1  39.6

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 3 outcome measures. The primary outcome is objective response at 12 weeks; the listed secondary outcomes concern lymphocyte recovery measured by blood count and time to progression measured by RECIST. Considering multiple outcomes can raise a general multiplicity issue: the more hypotheses examined, the greater the chance that at least one apparently notable result arises by chance if each is interpreted without adjustment. Whether adjustment is needed depends on the objectives and analysis plan. A multiplicity strategy is not reported in the registry record.

The record lists 0 analyses in the information used. This means no analyses are recorded in that information; it does not establish whether analyses were conducted elsewhere or whether any adjustment was applied. The statistical analysis plan and any interim analyses are not reported in the registry record.

Missing outcome data can affect both the estimated response frequency and its uncertainty. In general, interpretation depends on how many participants were assessed, why assessments were missing, and how missing or unevaluable results were handled. The primary outcome description refers to the total number of patients treated, but the handling of missing assessments is not reported in the registry record.

The enrollment figure is 20, while the safety summaries report 18 participants at risk for each listed category. The registry record does not explain that difference. It is not possible to infer from these figures alone whether it reflects follow-up, eligibility for the safety summary, missing records, or another reason. No further analysis-population definitions are reported in the registry record.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: anemia (44.4%).

The registry safety summary lists 18 participants at risk for serious adverse events, with 8 affected. For other adverse events, it lists 18 at risk, with 4 affected. Anemia is the top serious adverse event term, reported as 44.4%. These are descriptive figures from the treated group; there is no comparator group in this trial with which to estimate a relative difference.

In general, a participant count is not necessarily the same as an event count: a participant can experience more than one event, depending on the reporting definition. The registry entries identify participants affected, but do not give event-level counts or further detail about timing, duration, severity grading, or attribution. The listed anemia percentage should be read as a reported term-level figure; the registry record does not provide enough detail to identify its numerator or denominator beyond the percentage itself.

Enrollment was 20, whereas the safety categories list 18 participants at risk. The reason for the different figures is not reported in the registry record. It should not be assumed that the figures describe the same analysis population or that the difference has a particular explanation. Serious adverse event summaries describe reported harms; without a control group and additional context, they do not quantify comparative risk or establish causation.

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

The registry record establishes that this completed phase II study evaluated a regimen described as cyclophosphamide, fludarabine, and high-dose interleukin-2 in metastatic melanoma. It identifies objective response at 12 weeks as the primary outcome and specifies physical examination and radiologic assessment using RECIST criteria. It also lists lymphocyte recovery and time to progression as secondary outcomes.

The record does not report the primary response count or percentage. It therefore does not show how many participants met the response definition, how precisely that result was estimated, or whether the observed outcome was consistent across participants. The secondary outcome results are also not reported in the record information used. No numerical treatment effect or comparative estimate can be drawn from these registry entries.

The study’s single-group design matters independently of the missing outcome values. Even if a response estimate were available, it would describe outcomes among treated participants. It would not establish that the regimen caused those outcomes, or that outcomes would differ from those under another treatment. The registry record contains no randomized control group for such a comparison.

The safety information records 8 participants with serious adverse events and 4 with other adverse events, each among 18 participants at risk, and lists anemia at 44.4% as the top serious adverse event term. These summaries describe reported events in the study group. They do not show a comparative safety profile or determine whether an individual event was caused by treatment.

Accordingly, the registry entries support a description of the study’s design, endpoints, and selected safety reporting, but not a conclusion about efficacy or comparative benefit. Important interpretive details—including the primary outcome result, missing-data handling, and statistical analysis plan—are not reported in the registry record. The absence of those details should be treated as uncertainty, not filled with assumptions.

14. Why This Trial Matters Statistically

This trial is statistically notable because its design and recorded endpoint call for different kinds of interpretation. The primary endpoint is a count of participants meeting an objective-response definition, which can describe tumor response in the treated group. But the single-group structure does not provide a randomized comparison. A response estimate, if reported, would not by itself answer whether outcomes differ from those under another treatment.

The registry record also illustrates why an endpoint definition is not the same as an endpoint result. It names RECIST-based assessment at 12 weeks and explains that response was assessed through physical examination and radiologic testing. Yet it does not report the response count or percentage. Without those values, neither the observed response frequency nor its precision can be interpreted from the registry information.

Denominators also deserve attention. Enrollment is reported as 20, while safety summaries use 18 participants at risk. The record does not explain the distinction. Recognizing that difference prevents readers from treating every population count as interchangeable or assuming that all outcomes were assessed in the same participants.

Finally, planning illustrations should not be confused with this study’s design or with observed power. Their assumptions describe hypothetical planning, including equal allocation between two arms, whereas the registry classifies this trial as single-group. The trial-specific sample-size justification and statistical plan are not reported in the registry record. These points show why design, endpoint results, denominators, and analysis assumptions each need to be read separately.

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 information recorded for this trial leaves important limitations for interpretation. The primary response result is not reported in the registry record, so the endpoint’s observed frequency and precision cannot be described. Although the outcome definition and 12-week timeframe are stated, the record does not give the number assessed, the number unevaluable, or how missing assessments were handled.

The single-group design has no randomized control comparison. This limits interpretation to outcomes observed among treated participants and prevents a direct within-trial estimate of a treatment contrast. Masking is listed as none; details on assessment review or other procedures to reduce measurement bias are not reported in the registry record.

Enrollment is 20, but the safety summaries list 18 participants at risk. The reason for this difference is not reported. The registry information does not clarify whether the safety and primary-outcome populations were defined differently or whether any participants lacked particular assessments. Those explanations should not be assumed.

The study’s sample-size justification, analysis plan, interim analyses, and multiplicity procedures are not reported in the registry record. The record lists 3 outcome measures and 0 analyses in the information used here, but that does not establish whether analyses were conducted elsewhere. The listed secondary outcomes also lack numerical results in the registry information.

Safety reporting is limited to the stated participant counts and the anemia term percentage. Further details about event timing, severity, duration, attribution, and event-level counts are not reported in the registry record. These omissions constrain both efficacy and safety interpretation; they do not establish that unreported outcomes were absent.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Cyclophosphamide, Fludarabine, and High-Dose Interleukin-2 in Treating Patients With Metastatic Melanoma — NCT00085423.
• Registry record last updated 2013-04-10; status last verified 2013-04.
• Results first posted 2013-04-10.
• 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

NCT00085423 is a completed phase II, single-group study sponsored by Dartmouth-Hitchcock Medical Center. It enrolled 20 participants with metastatic melanoma and evaluated a regimen described as cyclophosphamide, fludarabine, and high-dose interleukin-2. The record lists sargramostim among the interventions and GM-CSF in the arm description.

The primary outcome is objective response at 12 weeks, assessed by physical examination and radiologic testing using RECIST criteria. The registry record does not report the primary response count or percentage. Listed secondary outcomes concern lymphocyte recovery and time to progression. The registry information lists 3 outcome measures and 0 analyses.

Safety summaries report 8 participants with serious adverse events and 4 with other adverse events, each among 18 at risk; anemia is listed at 44.4% as the top serious adverse event term. The record does not explain why safety denominators differ from enrollment. The trial-specific statistical plan, sample-size justification, missing-data methods, and multiplicity procedures are not reported in the registry record.