Pegylated Arginine Deiminase in Treating Patients With Metastatic Melanoma That Cannot Be Removed by Surgery: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pegylated Arginine Deiminase in Treating Patients With Metastatic Melanoma That Cannot Be Removed by Surgery (NCT00450372), a na phase 2 study. The primary outcome is Response Rate (Partial and Complete Response) in Patients With or Without ASS Expression Present in Tumor..

2. Clinical Question

3. Trial Design

This was a phase II, completed, single-group trial sponsored by the University of Miami. The registry lists 38 enrolled participants. The start is recorded as 2004-06 and primary completion as 2011-01. The study title and summary describe treatment of metastatic melanoma that could not be removed by surgery.

ADI-PEG 20 is the named biological intervention; pharmacology studies are also listed. The record does not describe a randomized allocation or masking: allocation is listed as not applicable, masking as none, and the model as single group. Consequently, the design does not provide a concurrent control arm for comparing treatment outcomes. ASS status defines subgroups for the primary response question, rather than separate randomized arms.

The primary outcome is response rate, defined in terms of partial and complete response and assessed up to 16 months. The registry also lists median overall survival and median time to progression as secondary outcomes. Although three outcome measures are listed, the record reports zero analyses. It does not report numerical results for the primary response endpoint or the secondary outcomes.

The registry record does not report a sample-size justification, the statistical analysis plan, the method for assigning participants to any analysis population, or details of interim analyses. Completion status describes the trial's registry status; it does not, by itself, establish that every planned analysis or result is available in the 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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Of the 38 subjects enrolled, only 10 were ASS-positive and 17 were ASS-negative. The remaining 11 subjects, who declined pre-treatment biopsies, were not assessed.

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 Rate (Partial and Complete Response) in Patients With or Without ASS Expression Present in Tumor., measured over Up to 16 months.

The primary endpoint is the number of participants with a partial or complete response, assessed separately by whether ASS expression was present in the tumor. The registry defines response using RECIST version 1.0: a complete response requires disappearance of all target lesions, while a partial response requires at least a 30% decrease in the sum of the longest diameters of target lesions relative to the baseline sum. Either response had to last at least 30 days. The stated assessment timeframe is up to 16 months.

General: a binary response endpoint classifies each assessed participant as meeting or not meeting the response definition. It offers a direct way to describe the proportion of an assessed group with a specified tumor response. Its interpretation depends on consistent assessment, a clearly defined analysis population, and transparent reporting of both responders and the number assessed.

The registry record identifies the endpoint and the ASS subgroups but does not report the number of responders, response rates, or uncertainty estimates. It also states that 11 enrolled subjects were not assessed for ASS status after declining pre-treatment biopsies. Without the subgroup outcome counts, the endpoint's observed results cannot be described or compared.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What kind of endpoint is response?

General: a binary endpoint records whether each participant did or did not meet a defined event criterion. For this trial, the criterion is a partial or complete response that lasts at least 30 days, using RECIST version 1.0. The endpoint is therefore based on a classification of tumor response, rather than a continuous measurement such as change in tumor diameter alone. A response count needs a denominator: the number of participants assessed under the endpoint definition. Both should be reported for each group being described.

The registry describes the primary outcome in participants with or without ASS expression. It reports 10 ASS-positive and 17 ASS-negative participants, while 11 participants who declined pre-treatment biopsies were not assessed for ASS status. It does not report response counts within these groups, so no response proportion can be interpreted from the record.

What would uncertainty measures add?

General: a confidence interval communicates the statistical uncertainty associated with an estimate, given the method and assumptions used. For a binary response outcome, an interval around a response proportion would help readers distinguish a relatively precise estimate from one compatible with a broad range of values. A p-value, when appropriate, addresses a specific hypothesis under a statistical model; it does not measure the size or clinical importance of an effect.

The registry record does not report response estimates, confidence intervals, p-values, or the methods used to calculate them. Therefore, neither the size nor the precision of the response results can be evaluated. No inferential approach should be attributed to the trial based only on its endpoint definition.

How should the subgroup comparison be understood?

General: randomization helps make groups comparable, on average, with respect to factors that could affect an outcome. Here the registry lists a single-group model, no masking, and allocation as not applicable. ASS status distinguishes tumor subgroups; it is not a randomized assignment. A difference in response between ASS categories, if reported, would not by itself establish that ASS status caused the difference or that the treatment effect differs by ASS status.

Subgroup estimates can also be less precise when based on limited numbers of assessed participants. The registry does not provide response counts or uncertainty estimates for these subgroups, nor does it describe adjustment for other factors. The appropriate interpretation is consequently limited to the registry's stated subgroup structure, not an assumption that the groups are otherwise comparable.

What does over-dispersion mean generally?

General: over-dispersion occurs when observed variability is greater than a statistical model expects. It is a concern in some count-data analyses and can make standard errors too small if the model does not allow for the extra variability. It is not a property that can be diagnosed from the enrollment counts alone. The primary outcome is described as participants with a binary response, and the registry record does not report a model or any over-dispersion assessment. No conclusion about over-dispersion or its handling can be drawn.

Are the planning calculations trial results?

General: sample-size planning illustrations estimate how many participants might be needed under specified assumptions about an effect, significance level, allocation, and analysis. Such illustrations are not observed power and do not demonstrate that a trial had a particular probability of finding an effect. They are also distinct from the study's actual enrollment and from observed outcome estimates. The registry record does not report its own sample-size justification or statistical plan. Any planning illustration associated with these results should therefore be read as hypothetical, not as the trial's protocol rationale or as evidence about its outcomes.

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("ADI-PED 20: Argininosuccinate Synthetase Positive ", "ADI-PEG 20: Argininosuccinate Synthetase Negative ")
n      <- c(10, 17)
events <- c(0, 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  ADI-PED 20: Argininosuccinate Synthetase Positive   10  0  0.0  0.0  30.8  0.0  27.8  0.2  28.5
ARM  ADI-PEG 20: Argininosuccinate Synthetase Negative   17  4  23.5  6.8  49.9  9.6  47.3  9.7  47.6

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary response outcome and two secondary outcomes: median overall survival and median time to progression. It records three outcome measures and zero analyses. The record does not report numerical results for these outcomes, nor does it describe how many statistical tests were planned or performed.

Multiplicity arises when several outcomes, comparisons, or analyses are considered. General: testing many hypotheses can increase the chance of at least one apparently notable result under a setting where none of the tested effects is real. Statistical plans may address this through a prespecified hierarchy or adjustment, but the appropriate approach depends on the design and aims. The registry record does not report whether any multiplicity strategy was specified or used, so none can be inferred.

The primary endpoint is defined by ASS expression status, but the record does not say whether subgroup comparisons were prespecified, whether other subgroup analyses were considered, or how they were analyzed. No adjusted or unadjusted results are reported. The registry also does not report whether the secondary outcomes were analyzed or how missing outcome data were handled.

For ASS classification, the record explicitly states that 11 subjects declined pre-treatment biopsies and were not assessed. It does not report whether these participants were included in any outcome analysis, how response was handled for them, or whether any imputation or sensitivity analysis was used. The record does not describe the analysis populations for the primary or secondary outcomes beyond the stated ASS subgroup counts. These omissions limit assessment of how outcome availability, subgroup definition, and the selection of analyzed participants may affect interpretation.

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 3% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: neutropenia - grade 3 (8.1%), fatigue (5.4%), allergic reaction (2.7%), neutropenia - grade 4 (2.7%), thrombocytopenia (2.7%).

The registry lists one safety group, with 37 participants at risk for serious adverse events and 9 affected. For other adverse events, it lists 37 at risk and 5 affected. The record also lists serious adverse-event terms with percentages: Neutropenia - Grade 3, 8.1%; Fatigue, 5.4%; Allergic Reaction, 2.7%; Neutropenia - Grade 4, 2.7%; Thrombocytopenia, 2.7%; and Anaemia, 2.7%.

General: an at-risk count identifies the denominator used for the listed safety category, while an affected count describes the number recorded as experiencing that category. The term-specific percentages describe the registry's reported frequencies; they should not be treated as response outcomes or as evidence of comparative risk. The record does not provide a control group, so these figures do not support a controlled comparison.

The registry record does not report the number of deaths in this safety group. It also does not give enough detail to determine from these summaries whether participants could contribute more than one event, how event terms were coded, or how the term-specific percentages relate to the affected count. The listed figures should therefore be read as registry safety summaries, not as a complete account of event timing, attribution, or severity across all participants.

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

The record establishes that a phase II, single-group study of ADI-PEG 20 enrolled 38 participants with metastatic melanoma that could not be removed by surgery. It defines a primary tumor-response endpoint and describes assessment by tumor ASS expression. It also identifies two secondary outcomes and reports selected safety counts and event terms. These are useful descriptions of the registered study and its posted data.

However, the record does not report the primary response counts or rates, subgroup effect estimates, confidence intervals, or p-values. It does not report numerical results for median overall survival or median time to progression. As a result, the posted information does not establish how often response occurred, whether response differed across ASS subgroups, or how precise any such result might be. Absence of numerical efficacy results in the registry record is not evidence that no responses occurred.

The design also limits what a comparison could establish. There is no concurrent randomized control arm, and the ASS-defined subgroups are not treatment-assignment groups. Even if subgroup outcome estimates were available, differences would not automatically be attributable to ASS status or establish a treatment effect relative to another intervention or to no intervention.

General: a trial's endpoint definition, observed estimates, uncertainty, and design all contribute to interpretation. A clearly defined endpoint helps explain what was measured, but it does not substitute for results. Likewise, enrollment and safety summaries cannot answer the efficacy question. The record supports a description of the research question, enrollment, response definition, and listed safety events; it does not support a conclusion about the magnitude or precision of clinical benefit.

14. Why This Trial Matters Statistically

This trial illustrates why a registered endpoint and its numerical results need to be read separately. The record specifies a response definition based on RECIST version 1.0, including a minimum duration, and describes the response question by ASS tumor-expression status. Those details make the intended outcome recognizable. Yet the record does not report the response counts or estimates needed to interpret the outcome itself.

The enrollment description also makes analysis-population questions visible. Of 38 enrolled subjects, 10 were ASS-positive and 17 were ASS-negative; 11 who declined pre-treatment biopsies were not assessed for ASS status. For readers evaluating a subgroup endpoint, knowing which participants could be classified is important. The record does not explain how those without ASS classification were handled in outcome analyses.

The study's single-group design is another statistical distinction worth recognizing. A subgroup contrast within a single treatment group is not equivalent to a randomized comparison of treatments. Design determines which interpretations are supported, not just which statistical test might be used. Without a concurrent control arm, the record cannot provide a direct randomized estimate of treatment contrast.

Finally, safety counts and event-term percentages answer a different descriptive question from tumor response. Keeping efficacy, safety, and design information distinct prevents enrollment or adverse-event data from being mistaken for evidence about the primary endpoint. The registry record is informative about the trial's structure and stated measures, while its missing numerical efficacy results sharply limit statistical interpretation.

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 main trial-specific limitation in interpreting the registry record is that it does not report numerical results for the primary response endpoint. Although the response definition, timeframe, and ASS subgroup counts are stated, there are no response counts or rates, and no uncertainty estimates. The record therefore does not permit an assessment of response frequency or precision.

The primary outcome population also has incomplete ASS classification: 11 enrolled subjects declined pre-treatment biopsies and were not assessed. The record does not explain how these participants were handled in any response analysis, whether their response outcomes were available, or whether analyses addressed this missing classification. It does not describe the analysis population for the primary endpoint in further detail.

The design is single group, with no concurrent control arm and no masking. As a result, there is no randomized treatment comparison described in the registry. ASS-positive and ASS-negative status defines subgroups, not randomized arms. The record does not report methods for adjusting subgroup comparisons or addressing other differences between these groups.

Further limitations of the available record include no reported statistical analysis plan, sample-size justification, interim-analysis information, multiplicity strategy, or missing-outcome-data methods. The secondary outcomes are listed without numerical results. The safety summary gives counts and term-specific percentages, but does not report deaths for the group or enough detail to reconstruct event timing or attribution. These are limitations of what the registry record reports; they do not establish that the omitted analyses or information were absent from other trial documents.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Pegylated Arginine Deiminase in Treating Patients With Metastatic Melanoma That Cannot Be Removed by Surgery — NCT00450372.
• Registry record last updated 2017-02-08; status last verified 2016-12.
• Results first posted 2013-05-01.
• 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

NCT00450372 is a completed phase II, single-group trial sponsored by the University of Miami. The record lists 38 enrolled participants with metastatic melanoma that could not be removed by surgery and names ADI-PEG 20 as the biological intervention. The primary endpoint is partial or complete response by ASS tumor-expression status, defined using RECIST version 1.0 and requiring at least 30 days' duration. The registry lists median overall survival and median time to progression as secondary outcomes.

The primary outcome description identifies 10 ASS-positive and 17 ASS-negative participants; 11 others declined pre-treatment biopsies and were not assessed for ASS status. Numerical efficacy results and analysis methods are not reported in the registry record. Safety summaries list 37 at risk and 9 affected for serious adverse events, and 37 at risk and 5 affected for other adverse events. The design has no concurrent control arm, so ASS subgroup categories are not randomized comparators.