Study of Zalypsis® (PM00104) in Patients With Unresectable Locally Advanced and/or Metastatic Ewing Family of Tumors (EFT) Progressing After at Least One Prior Line of Chemotherapy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Zalypsis® (PM00104) in Patients With Unresectable Locally Advanced and/or Metastatic Ewing Family of Tumors (EFT) Progressing After at Least One Prior Line of Chemotherapy (NCT01222767), a na phase 2 study. The primary outcome is Overall Response Rate (ORR).

2. Clinical Question

3. Trial Design

This was a phase II, multicenter, open-label clinical and pharmacokinetic study of Zalypsis (PM00104). The stated purpose was to determine antitumor activity in patients with unresectable locally advanced and/or metastatic Ewing family of tumors progressing after at least one prior line of chemotherapy. The registry identifies the study model as single group and allocation as not applicable. Masking was listed as none.

Enrollment was 17. The registry lists Ewing's sarcoma, primitive neuroectodermal tumor, Askin's tumor of the chest wall, and extraosseous Ewing's sarcoma among the conditions. The listed intervention was Zalypsis. The arm description is blank, so the registry record does not give further details about treatment administration in the study group. Dose, schedule, treatment duration, and rules for modifying or stopping treatment are not reported in the registry record.

The record gives a study start of 2010-12, primary completion of 2012-04, and status of completed. These dates describe the registration record; they do not supply additional outcome findings. The primary outcome was overall response rate. Secondary outcomes included best tumor response, progression-free survival and progression-free survival at 3 months, overall survival and survival rates at 6 and 12 months, and PM00104 plasma pharmacokinetic measures at the first infusion.

Because this was a single-group study without masking, the design can describe outcomes in participants receiving the intervention but cannot establish a randomized treatment contrast. The protocol's sample-size justification, planned interim analyses, and detailed statistical analysis plan are not reported in the registry record. The primary outcome population note says “One patient never treated,” despite the eligibility description requiring prior chemotherapy; the record does not explain how that note relates to the enrolled group or primary analysis.

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: One patient never treated

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 Overall Response Rate (ORR), measured over At baseline and every other cycle (± 1 week) until evidence of PD, up to 2 years.

Overall response rate is a binary participant-level endpoint: each participant is classified according to whether a confirmed objective response occurred, and the response rate is the percentage classified as responders. The registry defines objective response as complete response or partial response under RECIST v.1.1. A complete response is described as disappearance of all lesions. A partial response is defined using decreases in target lesion size or tumor density. Stable disease and progression are distinguished by whether the response criteria for complete response, partial response, or progression are met.

Response rate is used in oncology studies to summarize observed tumor shrinkage under prespecified assessment criteria. It is different from a time-to-event outcome: the endpoint concerns whether a qualifying response was observed, not how long participants remained free of progression or survived. The registry specifies assessment at baseline and every other cycle, with a one-week allowance, until evidence of progression, for up to 2 years.

The endpoint's interpretation depends on confirmed responses and the participants included in its denominator. The record does not report the number of confirmed complete or partial responses, the response-rate estimate, or an uncertainty interval. It also describes the primary outcome population as “One patient never treated,” without explaining that wording. Therefore, the endpoint definition is available, but the registry record does not provide the result needed to quantify the observed response rate.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Several statistical ideas are relevant to interpreting the registry record, but the record does not give enough detail to identify the full methods actually used. The study is described as phase II, open-label, and single group. Those design labels establish that outcomes were collected in a group receiving Zalypsis without a randomized comparator listed. They do not specify the statistical model, analysis population, handling of incomplete assessments, or decision criteria.

What does an overall response rate estimate?

Overall response rate summarizes the fraction of participants meeting the response definition. In this study, a responder was to have a confirmed complete or partial response by RECIST v.1.1. The binary endpoint assigns each participant a response status rather than measuring the duration of response or the time until progression. A response-rate estimate is usually interpreted alongside its denominator and an uncertainty interval, because the same estimated fraction can be more or less precise depending on how much information it is based on. The registry record does not report the response count, estimate, denominator used, or confidence interval.

Confirmation is part of the stated definition. It matters because a response must satisfy the study's confirmation rule, not merely appear at an isolated assessment. The registry gives the assessment schedule as baseline and every other cycle, with a one-week allowance, until evidence of progression, for up to 2 years. It does not report the details of response confirmation, whether all assessments were available, or how missing assessments affected classification.

Why does the single-group design matter?

A single-group study can describe the outcomes recorded among participants receiving the intervention. Without a concurrent control arm, it cannot separate an intervention-associated outcome from changes that might have occurred because of disease course, prior treatment, participant selection, supportive care, or other influences. This is a general limitation of uncontrolled comparisons, not a claim about what happened to participants in this study. The lack of masking also means that participants and study personnel were not reported as blinded. The registry does not say whether outcome assessors were independent or whether any other safeguards were used.

For these reasons, an outcome observed in a single group should not be interpreted as a randomized treatment effect. Historical or external comparisons can be difficult to interpret because populations, eligibility, assessment timing, and outcome definitions may differ. The registry record does not identify a formal external comparator or provide methods for such a comparison.

What do uncertainty measures contribute?

A confidence interval is a statistical range that expresses uncertainty around an estimate under the assumptions of the method used. It is not a guarantee that the true value lies within a particular interval, and it does not remedy bias from study design or missing data. A narrow interval generally indicates greater statistical precision than a wide interval, while neither width nor a point estimate alone establishes causality. No confidence interval for the primary response endpoint is reported in the registry record.

For a binary endpoint, the choice of interval method can matter, particularly when the number of participants or responses is limited. The registry does not report the interval method, any hypothesis test, or a prespecified response threshold for interpreting the result. These omissions prevent a reader from evaluating whether a particular inferential procedure was used or whether the primary analysis followed a planned decision rule.

How should time-to-event outcomes be understood?

Progression-free survival and overall survival are listed as secondary outcomes. In general, time-to-event methods use information about both whether an event occurred and the time to that event. Participants without a recorded event by the end of observation may have incomplete follow-up and are often handled through censoring methods. These methods rely on assumptions about follow-up and censoring. The registry record does not report event counts, follow-up summaries, survival estimates, censoring rules, or statistical methods for these outcomes. Therefore, the presence of these outcomes in the registry cannot be treated as evidence of a particular progression-free or overall survival result.

The registry also lists progression-free survival at 3 months and overall survival rates at 6 months and 12 months. A time-specific rate is a distinct summary from a response rate or a median time-to-event. Its interpretation depends on how the estimate was calculated and how many participants remained under observation. Those details and the corresponding results are not reported in the registry record.

What can the pharmacokinetic outcomes show?

The listed pharmacokinetic measures are PM00104 plasma Cmax and AUC at the first infusion. In general, Cmax describes a peak concentration measure and AUC summarizes exposure over a specified interval. Their interpretation depends on sampling times, assay methods, dosing, and the calculation rules. Those details and numerical results are not reported in the registry record, so the listed outcomes alone do not permit interpretation of drug exposure.

Finally, sample-size calculations are planning tools, not measures of what a completed trial observed. The registry's planning-illustration description refers to hypothetical two-arm assumptions and an effect expressed as a fraction of an observed effect. Such illustrations should not be mistaken for the study's original design justification or for observed power. The protocol's sample-size justification and the analysis plan are not reported in the registry record. No calculated planning results are available 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("PM00104")
n      <- c(16)
events <- c(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  PM00104  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 lists several outcomes: overall response rate as the primary outcome, plus best tumor response, progression-free survival, progression-free survival at 3 months, overall survival, overall survival rates at 6 and 12 months, and pharmacokinetic measures. Considering multiple outcomes can raise multiplicity concerns. In general, when many hypotheses are tested, the chance of at least one apparently notable result may increase unless the analysis plan accounts for the number and relationship of tests. The registry record does not report a multiplicity adjustment, a hierarchy among secondary outcomes, or a detailed testing strategy.

The record lists 11 outcome measures and no analyses. It does not provide results for the primary endpoint or the listed secondary outcomes. It also does not report whether all planned outcomes were analyzed, whether outcomes were changed after the study began, or how any deviations from the protocol were handled. Those details are not reported in the registry record and cannot be inferred from the outcome list alone.

Missing-data handling is also important. The record does not state how participants with no post-baseline assessment, incomplete response confirmation, or incomplete follow-up were treated. It does not report an analysis population definition, participant disposition, or whether the primary outcome used all enrolled participants or an evaluable subset. The primary outcome population note, “One patient never treated,” is not explained. As a result, the denominator and completeness of the primary endpoint cannot be established from the registry record.

These gaps limit interpretation of both efficacy and safety summaries. Missing outcomes can affect estimates when the probability of missingness is related to participants' health or observed outcomes. This is a general statistical concern; the record does not establish that such a pattern occurred. Without a prespecified analysis plan and transparent population accounting, the robustness of any outcome analysis cannot be evaluated.

12. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: acute sinusitis (6.2%), bronchitis (6.2%), pneumonia (6.2%), dehydration (6.2%), respiratory failure (6.2%).

The registry's adverse-event summary identifies the PM00104 group and lists 16 participants at risk for the serious-event and other-event summaries. Two participants are recorded as affected by serious adverse events, while 16 are recorded as affected by other adverse events. The record also lists 7 deaths. These are separate summary counts; they should not be combined or interpreted as mutually exclusive categories without further information about their definitions and overlap.

Five serious adverse event terms are listed: acute sinusitis, bronchitis, pneumonia, dehydration, and respiratory failure. Each term is displayed with a frequency of 6.2%. These entries describe the registry's reported terms and frequencies. The record does not clarify whether the terms refer to distinct participants, whether one participant could contribute more than one event, or the detailed denominator used for each displayed frequency.

A serious adverse event is a regulatory classification and is not synonymous with an event caused by treatment. The registry record does not report attribution, timing, duration, severity grading, or causes of death. The counts therefore describe reported safety events in the study group; they do not establish causation or permit a comparative safety assessment. Since no control group is listed, the registry record does not provide a randomized comparison of adverse-event frequency.

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

The record establishes that a phase II, open-label, single-group study of Zalypsis was registered for patients with unresectable locally advanced and/or metastatic Ewing family of tumors progressing after at least one prior line of chemotherapy. Enrollment was 17. The stated primary endpoint was overall response rate, based on confirmed complete or partial response under RECIST v.1.1, with assessments scheduled at baseline and every other cycle, with a one-week allowance, until progression, for up to 2 years.

What the registry record does not establish is the primary response result. No response count, response-rate estimate, confidence interval, or statistical test is reported. The missing result must not be interpreted as zero responses or as evidence that the endpoint was not met. It means that the registry record does not provide the information required to quantify the primary outcome.

The safety summary reports 2 participants with serious adverse events, 16 with other adverse events, and 7 deaths among the 16 participants listed at risk for those summaries. Five serious adverse event terms are displayed at 6.2% each. These observations describe reported events in the study group. Without attribution details or a comparator, they do not show that Zalypsis caused an event or establish how its safety compares with another option.

The single-group design can support description of outcomes among participants in the study, but it cannot provide a randomized estimate of a treatment effect. The listed secondary outcomes and pharmacokinetic measures indicate additional topics assessed or intended for assessment; their numerical results and analysis methods are not reported in the registry record. The record also does not explain the primary outcome population note, “One patient never treated.” Overall, it documents the study design and selected safety counts, while leaving the principal efficacy result and several details needed for fuller interpretation unavailable.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of the difference between a registered endpoint and a reported result. Overall response rate is clearly named as the primary outcome, and the registry describes its response criteria and assessment schedule. Yet the endpoint's numerical result is not reported. Without a numerator, denominator, estimate, or uncertainty interval, readers cannot evaluate the magnitude or precision of response from the registry record.

The study's single-group design is also central to interpretation. It can describe outcomes among participants receiving Zalypsis, but it does not offer a randomized comparator. This distinction matters because an observed response in a treated group is not equivalent to an estimate of how outcomes differ because of treatment. The design's open-label status is another relevant feature, while the record does not describe whether any independent response review occurred.

The mismatch between the eligibility description and the primary outcome population note deserves attention. Eligibility specifies progression after at least one prior line of chemotherapy, while the outcome population is described as “One patient never treated.” The registry does not explain the relationship between these statements. It is not possible to decide from the record whether this reflects an analysis-set description, a data-entry issue, or another circumstance.

The safety counts illustrate why event summaries need context. Counts and listed frequencies can describe what was recorded, but attribution, timing, overlap, and comparison information are needed for broader interpretation. The listed survival, response, and pharmacokinetic outcomes likewise cannot be interpreted from their names alone when results and analytic details are absent. Taken together, the record supports careful description of the design and reported counts, while demonstrating why transparent results and population accounting are essential for 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 limitation for interpreting efficacy is that the registry record does not report the primary overall response rate. It gives no response count, denominator, estimate, or confidence interval. Consequently, neither the observed response level nor its statistical precision can be assessed. The listed secondary outcomes also lack numerical results and analysis details.

The single-group, open-label design provides no randomized control comparison. Outcomes in the study group therefore cannot be interpreted as a randomized difference attributable to the intervention. The record does not state whether response assessments were independently reviewed, whether assessors were blinded, or whether other measures were used to reduce assessment bias.

The study population description is difficult to reconcile with the primary outcome population note. Eligibility refers to progression after at least one prior line of chemotherapy, whereas the primary outcome population is described as “One patient never treated.” The record does not explain the discrepancy, define the primary analysis population, or give participant-level accounting that would clarify it.

Important implementation and analysis details are absent, including dosing information, the sample-size justification, a detailed statistical analysis plan, missing-data rules, and any interim-analysis plan. The record also does not give response confirmation details, follow-up summaries, censoring methods for time-to-event outcomes, or pharmacokinetic sampling and calculation methods. These limitations are specific to the information recorded and do not establish that such procedures were absent from the conduct of the study; they are not reported in the registry record.

The adverse-event summary provides counts and selected terms but not attribution, timing, event-level detail, or causes of death. With no comparator, these safety counts do not support a comparative assessment. The listed outcomes and study status alone cannot fill these gaps.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study of Zalypsis® (PM00104) in Patients With Unresectable Locally Advanced and/or Metastatic Ewing Family of Tumors (EFT) Progressing After at Least One Prior Line of Chemotherapy — NCT01222767.
• Registry record last updated 2021-10-29; status last verified 2021-07.
• Results first posted 2021-10-29.
• 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

The registry record describes a completed phase II, multicenter, open-label, single-group study of Zalypsis (PM00104) in patients with unresectable locally advanced and/or metastatic Ewing family of tumors progressing after at least one prior line of chemotherapy. Enrollment was 17. The stated primary outcome was overall response rate, defined using confirmed complete or partial response under RECIST v.1.1.

The record gives an assessment schedule for response but does not report the primary response result or its uncertainty. Secondary outcomes include tumor response, progression-free survival, overall survival, and first-infusion pharmacokinetic measures; numerical results and detailed analysis methods are not reported in the registry record.

The safety summary lists 16 participants at risk, 2 with serious adverse events, 16 with other adverse events, and 7 deaths. Five serious adverse event terms are displayed at 6.2% each. The record does not report event attribution or explain the primary outcome population note, “One patient never treated.”