SARC016: Study of Everolimus With Bevacizumab to Treat Refractory Malignant Peripheral Nerve Sheath Tumors: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for SARC016: Study of Everolimus With Bevacizumab to Treat Refractory Malignant Peripheral Nerve Sheath Tumors (NCT01661283), a na phase 2 study. The primary outcome is Clinical Benefit Rate (Complete Response, Partial Response, and Stable Disease at ≥ 4 Months Using World Health Organization (WHO) Criteria) of Everolimus in Combination With Bevacizumab.

2. Clinical Question

The study set out to evaluate clinical benefit from the combination in patients whose MPNST was refractory to chemotherapy. Its primary endpoint combines tumor response and durable disease stability: a participant could meet the endpoint through complete response, partial response, or stable disease lasting at least 4 months. The registry description also identifies toxicity and safety evaluation as a study objective.

This is a single-group clinical question, not a head-to-head estimate of the combination against another treatment. The registry record describes outcomes to be assessed during treatment, but it does not report the observed number of participants meeting the primary endpoint. It therefore does not establish the size or precision of any clinical-benefit proportion in the posted record.

3. Trial Design

SARC016 is listed as a phase 2 study of everolimus combined with bevacizumab in refractory MPNST. The registry record identifies sporadic and NF1-associated tumors as the populations of interest. It lists the study as completed and gives an enrollment of 25. The recorded start is 2012-09 and primary completion is 2017-06.

The design is single-group, with allocation recorded as NA and masking recorded as none. The arm description specifies continued everolimus 10 mg daily and bevacizumab 10 mg/kg every 14 days for patients with MPNST. Because there is no concurrent control group, the design does not support a randomized comparison with another treatment or with no treatment.

The main outcome was clinical benefit under WHO response criteria: complete response, partial response, or stable disease for at least 4 months. Assessments were scheduled at baseline and before cycle 3, 5, 7, 9, and later cycles, for up to 2 years; the record defines a cycle as 28 days. The registry also lists secondary questions about germline NF1 mutations, response by sporadic or NF1-associated status, tumor mutation or inactivation, VEGF and VEGFR2 levels, and MRI measurement approaches.

The registry record does not report a statistical analysis plan, a sample-size justification, interim-analysis procedures, or a description of how enrollment translated into the analysis population. The posted record lists no analyses. Those omissions limit what can be inferred about how the investigators intended to estimate or test the primary outcome.

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

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: 17 patients enrolled with NF1 and 8 patients enrolled with sporadic MPNST.

6. Primary Endpoint

The registry lists the primary outcome as Clinical Benefit Rate (Complete Response, Partial Response, and Stable Disease at ≥ 4 Months Using World Health Organization (WHO) Criteria) of Everolimus in Combination With Bevacizumab, measured over Assessed at Baseline and prior to Cycle 3, 5, 7, 9, etc., for up to 2 years. 1 cycle =28 days.

The primary endpoint is the number of participants with clinical benefit, defined as complete response, partial response, or stable disease lasting at least 4 months under WHO criteria. It combines tumor shrinkage with prolonged disease stability. The endpoint therefore asks whether a participant met at least one of these response categories over the specified duration, rather than measuring only tumor shrinkage.

In the registry description, complete response means disappearance of all known disease, confirmed by two consecutive observations at least 4 weeks apart. Partial response requires a decrease greater than 50% in the total tumor load of measured lesions, with consecutive observations at least four weeks apart. Stable disease means that neither the specified decrease nor a 25% increase in the size of one or more measurable lesions has been established. The primary endpoint requires stable disease to persist for at least 4 months.

A composite endpoint can capture different ways a treatment course might be classified as beneficial under the study criteria. It also means that the overall count alone would not show how many participants had each response category. The registry record does not report the observed primary endpoint count, category-specific counts, or an estimate of the clinical-benefit rate. It therefore does not allow a numerical assessment of the endpoint result.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record identifies the primary measure as a count of participants meeting a clinical-benefit definition. For a binary participant-level outcome, each person is classified as meeting or not meeting the endpoint, and the count records those meeting it. If an analysis reports a proportion, its denominator should be the participants included in that analysis. The registry record does not report the primary count, the denominator used for an analysis, or an estimated proportion.

What does the endpoint combine?

The endpoint combines complete response, partial response, and stable disease lasting at least 4 months. These categories have different meanings under the WHO criteria. Complete response concerns disappearance of all known disease, while partial response concerns a specified decrease in total tumor load. Stable disease is defined by the absence of the stated response and progression thresholds, with the primary endpoint adding a duration requirement. Because the endpoint combines these categories, a total clinical-benefit count would not, on its own, reveal the distribution across them.

The registry description requires consecutive observations for complete and partial response. It specifies that observations for those response categories be separated by at least 4 weeks. The assessment schedule is baseline and before cycle 3, 5, 7, 9, and later cycles, for up to 2 years; the record defines a cycle as 28 days. In general, repeated assessment helps determine whether a response category is sustained rather than appearing at just one assessment. The registry record does not describe the detailed analysis rules for measurements that were missed or could not be evaluated.

What would an uncertainty interval mean?

In general, a confidence interval around a proportion expresses the statistical uncertainty associated with estimating an underlying event frequency from observed participants. A narrower interval indicates greater precision under the assumptions of the method; a wider interval indicates less precision. An interval does not correct for limitations such as lack of a comparison group, incomplete outcome assessment, or selection into a study. No confidence interval for the primary endpoint is reported in the registry record.

In general, a binary endpoint analysis depends on defining the event and the analysis population consistently. Here, the event definition includes response criteria and a duration threshold. The registry record does not state whether the primary analysis was intended to include all enrolled participants, only participants with a response assessment, or another population. Nor does it state how missing assessments, treatment discontinuation, or incomplete follow-up were to be classified. These choices can change the estimated frequency of an outcome and its interpretation.

Why does the design affect interpretation?

The study is recorded as single-group, with no masking and allocation recorded as NA. A single-group outcome can describe what occurred among participants treated in the study, but there is no concurrent randomized arm to provide a like-for-like comparison. General statistical methods cannot create that missing comparison from the study’s outcome count alone. Differences between this study population and a separate population could reflect differences in participants, disease characteristics, follow-up, outcome definitions, or other factors rather than a treatment effect.

Randomization, when used, can make comparison groups more alike on average with respect to measured and unmeasured baseline factors. This study’s registry record does not describe random allocation or a control arm. Therefore, statistical adjustment, even if it had been reported, would not be equivalent to a randomized comparison. The record does not report an adjusted efficacy analysis.

What do the safety counts represent?

The safety summary gives participants at risk and participants affected for serious adverse events and other adverse events, along with a death count and selected serious-event terms. In general, a participant count indicates how many people experienced an event category, whereas an event count can include repeated events in the same person. The listed fields are presented as participant counts, but the record does not provide event-level detail, timing, duration, severity grades, or causal attribution. It also does not explain the relationship between the death count and the listed term death NOS.

Adverse-event categories need not represent mutually exclusive groups: a participant could potentially experience more than one type of event. The registry record does not specify overlap across the serious and other-event summaries. Percentages attached to the selected terms should be read as the posted summaries, not as a basis for inferring unreported counts or individual-level event histories.

Finally, the registry record lists no analyses. It does not report a statistical analysis plan, a hypothesis-testing procedure, adjustment for multiple outcomes, a missing-data strategy, or interim analyses. General explanations of counts, proportions, uncertainty, and comparison designs clarify how such methods are usually interpreted; they do not establish which methods were used in this study.

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("Treatment")
n      <- c(25)
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  Treatment  25  3  12.0  2.5  31.2  4.2  30.0  4.4  30.2

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists one primary clinical-benefit endpoint and several secondary objectives, including NF1 mutation characterization, response by sporadic or NF1-associated status, tumor mutation or inactivation, VEGF and VEGFR2 measurements, and comparison of MRI measurement approaches. When multiple outcomes or subgroup comparisons are examined, the chance of finding an apparently notable result by chance can increase. In general, multiplicity procedures can control or describe this issue, but the record does not report whether any such procedure was planned or used.

The record lists no analyses and does not report a statistical analysis plan, prespecified testing sequence, or adjustment for multiple comparisons. It is therefore not possible to determine whether secondary findings were confirmatory or exploratory, or how their uncertainty was handled.

Missing-data handling and analysis populations are also not reported in the registry record. The record does not state how many participants had an evaluable primary endpoint, how missing response assessments were treated, or whether participants who stopped treatment or lacked later assessments remained in the analysis. It does not identify an intention-to-treat or other analysis population. The enrollment figure should not be treated as the primary endpoint denominator without that information.

These gaps matter because eligibility for analysis and the handling of incomplete follow-up can affect the reported outcome frequency. They also limit reproducibility: a reader cannot determine from the registry record which data would count toward the primary endpoint or how planned secondary comparisons were interpreted.

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 4% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: mucositis oral (8.0%), abdominal pain (4.0%), alanine aminotransferase increased (4.0%), death nos (4.0%), dehydration (4.0%).

The registry safety summary lists 11 participants with serious adverse events among 25 at risk. It separately lists 23 participants with other adverse events among 25 at risk, and 3 deaths. These figures describe the posted safety summary; the record does not establish that the serious-event and other-event groups are mutually exclusive or explain how the death count relates to the adverse-event categories.

The selected serious-event terms are mucositis oral at 8.0%, and abdominal pain, alanine aminotransferase increased, death NOS, dehydration, and diarrhea at 4.0% each. These percentages are registry entries for the named terms. The record does not provide individual event histories, timing, duration, severity grades, or an assessment of whether events were caused by treatment. The term list also does not describe every possible safety outcome.

In general, adverse-event summaries describe observed events, not necessarily events attributable to a treatment. Without a comparison group and further event detail, these counts cannot establish comparative safety or explain the cause of any particular event.

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

The registry record establishes that SARC016 was a completed phase 2, single-group study of everolimus with bevacizumab for refractory MPNST. It specifies the treatment schedule, the clinical-benefit endpoint, its WHO response criteria, and selected safety summaries. It also records secondary objectives concerning NF1 status, tumor markers, and imaging measurements.

The record does not report the observed primary endpoint count, a clinical-benefit rate, or an uncertainty interval. Consequently, it does not show how many participants met the endpoint, how precisely any response frequency was estimated, or how outcomes were divided among complete response, partial response, and durable stable disease. It also does not report analyses for the listed secondary objectives.

Even if an outcome count were reported, a single-group study would describe what happened among participants receiving the regimen, not the effect of the regimen relative to a randomized alternative. No concurrent control is described in the registry record. The observed course of disease in a treated group can reflect factors beyond treatment, and the design does not isolate those influences through a like-for-like comparison.

The posted safety figures describe reported participant counts and selected event terms, but do not establish causality or comparative risk. Missing information about event timing, severity, overlap, analysis populations, and incomplete assessments further limits interpretation.

The result, in statistical terms, is an incomplete public record for assessing the primary outcome: the endpoint is defined, but its observed result and analysis are not reported. The record can support an account of the study’s design and objectives, but not a numerical conclusion about clinical benefit, treatment effect, or comparative safety.

14. Why This Trial Matters Statistically

This trial is statistically notable for the way its primary endpoint combines different forms of disease status. Complete response and partial response reflect tumor changes under WHO criteria, while stable disease can also qualify when it persists for at least 4 months. Such a composite can summarize more than one clinically meaningful outcome, but interpretation requires knowing the component results as well as the overall count. The registry record does not report those results.

The study also illustrates the distinction between an outcome description and a treatment comparison. A single-group phase 2 study can record responses and safety events among people receiving a regimen, but without a concurrent comparator it cannot provide a randomized estimate of how outcomes differ under another treatment. That distinction is essential when reading outcome counts from a non-randomized design.

Assessment timing is part of the endpoint definition, not merely a logistical detail. The registry specifies repeated assessments and requires response confirmation under the stated WHO criteria; stable disease must also satisfy the duration threshold. Missing or unevaluable assessments could therefore affect endpoint classification. The registry record does not describe how those situations were handled.

Finally, a clearly stated endpoint does not substitute for a posted result or analysis. The record identifies the intended question and selected safety summaries but lists no analyses and does not report the primary outcome result. Statistically, the main lesson is to separate what the design set out to measure from what the registry record actually quantifies.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The primary limitation for interpreting efficacy is that the registry record does not report the observed primary endpoint result. It gives no count of participants with clinical benefit, no clinical-benefit rate, and no uncertainty interval. The record also does not state the denominator for a primary endpoint analysis or how many participants had sufficient assessment data.

The single-group design has no concurrent control arm. It can describe outcomes in the treated group, but cannot provide a randomized treatment comparison. Masking is recorded as none, and the record does not describe independent or blinded outcome assessment. It does not report whether such assessment procedures were used.

The endpoint combines complete response, partial response, and stable disease lasting at least 4 months. The record does not provide component-specific outcome counts, so an overall endpoint result, if available elsewhere, could not be understood in terms of its component categories from this registry entry alone. It also does not report how missing assessments, discontinuation, or unevaluable response measurements were handled.

The study includes sporadic and NF1-associated MPNST and lists secondary questions about molecular features and response subgroups. The registry record does not report subgroup results or analyses, and it does not describe any multiplicity strategy. It is not possible to assess the precision or interpretability of those secondary questions from the posted record.

The safety summary lacks detailed information about event timing, duration, severity grading, causal attribution, and overlap between categories. The record does not report a statistical analysis plan, sample-size justification, interim analyses, or analysis populations. These omissions restrict reproducibility and prevent a fuller appraisal of how the study outcomes were analyzed.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: SARC016: Study of Everolimus With Bevacizumab to Treat Refractory Malignant Peripheral Nerve Sheath Tumors — NCT01661283.
• Registry record last updated 2019-03-06; status last verified 2019-02.
• Results first posted 2019-03-06.
• 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

SARC016 (NCT01661283) is recorded as a completed phase 2, single-group study sponsored by the Sarcoma Alliance for Research through Collaboration. Its listed enrollment is 25; the recorded start is 2012-09 and primary completion is 2017-06. The study evaluated everolimus with bevacizumab in patients with refractory sporadic or NF1-associated MPNST.

The primary endpoint was the number of participants with complete response, partial response, or stable disease lasting at least 4 months under WHO criteria. The registry record lists treatment dosing and assessment timing, along with secondary objectives and selected safety summaries. It does not report the primary endpoint result, statistical analyses, analysis population, or missing-data approach. The design has no concurrent comparator, so the record does not provide a randomized treatment comparison.