Everolimus in Patients With Advanced Solid Malignancies With TSC1, TSC2, NF1, NF2, or STK11 Mutations: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Everolimus in Patients With Advanced Solid Malignancies With TSC1, TSC2, NF1, NF2, or STK11 Mutations (NCT02352844), a na phase 2 study. The primary outcome is Response Rate (RR).

2. Clinical Question

The study asks whether participants with these specified mutations have a tumor response during treatment with everolimus. Under the registry definition, complete response means disappearance of all target lesions. Partial response means at least a 30% decrease in the sum of target-lesion diameters. These criteria define which participants count as responders; they do not, by themselves, establish how often response occurred.

The registry record does not report the number of complete or partial responses, a response rate, or an uncertainty interval for that endpoint. It notes that 4 participants were not evaluable because they discontinued treatment before disease assessment. Without the response counts and the analysis denominator, the primary question cannot be answered from the recorded information.

Because the study has no control group, its primary question is descriptive rather than a randomized comparison of everolimus with another treatment or with no treatment. A response observed in this study would describe outcomes among the enrolled participants, but the design alone cannot isolate the effect of everolimus from other explanations for those outcomes.

3. Trial Design

NCT02352844 is a Phase II, single-group study sponsored by Washington University School of Medicine. It evaluates everolimus in participants with advanced solid malignancies carrying TSC1, TSC2, NF1, NF2, or STK11 mutations. The registry reports an enrollment of 12 and lists the study status as completed. The recorded start date is 2015-10-07, and the primary completion date is 2017-08-15.

The design has no randomized allocation, masking, or comparator arm. All participants are described under Arm 1 (everolimus). The intervention is an oral drug administered on an outpatient basis at 10 mg daily on a 28-day cycle. Since there is no control group, the study cannot provide a like-for-like estimate of how outcomes would have differed under another assigned treatment.

The primary endpoint is response rate using RECIST 1.1. Its stated timeframe is completion of treatment, described as an estimated average of 6 months. The record also lists secondary outcomes concerning mutations associated with therapeutic response and genetic changes associated with disease progression. It reports 3 outcome measures in total.

The record identifies 4 participants as not evaluable for the primary outcome because they discontinued treatment before disease assessment. It does not report how the response analysis handled these participants, nor does it specify an analysis population or a method for addressing missing response assessments.

The registry record does not report a sample-size justification, an interim-analysis plan, or a detailed statistical analysis plan. It records 0 analyses. That entry means no analyses are listed in the record; it should not be interpreted as proof that investigators conducted no analyses outside the registry. The design and registration information describe the study structure, but do not supply the response result needed to assess its primary endpoint.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Analysis population for the primary outcome, as defined in the registry: 4 participants were not evaluable for this outcome measure as they discontinued treatment prior to disease assessment.

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 (RR), measured over Completion of treatment (estimated average of 6 months).

The primary endpoint is response rate, a binary outcome based on whether a participant meets the registry’s RECIST 1.1 definition of complete or partial response. Complete response is defined as disappearance of all target lesions. Partial response is defined as at least a 30% decrease in the sum of the diameters of target lesions. A participant meeting either definition is classified as a responder for this endpoint.

Response rate is used to describe the proportion of an analyzed group that meets a prespecified tumor-response criterion. It focuses on measured changes in target lesions during treatment. As a general statistical point, a clear endpoint definition helps make outcome classification more consistent; however, the definition does not explain how missing assessments are handled or establish that a response is caused by the intervention.

The registry sets the assessment timeframe at completion of treatment, with an estimated average of 6 months. It notes that 4 participants discontinued treatment before disease assessment and were not evaluable for this outcome. The registry record does not report the responder count, the denominator used to calculate response rate, or an estimate of the rate. It also does not report a confidence interval. Therefore, the endpoint is defined, but its result and precision are not available in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The endpoint is binary at the participant level: a participant either meets the stated response definition or does not. The response definition combines complete response and partial response. Complete response is the disappearance of all target lesions; partial response is at least a 30% decrease in the sum of target-lesion diameters. These are the registry’s criteria for classifying response under RECIST 1.1.

As a general statistical explanation, a response rate is calculated from the number classified as responders relative to a defined analysis group. The numerator and denominator must both be known to interpret the rate. The denominator may depend on prespecified analysis rules, particularly when some participants lack an assessment. In this study, 4 participants were not evaluable because they discontinued treatment before disease assessment. The registry record does not state how these participants were handled in the response analysis, and it does not report the responder count or analysis denominator.

A confidence interval is a way to express the uncertainty around an estimated rate. A narrow interval indicates greater precision, while a wide interval indicates greater uncertainty. This is a general concept, not a claim about the method used in this study. The registry does not report a confidence interval for response rate or describe a method for calculating one. Without an estimate and its interval, neither the observed response frequency nor its precision can be assessed from the registry record.

The trial is registered as single-group, with allocation listed as not applicable and masking listed as none. In general, a single-group study can describe outcomes in the group that receives the intervention, but it does not directly estimate a difference between assigned treatments. A randomized comparison can help distinguish treatment-related differences from differences that arise through other factors; that comparison is not part of this design. The record therefore supports a descriptive study question rather than a comparative treatment-effect estimate.

The study is identified as Phase II. That phase label describes the registered trial category; it does not supply the statistical methods or findings. The registry does not report a detailed statistical analysis plan, a sample-size justification, an interim-analysis plan, or a model for the primary endpoint. The record lists 0 analyses. This indicates that no analyses are listed in the registry record, not that no analysis was performed in any setting.

In general, an analysis plan specifies the outcome definition, analysis population, handling of missing observations, statistical methods, and how uncertainty will be reported. Prespecification makes it easier to distinguish planned analyses from choices made after results are known. Those details are not reported in the registry record for this trial. In particular, the record does not identify an intention-to-treat, per-protocol, or other response-analysis population. No such population should be inferred from the enrollment figure or from the count of participants not evaluable.

The registry lists 3 outcome measures, including secondary outcomes concerning mutations associated with therapeutic response and genetic changes associated with disease progression. Multiple outcomes can address different scientific questions, but they also raise questions about how results are selected and interpreted. As a general statistical matter, multiplicity procedures may be used to control the chance of false-positive findings across a family of tests. The registry record does not report whether any such procedure was planned or used. The count of outcome measures does not establish that each was tested, and the record lists no analysis entries.

Safety events are also counts or proportions, but they answer a different question from the tumor-response endpoint. The registry lists participants at risk and affected participants for serious and other adverse events, as well as deaths. These summaries describe events recorded in the group. Without a comparison group and further analysis details, they do not estimate a comparative safety effect or establish causation. General principles of statistical interpretation apply, but the registry does not identify a particular safety model or inferential procedure.

The record’s missing assessment information deserves separate treatment from a negative response. A participant without disease assessment cannot be classified from the stated RECIST criteria using that absent assessment. General approaches to missing outcomes include reporting the missingness transparently and applying prespecified rules; different choices can affect the estimate. The registry identifies the reason for non-evaluability as discontinuation before disease assessment, but does not report an imputation method or a sensitivity analysis. Thus, neither a missing-data assumption nor its effect on the response result can be assessed.

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("Arm 1 (Everolimus)")
n      <- c(8)
events <- c(1)
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  Arm 1 (Everolimus)  8  1  12.5  0.3  52.7  2.2  47.1  2.8  48.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 3 outcome measures: the primary response-rate measure and secondary outcomes concerning mutations associated with therapeutic response and genetic changes associated with disease progression. It records 0 analyses. This means that analysis entries are not reported in the registry record; it does not establish that investigators performed no analyses outside the record.

The record does not describe a plan for multiplicity, such as a hierarchy among outcomes or an adjustment for testing multiple hypotheses. As a general statistical matter, examining several outcomes can increase the chance of finding an apparently notable result by chance if each is treated as a separate test. Without a stated plan and posted analyses, the relationship among outcomes and any control of that risk cannot be evaluated.

For the primary endpoint, 4 participants were not evaluable because they discontinued treatment before disease assessment. The registry record does not report how these missing assessments were handled, what analysis population was used, or whether any sensitivity analysis was conducted. It also does not state whether participants without assessments were excluded from the denominator, treated under another rule, or addressed through imputation.

These omissions prevent evaluation of how missing outcome data might affect the response estimate. A missing assessment should not be interpreted as a complete response, a partial response, or a lack of response unless an analysis rule explicitly defines that treatment. The record establishes the non-evaluable count and reason, but leaves the analysis consequences unreported.

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: pericardial effusion (25.0%), abdominal pain (16.7%), constipation (16.7%), hyponatremia (16.7%), nausea (16.7%).

For Arm 1 (Everolimus), the registry lists 12 participants at risk for serious adverse events and 8 affected. For other adverse events, it lists 12 at risk and 12 affected. The record also lists 2 deaths. These figures describe the recorded study group; they do not, on their own, establish that everolimus caused an event or death.

The serious adverse event terms with the highest listed frequencies are Pericardial Effusion at 25.0%, and Abdominal pain, Constipation, Hyponatremia, Nausea, and Pleural effusion at 16.7% each. These are registry-listed frequencies for event terms. The record does not provide a randomized comparator for comparing those frequencies with another group.

As a general point, adverse-event terms may describe different events, and one participant may contribute to more than one term. The listed percentages should therefore be read as event-specific summaries, not combined into a total. The registry record does not provide enough detail to infer causality, timing, duration, or severity beyond the serious-event classification shown in its safety information.

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

This record establishes that a Phase II, single-group study evaluated everolimus in participants with advanced solid malignancies and specified mutations. It defines response using RECIST 1.1 and states the treatment schedule and endpoint timeframe. It also reports that 4 participants were not evaluable for the response outcome because they discontinued treatment before disease assessment, and it includes descriptive safety figures.

The record does not report the number of participants with complete or partial response, the response rate, or a confidence interval. It therefore does not establish what response frequency was observed or how precisely that frequency was estimated. The absence of a posted result should not be read as a result of zero responses or as evidence that the treatment did or did not produce responses.

The design also limits what could be concluded from a response rate alone. With no comparator group, the study cannot estimate a difference in response between everolimus and another treatment. A descriptive result, if reported, would apply to the participants assessed under the study’s criteria; it would not by itself show that the intervention caused the responses or determine outcomes in other populations.

The mutation-defined population is central to the study question, but the registry does not report mutation-specific response results. The secondary outcome descriptions indicate interest in mutations associated with response and genetic changes associated with progression, yet no analyses for these outcomes are listed. Their results and interpretation are therefore not available in the registry record.

The safety figures describe adverse events and deaths recorded in the study group. They should not be treated as comparative risks or proof of causation. The registry record does not provide a control group or detailed analysis methods to support those stronger interpretations.

14. Why This Trial Matters Statistically

This study raises a statistical question about how to evaluate a targeted treatment in a population selected by tumor mutations. The registry specifies TSC1, TSC2, NF1, NF2, or STK11 mutations and defines a tumor-response endpoint using RECIST 1.1. A clear response definition is important because the endpoint depends on classifying measured lesion changes according to stated criteria.

The design illustrates the distinction between describing an outcome and estimating a comparative effect. A single-group study can record outcomes among participants receiving everolimus, but it lacks a control group for a direct treatment comparison. Statistical interpretation should therefore stay aligned with what the design can address.

The record also highlights why outcome completeness and analysis populations matter. It identifies 4 participants who were not evaluable after discontinuing treatment before disease assessment, while leaving the response-analysis denominator and missing-data method unreported. Those details are essential for understanding how a response estimate is formed and how sensitive it might be to analysis choices.

Finally, the record demonstrates that a fully defined endpoint is not the same as a reported result. The response criteria and study structure are available, but the primary response count, rate, and precision are not. Separating design information, outcome definitions, analysis methods, and numerical findings helps prevent conclusions from going beyond the evidence recorded.

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 primary response result. There is no response count, response rate, or confidence interval. Consequently, the frequency of response and its precision cannot be assessed from the record.

The study has a single-group design, with no randomized comparator. Any reported outcome would be descriptive for the study group rather than a direct estimate of the difference between everolimus and another treatment. The record also does not report mutation-specific response findings, despite listing several mutations as eligibility features and secondary interests.

Missing response assessments are another limitation. The record says 4 participants were not evaluable because treatment was discontinued before disease assessment, but does not state how they were handled in analysis. It does not identify an analysis population, an imputation approach, or a sensitivity analysis. The effect of missing assessments on any response estimate is therefore unknown.

Statistical methods are sparsely documented. A sample-size justification, interim-analysis plan, detailed analysis plan, and multiplicity procedure are not reported in the registry record. Although 3 outcome measures are listed, the record lists 0 analyses. These omissions prevent evaluation of planned testing, analysis choices, or the interpretation of any unposted results.

The safety information is descriptive and has no comparator group. It cannot establish comparative event risk or causality. The registry also does not provide further detail on event timing or duration in the information recorded for this analysis.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Everolimus in Patients With Advanced Solid Malignancies With TSC1, TSC2, NF1, NF2, or STK11 Mutations — NCT02352844.
• Registry record last updated 2018-10-02; status last verified 2018-09.
• Results first posted 2018-10-02.
• 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

NCT02352844 is a completed Phase II, single-group study sponsored by Washington University School of Medicine. It enrolled 12 participants with advanced solid malignancies and TSC1, TSC2, NF1, NF2, or STK11 mutations. The recorded study dates are 2015-10-07 for the start and 2017-08-15 for primary completion.

Participants received oral everolimus at 10 mg daily on a 28-day cycle. The primary endpoint was response rate by RECIST 1.1 at completion of treatment, with an estimated average timeframe of 6 months. The registry lists secondary outcomes related to mutations associated with therapeutic response and genetic changes associated with disease progression.

The record notes 4 participants were not evaluable for the primary outcome after discontinuing treatment before disease assessment. It does not report the response result, its analysis denominator, or a confidence interval. Safety information includes serious and other adverse-event summaries and 2 deaths. No comparator group is registered, and detailed statistical methods are not reported.