Safety/Efficacy of Everolimus in Adults With Advanced Pancreatic Neuroendocrine Cancer Not Responsive to Chemotherapy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety/Efficacy of Everolimus in Adults With Advanced Pancreatic Neuroendocrine Cancer Not Responsive to Chemotherapy (NCT00363051), a na phase 2 study. The primary outcome is Objective Response Rate: Percentage of Participants With Best Over All Response of Complete Response or Partial Response by Central Radiology Review (Stratum 1) Based on Response Evaluation Criteria in Solid Tumors (RECIST).

2. Clinical Question

The clinical question concerns tumor response in patients whose advanced pancreatic neuroendocrine tumors had not responded to cytotoxic chemotherapy. Response was defined using RECIST, a framework based on changes in tumor measurements and the appearance or progression of lesions. A complete response required disappearance of target and non-target lesions. A partial response required a decrease in the summed longest diameters of target lesions from baseline. Either response required confirmation by a follow-up assessment within 4 weeks.

This was not a randomized comparison of everolimus against another treatment. The study instead assessed response and safety in patients receiving everolimus, with a distinction between those not receiving regular Octreotide Depot therapy and those continuing that therapy. The registry record does not report the primary response result, so it does not establish from the posted results how often responses occurred or how precisely that percentage was estimated.

3. Trial Design

This was an open-label, stratified, single-arm phase II study of everolimus in patients with advanced pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy. Its listed enrollment was 160. The registry lists a start of 2006-06, primary completion in 2008-01, and status as completed.

The study divided treatment according to regular Octreotide Depot use at entry. Stratum 1 included patients who were not receiving regular Octreotide Depot therapy and were to receive everolimus monotherapy at 10 mg per day. Stratum 2 included patients who were to receive everolimus 10 mg per day in addition to continuing their entry dose of Octreotide Depot. These strata are not randomized treatment arms, and the registry record does not describe them as a like-for-like control comparison.

Participants and investigators were not masked. The study summary says treatment continued until tumor progression was documented using RECIST, unacceptable toxicity occurred, or the patient or investigator requested discontinuation. Central radiology review was specified for the primary response outcome and several listed secondary outcomes.

The primary outcome was the objective response rate in Stratum 1, defined as the percentage with a best overall response of complete or partial response by central radiology review. The full analysis set consisted of patients who received at least one dose of everolimus. The registry record does not report the observed primary response percentage or its confidence interval, nor does it report a sample-size justification or a detailed statistical analysis plan.

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: The full analysis set (FAS) consisted of all patients who received at least one dose of everolimus.

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 Objective Response Rate: Percentage of Participants With Best Over All Response of Complete Response or Partial Response by Central Radiology Review (Stratum 1) Based on Response Evaluation Criteria in Solid Tumors (RECIST), measured over from date of randomization/start of treatment until first documented response confirmed 4 weeks later( at least 3 months).

The primary endpoint is the objective response rate in Stratum 1: the percentage of participants whose best overall response was complete response or partial response under RECIST, as assessed by central radiology review. The full analysis set was defined as patients who received at least one dose of everolimus. The registry record does not report the number of responses, the response percentage, or its stated 95% confidence interval.

RECIST provides a standardized way to classify tumor change. A partial response required at least 30% decrease in the sum of the longest diameters of target lesions from baseline. A complete response required disappearance of all target and non-target lesions. Either response needed confirmation by a later assessment within 4 weeks. Progression could be based on an increase in the summed diameters from the smallest recorded sum, a new lesion, or progression of non-target lesions.

Response rate is used to describe the proportion meeting a defined tumor-response threshold. It does not describe how long a response lasts or, by itself, establish a comparative treatment effect. Duration of response, progression-free survival, overall survival, and safety were listed among secondary outcomes, but their results are not reported in the available registry entries.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Several statistical ideas help interpret a single-arm response study. The explanations below are general unless they refer specifically to the design or outcome definitions in the registry record.

What does a single-arm design estimate?

In general, a single-arm study describes outcomes among participants who received the study treatment. For a binary endpoint such as response, the basic quantity is the proportion of participants meeting the response definition. That proportion describes the observed study group; without a concurrent randomized comparison, it does not estimate a treatment contrast. It cannot separate a treatment-related effect from other explanations for the observed outcome, including the natural course of disease or changes in care over time.

This study was listed as single-arm, with allocation recorded as not applicable. Its two strata reflect whether participants were receiving regular Octreotide Depot therapy at entry. The strata therefore should not be interpreted as randomized groups. Any difference between their outcomes could reflect differences between the people in the strata as well as treatment context.

What is a binary response endpoint?

For a binary endpoint, each participant is classified as either meeting the response definition or not meeting it. The objective response rate is the percentage classified as having complete or partial response. The RECIST definitions in the registry make the classification depend on lesion measurements and on whether the change is confirmed. Central radiology review is intended to apply a consistent assessment process; it does not remove the limitations of an uncontrolled design.

The endpoint is not a continuous measure of tumor-size change. It compresses measurements into response categories. This can make the outcome easier to interpret, but it also means that a participant near a category boundary may be classified differently from one with a more pronounced change, even where their underlying measurements are similar. The registry record does not report the response distribution or measurements underlying the categories.

What does a confidence interval add?

In general, a confidence interval gives a range of values compatible with the observed data under the statistical method used. It provides information about uncertainty that a point estimate alone cannot convey. A confidence interval is not a guarantee that the true value lies within the reported limits, and it does not address biases caused by study design or outcome measurement.

The primary outcome description specifies a 95% confidence interval, but the registry record does not report its limits or the response estimate. Therefore no numerical assessment of precision is possible from the posted primary outcome details. The interval’s absence also means that the endpoint cannot be compared statistically with a target value on the basis of this record.

Why does central review matter?

In general, central review can help standardize outcome assessment across participants by applying a common review process. That is relevant for RECIST, which depends on measurements and judgments about target lesions, non-target lesions, and new lesions. The registry identifies central radiology review for the primary response endpoint. It does not report further details about reviewer masking, adjudication, or agreement between reviewers, so those aspects cannot be assessed.

How should planning illustrations be read?

In general, sample-size calculations use assumptions about the effect to detect, statistical significance level, allocation, and analysis method. A planning illustration based on an observed effect is not evidence that the original study was designed around that effect, and it is not a measure of the study’s observed power. The stated illustration assumptions for this record are a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect to detect expressed as a stated fraction of the observed effect. Those assumptions describe a hypothetical planning exercise, not this single-arm trial’s allocation.

The record does not report the numerical sample-size illustrations or the primary response estimate needed to interpret an effect-based planning exercise. The study’s listed enrollment should not be treated as evidence that a particular precision or power target was achieved. The trial’s own sample-size justification is not reported in the registry record.

What can safety counts tell us?

Safety counts summarize how many participants experienced reported events in a group. Serious adverse events are a subset distinguished by seriousness criteria; they are not interchangeable with all adverse events. Counts need to be read with their group denominators and with the event definitions and follow-up context in mind. The record provides group counts and selected serious-event terms, but does not provide enough detail to compare risk causally between strata. In general, a comparison across nonrandomized strata can be affected by differences in participant characteristics, treatment context, and observation time.

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("Stratum 1: Everolimus 10 mg")
n      <- c(115)
events <- c(11)
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  Stratum 1: Everolimus 10 mg  115  11  9.6  4.9  16.5  5.4  16.3  5.5  16.3

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary response endpoint and multiple secondary outcomes, including duration of overall response by stratum, objective response rate in Stratum 2, adverse events, progression-free survival, and overall survival. When many outcomes are examined, the chance of at least one apparently notable result can increase. Statistical approaches for addressing this issue can include prespecifying a hierarchy or adjusting interpretation for multiple testing. The multiplicity strategy is not reported in the registry record, and the listed outcomes should not be treated as if a particular adjustment method had been used.

The record does not report a detailed statistical analysis plan or inferential analyses for the outcomes described. It does not state how missing outcome assessments were handled, whether any imputation was used, or how participants without evaluable response assessments were classified. These details matter because missing assessments can affect the estimated response percentage, particularly if missingness is related to a participant’s health or treatment course.

The primary analysis population is described as the full analysis set, consisting of patients who received at least one dose of everolimus. The registry does not report the number included in the primary endpoint analysis or how that set was applied to the response outcome. The listed enrollment is not interchangeable with an endpoint-specific analysis denominator.

Because the study was single-arm and stratified by background Octreotide Depot use, there is no randomized treatment contrast to test across the strata. The registry record also does not report a multiplicity procedure for comparisons between strata or outcomes. Without results, missing-data methods, and a prespecified analysis strategy, the robustness of any endpoint finding cannot be assessed from the registry entries.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: abdominal pain (8.9%), thrombocytopenia (6.7%), cardiac failure (6.7%), vomiting (6.7%), renal failure (6.7%).

The registry reports serious adverse events for each stratum. In Stratum 1, 63 of 115 participants were recorded as affected by serious adverse events. In Stratum 2, 27 of 45 were recorded as affected. These counts describe participants with serious adverse events in the posted group summaries; they do not indicate that each participant experienced only one event.

The listed serious-event terms and percentages are abdominal pain at 8.9%, and thrombocytopenia, cardiac failure, vomiting, renal failure, and dyspnoea at 6.7% each. The registry record does not specify the denominator used for each listed percentage in the details, so these percentages should be read as reported rather than recalculated. The record also includes counts for participants with other adverse events: 115 of 115 in Stratum 1 and 44 of 45 in Stratum 2.

Serious adverse events are not the same as all adverse events. Counts across strata are not a randomized safety comparison, and the record does not provide exposure-adjusted rates or sufficient detail to account for differences in follow-up. Death counts are not reported in the registry record. These safety summaries describe recorded events but do not establish their cause.

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

The record establishes that an open-label, single-arm phase II study evaluated everolimus in patients with advanced pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy. It also defines the primary endpoint as the objective response rate in Stratum 1, using complete or partial response under RECIST and central radiology review. The primary response estimate and its 95% confidence interval are not reported in the registry record.

That omission means the posted primary outcome details cannot show how many participants responded, what percentage responded, or how precisely the response rate was estimated. The endpoint definition alone is not evidence that responses occurred. Nor can the presence of a response endpoint establish that everolimus caused a response, since the design has no randomized control group.

The safety summaries describe serious adverse events and other adverse events in each stratum. They do not provide a randomized comparison or establish causation. The listed serious-event terms are useful descriptions of reported event types, but interpretation of their percentages is limited because the denominator details are not reported in the registry record.

The registry lists additional outcomes, including response duration, progression-free survival, and overall survival. Their results are not reported in the details available for this analysis. The record also does not describe missing-data handling, multiplicity adjustment, or the trial’s own sample-size rationale. Consequently, the reported design and outcome definitions can be characterized, but the study’s efficacy findings and the statistical strength of those findings cannot be evaluated from the posted primary results.

In general, a single-arm study can provide descriptive information about outcomes in its treated participants. It cannot, on its own, determine how those outcomes compare with what would have happened under a different treatment or no treatment. That distinction remains important even when an endpoint is carefully defined and assessed centrally.

14. Why This Trial Matters Statistically

This study illustrates several important statistical distinctions in clinical research. First, a clearly defined endpoint is not the same as a reported result. The registry gives RECIST response criteria, identifies central radiology review, and names a 95% confidence interval as the measure of precision. However, it does not report the primary response estimate or interval. Readers therefore have information about what was intended to be measured, but not the observed primary outcome needed to judge its magnitude or uncertainty.

Second, a single-arm study answers a descriptive question rather than a randomized comparative question. The study can characterize outcomes among participants receiving everolimus, but there is no randomized control group against which to estimate a treatment difference. The two strata do not address that limitation because their distinction is based on regular Octreotide Depot therapy at entry, not random allocation.

Third, the endpoint depends on measurement and classification choices. RECIST provides a structured response definition, and central radiology review can support consistency. Response classification still differs from a direct description of every tumor measurement, and a response rate does not itself describe response duration or survival. Those are separate outcomes, listed as secondary measures in the registry.

Finally, safety summaries need context. Counts of participants with serious adverse events and selected event percentages are informative descriptions, but interpretation depends on denominators, follow-up, event ascertainment, and study design. This record reports some counts but does not provide enough information for a causal safety comparison between strata. Together, these features show why endpoint definitions, estimates, uncertainty, comparison design, and analysis details all matter when reading a trial record.

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 most consequential limitation for interpreting efficacy is that the registry record does not report the primary response estimate or its confidence interval. Although the endpoint definition is detailed, the posted result does not permit assessment of the observed response frequency or its precision. Results for the listed secondary outcomes are also not reported in the registry entries used for this analysis.

The study was open-label and single-arm, with no randomized control group. It therefore cannot provide a randomized estimate of the difference between everolimus and another treatment. The strata are distinguished by Octreotide Depot use at entry and should not be treated as randomized comparators. The record does not describe masking of central radiology reviewers.

The registry identifies the full analysis set as patients who received at least one dose, but does not report the endpoint-specific analysis denominator or missing-data handling. The methods for multiplicity control, the detailed statistical analysis plan, and the trial’s sample-size justification are not reported in the registry record. These omissions limit assessment of how analyses were specified and how incomplete outcome data may have been treated.

Safety interpretation is also limited. The record reports counts of affected participants and selected serious-event terms, but does not provide exposure-adjusted rates or sufficient information to account for duration of observation. Death counts are not reported in the registry record. The listed serious-event percentages lack stated denominator details in the available record information. These limitations mean the safety summaries should be read descriptively, not as evidence of causal differences between strata.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety/Efficacy of Everolimus in Adults With Advanced Pancreatic Neuroendocrine Cancer Not Responsive to Chemotherapy — NCT00363051.
• Registry record last updated 2013-05-10; status last verified 2013-05.
• Results first posted 2012-03-30.
• 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 an open-label, stratified, single-arm phase II study of everolimus in advanced pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy. Participants in Stratum 1 were not receiving regular Octreotide Depot therapy; participants in Stratum 2 continued their entry dose alongside everolimus. The primary endpoint was objective response rate in Stratum 1 by RECIST and central radiology review.

The endpoint definition and selected safety summaries are reported, but the primary response estimate and its 95% confidence interval are not reported in the registry record. The study has no randomized control group, and the strata are not like-for-like randomized comparators. Results for the listed secondary outcomes, missing-data methods, multiplicity approach, and trial-specific sample-size justification are not reported in the registry entries.