Sirolimus Before Surgery in Treating Patients With Advanced Localized Prostate Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Sirolimus Before Surgery in Treating Patients With Advanced Localized Prostate Cancer (NCT00311623), a non-randomized phase 1, phase 2 study. The primary outcome is Pharmocodynamically Optimal Dose (POD) of Rapamycin as Determined by Number of Participants With Greater Than or Equal to 60% Tumor S6 Kinase Inhibition by Immunohistochemistry (IHC)..

2. Clinical Question

This was a pre-surgery pharmacodynamic study, not a trial with a clinical outcome as its stated primary endpoint. The central question concerns a biological measure in tumor tissue collected around the treatment and surgery period. The registry identifies the primary outcome timeframe as Day 15 post-intervention and describes it as the number of participants crossing a specified inhibition threshold.

The population was a selected group of men with advanced localized prostate cancer who were candidates for radical prostatectomy. It was not a study of all people with prostate cancer, and the record does not support extending its findings to other populations or treatment settings. The enrollment was 32, but that figure does not establish how many participants contributed usable tissue to the primary endpoint. The record specifically notes that only 10 participants in the low-dose arm and 8 in the control arm had adequate paired tissue for evaluation. The 2 participants in the high-dose arm did not complete because of dose-limiting toxicity.

Because allocation was non-randomized and sequential, the comparison among groups should be read as exploratory and descriptive. The registry record does not report the number meeting the primary threshold in any group, so it does not answer whether one dose achieved more inhibition than another.

3. Trial Design

This completed study, NCT00311623, is titled “Sirolimus Before Surgery in Treating Patients With Advanced Localized Prostate Cancer.” Its official title describes a pharmacodynamic study of pre-prostatectomy rapamycin. The registry lists both phase 1 and phase 2, a non-randomized allocation, no masking, and a sequential model. Enrollment was 32. The study start is listed as 2006-08 and primary completion as 2008-01.

The intervention groups received rapamycin at 3mg or 6mg, and the trial also included radical prostatectomy. The control group description says participants received no intervention on Days 1-14 before surgery. All groups were described as candidates for radical prostatectomy. The registry's arm descriptions are truncated, so full eligibility details and the complete intervention schedules are not reported in the registry record.

Sequential allocation means the groups were not formed through random assignment, and the registry explicitly identifies the study as non-randomized. The dose groups therefore should not be interpreted as exchangeable treatment groups. Differences between groups could reflect how participants entered each stage or other group differences; the record does not provide enough detail to assess those possibilities. With no masking, participants and study personnel were not blinded according to the registry classification.

The stated objective was to study the best dose and assess rapamycin before surgery. The primary endpoint focuses on tumor S6 kinase inhibition in tissue, rather than on a patient-centered clinical outcome. Secondary outcomes include whole-blood pharmacokinetic assessments for both doses and tissue measures involving Akt phosphorylation, PTEN, p27, Gleason sum, activated caspase 3, and Ki-67.

The registry reports 13 outcome measures and no analyses in its analysis listing. A protocol-level statistical plan, sample-size justification, interim-analysis approach, and detailed analysis methods are not reported in the registry record. Consequently, the design description establishes what the study set out to examine, but it does not establish the rules used to analyze or interpret the results.

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: Only 10 participants from the low-dose arm and 8 participants from the control arm had adequate paired tissue for evaluation, due to the lack of availability or inadequacy of either biopsy or radical prostatectomy. The 2 patients from the high-dose arm did not complete due to dose-limiting toxicity.

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 Pharmocodynamically Optimal Dose (POD) of Rapamycin as Determined by Number of Participants With Greater Than or Equal to 60% Tumor S6 Kinase Inhibition by Immunohistochemistry (IHC)., measured over Day 15 post-intervention.

The primary endpoint is the number of participants with at least 60% tumor S6 kinase inhibition, assessed by immunohistochemistry. Its stated timeframe is Day 15 post-intervention. The registry labels the purpose as identifying a pharmacodynamically optimal dose, or POD, of rapamycin.

Immunohistochemistry is a laboratory method for assessing markers in tissue. Here, the endpoint uses a threshold: participants are counted according to whether their tumor tissue shows inhibition at or above the stated level. As a general statistical concept, a threshold-based endpoint turns a measured biological response into a count of participants meeting a predefined criterion. It can make the result easier to summarize, but it does not show the full range of individual tissue responses or how close measurements were to the cutoff.

The rationale for examining this endpoint is pharmacodynamic: it asks whether exposure to a dose is associated with a biological change in tumor tissue. That is different from measuring whether a participant lives longer, avoids disease progression, or experiences a clinical benefit. The registry does not describe such outcomes as the primary endpoint.

The registry does not report the number of participants who reached the threshold in any arm. It does report that adequate paired tissue was available for only 10 low-dose participants and 8 control participants, because biopsy or prostatectomy tissue was unavailable or inadequate. It also says the 2 high-dose participants did not complete because of dose-limiting toxicity. These details limit what can be concluded from the endpoint record: the threshold is defined, but the endpoint result itself is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

This discussion explains the statistical ideas relevant to the reported design and outcomes. The registry record does not report a detailed statistical analysis plan, so these are general explanations rather than claims about methods the investigators used.

A count endpoint. The primary outcome is a count of participants whose tumor tissue reached at least 60% S6 kinase inhibition by immunohistochemistry. A count can describe how many people met a criterion, while the threshold defines what qualifies as a response. To compare groups statistically, an analysis would ordinarily need the number meeting the criterion and the number assessed in each group. The registry supplies evaluable tissue counts for two groups but does not report the numbers meeting the endpoint. Without those outcome counts, an effect estimate and its precision cannot be interpreted from this record.

Thresholds also discard detail. Two tissue measurements on opposite sides of a cutoff are assigned to different categories even if they are close, while two measurements on the same side can be quite different. As a general matter, the continuous measurements and the binary threshold answer related but not identical questions. The registry names the threshold-based endpoint; it does not provide the underlying distribution of tissue measurements.

Precision and confidence intervals. A confidence interval is a statistical range that describes the uncertainty around an estimated quantity under a specified method. In general, a narrow interval indicates more precision than a wide interval, while neither an interval nor a point estimate alone establishes clinical importance. No confidence interval for the primary endpoint is reported in the registry record. Because the endpoint counts themselves are not reported, the interval cannot be evaluated.

Non-randomized, sequential allocation. Random allocation is used in general to reduce systematic differences between groups at the start of a study. This trial was non-randomized and sequential, so that protection cannot be assumed. The record does not report enough about the sequence or timing of dose assignment to establish how participants entered each group. A comparison across doses could reflect dose, differences in participant characteristics, or features of how enrollment proceeded. Statistical adjustment may address measured differences in some settings, but it cannot guarantee removal of unmeasured differences. The registry does not report an adjusted analysis for the primary endpoint.

Unmasked assessment. The registry lists masking as none. In general, knowledge of treatment assignment can influence decisions about care, data collection, or subjective assessments. The endpoint uses immunohistochemistry, but the record does not say whether tissue processing or scoring was performed without knowledge of group. Therefore, the registry classification alone does not establish whether endpoint assessors were aware of dose assignment, nor does it quantify any resulting bias.

Missing tissue and analysis populations. Paired tissue was adequate for evaluation in only 10 low-dose participants and 8 control participants. The registry explains that biopsy or prostatectomy tissue was unavailable or inadequate. In general, a complete-case analysis includes only participants with the required measurements. Such an analysis may be biased if availability of measurements is related to treatment or outcome. The record does not state the analysis population definition, how missing tissue was handled, or whether any sensitivity analysis was conducted. The two high-dose participants did not complete because of dose-limiting toxicity, which is a distinct reason for absence from the endpoint assessment.

Safety counts. The registry lists participants at risk and participants affected for serious and other adverse events by group. These counts are descriptive. Without definitions for the event categories, observation windows, repeated-event handling, and analysis method, they should not be treated as rates or comparative risk estimates. The record does not report confidence intervals or formal tests for these safety figures. A count of participants affected also does not reveal how many events each participant experienced or the timing and duration of events.

Planning illustrations. The sample-size section uses a planning illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is described as a stated fraction of the observed effect. Such calculations are hypothetical planning quantities, not evidence about how many participants were actually needed under the original protocol. They are never observed power. The registry record does not report the trial's own sample-size justification or protocol assumptions, and any planning values should not be mistaken for that missing design rationale.

Multiplicity and secondary outcomes. The record lists 13 outcome measures, including several laboratory and tissue endpoints. When many outcomes are examined, general statistical practice considers the possibility that some apparent findings arise by chance. Methods for controlling or describing this issue depend on the analysis plan and the intended role of each outcome. The registry does not report whether multiplicity adjustment was planned or used, or how secondary outcomes were prioritized. No conclusion about those methods can be drawn from the outcome list alone.

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("Control Group", "Low-dose Rapamycin (3mg)")
n      <- c(8, 10)
events <- c(1, 5)
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  Control Group  8  1  12.5  0.3  52.7  2.2  47.1  2.8  48.2
ARM  Low-dose Rapamycin (3mg)  10  5  50.0  18.7  81.3  23.7  76.3  23.4  76.6

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 13 outcome measures, including the primary tumor S6 kinase inhibition endpoint and secondary pharmacokinetic, tissue-marker, and pathology measures. Considering multiple outcomes can make interpretation more complicated: as a general statistical concept, examining many endpoints creates more opportunities for chance findings. The appropriate response depends on which outcomes are confirmatory and what analysis plan was set in advance. The registry record does not report a multiplicity strategy, hierarchy of endpoints, or whether any adjustment was used.

Missing tissue is a specific limitation for the primary endpoint. The registry says only 10 low-dose participants and 8 control participants had adequate paired tissue for evaluation, because biopsy or radical prostatectomy tissue was unavailable or inadequate. It also says the 2 high-dose participants did not complete because of dose-limiting toxicity. The reasons differ, and the record does not report how these participants were included in the primary analysis or whether missing values were otherwise addressed.

In general, restricting an analysis to participants with available measurements can be problematic if availability is related to treatment, disease features, or the outcome. A sensitivity analysis can examine how assumptions about missing data affect results, but whether one was performed is not reported in the registry record. The analysis population definitions, handling of incomplete assessments, and protocol deviations are also not reported. The record therefore does not establish whether the primary endpoint was analyzed among all enrolled participants, only those with paired tissue, or another defined group.

The registry's analysis listing reports no analyses. This does not establish that no analysis was performed; it means that analysis details are not reported in the registry record. The statistical plan, analysis population, and missing-data methods cannot be reconstructed from the outcome descriptions alone.

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: severe thrombocytopenia (100.0%).

The safety listing separates serious adverse events from other adverse events and reports the number at risk and the number affected in each group. For serious adverse events, the registry reports 0 affected among 10 at risk in the control group, 0 among 20 at risk in the low-dose group, and 2 among 2 at risk in the high-dose group. For other adverse events, it reports 1 affected in the control group, 8 in the low-dose group, and 2 in the high-dose group, with the corresponding at-risk counts listed in the registry.

The top serious term is severe thrombocytopenia, listed as 100.0%. The registry also states that the 2 high-dose participants did not complete because of dose-limiting toxicity. These are important descriptive details, but the record does not specify the event-level timing, severity grading rules beyond the term shown, or whether participants could contribute multiple events. The two statements should be read as separate reported details; the record does not explicitly provide a participant-by-participant mapping between the completion information and the serious-event term.

These figures are counts, not adjusted comparisons. They do not by themselves account for differences in group size, follow-up, or the sequential non-randomized design. The record reports 0 deaths in every group. It does not report comparative statistical tests, confidence intervals, or a complete narrative of each adverse event in the information.

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

This record describes a small, pre-surgery pharmacodynamic study that examined rapamycin at 3mg and 6mg and included a control group. Its primary question was whether tumor tissue showed at least 60% S6 kinase inhibition by immunohistochemistry. That is a biological endpoint intended to inform dose selection; it is not a direct measure of clinical benefit.

The registry record does not report the number of participants who reached the primary threshold. It therefore does not show whether either dose met the stated pharmacodynamic objective, how the doses compared, or which was deemed optimal. The tissue-evaluable counts do not substitute for those missing results. They describe availability of paired tissue in the low-dose and control groups, not success on the endpoint.

The design also limits causal interpretation. Participants were allocated non-randomly in a sequential model, and masking was none. Group differences, if reported elsewhere, would not automatically establish that dose caused those differences. The registry does not report a protocol-level analysis plan, an adjusted primary comparison, or the primary endpoint estimates and their precision.

The safety counts show that serious adverse events were recorded in the high-dose group and not in the control or low-dose groups, while other adverse events were reported in all groups. The two high-dose participants did not complete because of dose-limiting toxicity, and severe thrombocytopenia is listed as the top serious term. These observations should be read descriptively, particularly given the small high-dose group and non-randomized design. They do not constitute a complete comparative safety analysis.

In short, the posted record establishes the study question, design, endpoint definition, tissue availability, and selected safety counts. It does not report enough primary outcome information to determine the pharmacodynamic result. It also does not establish whether rapamycin improves clinical outcomes. The record supports a description of what was measured and what was reported, not a treatment recommendation or a definitive efficacy conclusion.

14. Why This Trial Matters Statistically

This trial is statistically informative because it illustrates the difference between defining an endpoint and reporting its result. The registry clearly identifies a threshold-based tissue measure and its intended role in dose selection, but it does not report the number of participants who met that threshold. Without the outcome counts, readers cannot assess the size or precision of the primary result. A precisely worded endpoint does not compensate for an absent estimate.

It also highlights the implications of tissue-dependent analyses. The primary measure required paired biopsy and prostatectomy tissue, yet the registry reports adequate paired tissue for only 10 low-dose participants and 8 control participants. This makes the analysis population and missing-data handling central statistical questions. The record explains why tissue could be unavailable or inadequate, but does not report how missing observations were handled.

The sequential, non-randomized design is another important feature. Dose groups in this design are not automatically comparable, so descriptive differences cannot be read as though they came from randomized allocation. This matters especially when the high-dose group had only 2 participants and both did not complete because of dose-limiting toxicity. A small group can still yield useful safety observations, but its counts offer limited precision and should not be generalized without caution.

Finally, the study lists several biological and pathology outcomes. This raises general questions about endpoint prioritization and multiplicity, but the registry does not report the planned statistical approach. The record is a useful example of why transparent reporting should include outcome estimates, uncertainty, analysis populations, missing-data methods, and the rationale for sample size, not only endpoint definitions and study characteristics.

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.

Several limitations specific to this study affect interpretation. First, the primary endpoint results are not reported in the registry record. The endpoint definition and timeframe are available, but the number reaching the inhibition threshold in any group is not. Neither a dose comparison nor a precision assessment can be made from the reported primary endpoint information.

Second, paired tissue availability was incomplete. Only 10 low-dose participants and 8 control participants had adequate tissue for evaluation, and the registry attributes this to unavailable or inadequate biopsy or prostatectomy material. The record does not report an analysis population, missing-data method, or sensitivity analysis. The 2 high-dose participants did not complete because of dose-limiting toxicity, further limiting assessment of that dose.

Third, the study was non-randomized, sequential, and unmasked. The registry does not provide enough detail to determine how the sequence affected group composition or to establish baseline comparability. The arm descriptions are truncated, and complete intervention schedules and eligibility details are not reported in the registry record. These gaps limit assessment of both the treatment contrast and generalizability.

Fourth, the record does not report a statistical analysis plan, sample-size justification, interim-analysis approach, or multiplicity strategy. Although it lists 13 outcome measures, it does not describe which secondary outcomes were confirmatory or how they were analyzed. Safety counts are also presented without the event-level detail or comparative estimates needed for a fuller assessment. These limitations mean the registry supports a description of the study and selected reported counts, but not a complete statistical evaluation.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Sirolimus Before Surgery in Treating Patients With Advanced Localized Prostate Cancer — NCT00311623.
• Registry record last updated 2019-02-22; status last verified 2019-02.
• Results first posted 2019-02-22.
• 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

NCT00311623 is a completed phase 1/phase 2, non-randomized, unmasked, sequential study of rapamycin before radical prostatectomy in men with advanced localized prostate cancer. Enrollment was 32. The registry lists rapamycin doses of 3mg and 6mg and a control group described as receiving no intervention on Days 1-14.

The primary outcome was the number of participants with at least 60% tumor S6 kinase inhibition by immunohistochemistry at Day 15 post-intervention, intended to identify a pharmacodynamically optimal dose. The primary endpoint counts are not reported in the registry record. Adequate paired tissue was available for 10 low-dose participants and 8 control participants; the 2 high-dose participants did not complete because of dose-limiting toxicity.

The registry lists 13 outcome measures and reports selected adverse-event counts, including severe thrombocytopenia as the top serious term. A statistical analysis plan, sample-size justification, missing-data methods, and multiplicity strategy are not reported in the registry record.