A Study of Ridaforolimus in Pediatric Participants With Advanced Solid Tumors (MK-8669-056): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of Ridaforolimus in Pediatric Participants With Advanced Solid Tumors (MK-8669-056) (NCT01431534), a non-randomized phase 1 study. The primary outcome is Number of Participants Experiencing a Dose Limiting Toxicity (DLT) According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v.4.0).

2. Clinical Question

3. Trial Design

This was a Phase I, nonrandomized, unmasked, parallel-group study of ridaforolimus in pediatric participants with advanced solid tumors. The registry lists enrollment of 20 and a status of terminated. The study began on 2012-01-30, and primary completion was recorded as 2013-08-20. Study-related visits concluded in August 2013. The reason for termination is not reported in the registry record.

The three listed groups received 22 mg/m^2, 28 mg/m^2, or 33 mg/m^2 of ridaforolimus. The planned schedule was oral dosing for 5 consecutive days each week, with 2 days of rest, in consecutive 28-day cycles. Treatment could continue for up to six months. Participants meeting the stated eligibility conditions could receive additional treatment in an extension phase.

The registry’s study summary describes two aims: finding a recommended dose by evaluating dose-limiting toxicities, and characterizing pharmacokinetics. The primary hypotheses concerned a dose relationship in toxicities that could inform a maximum tolerated dose, and a Day-5 area under the concentration-time curve benchmark at a tolerated dose. The primary outcome measure listed in the registry is the number of participants with a dose-limiting toxicity during Cycle 1. A detailed pharmacokinetic outcome result is not reported in the registry record.

Because allocation was nonrandomized and there was no masking, this design is best read as an early dose-finding investigation, not as a controlled estimate of comparative treatment effects. The registry record does not report how participants were assigned among dose levels or give the rationale for the allocation approach. A sample-size justification is not reported in the registry record.

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.

Treatment Phase

Reasons for not completing this period:

Extension Phase

Analysis population for the primary outcome, as defined in the registry: Participants who completed the first 28-day cycle of therapy with adequate drug exposure (\>75% of planned study drug doses, exclusive of doses missed due to related toxicity), or who discontinued from the study due to a related DLT, were evaluable for DLT.

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 Number of Participants Experiencing a Dose Limiting Toxicity (DLT) According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v.4.0), measured over Cycle 1 (cycle = 28 days).

The listed primary endpoint counts participants who experienced a dose-limiting toxicity (DLT) during Cycle 1, defined as 28 days. The registry defines a DLT using NCI-CTCAE version 4.0 and specifies events considered possibly, probably, or definitely related to study drug. The criteria include specified severe blood-count, glucose, gastrointestinal, and other non-hematological toxicities, as well as certain interruptions or delays in treatment because of related toxicity.

This endpoint is used in early dose-finding work because the frequency and nature of treatment-limiting toxicities can help inform whether a dose is tolerable enough to study further. The registry’s stated hypothesis was that observed DLTs would be dose-dependent and allow a maximum tolerated dose to be defined. That is the study’s objective, not a result that can be inferred without the endpoint counts.

The endpoint population is not simply everyone enrolled. Participants were evaluable if they completed the first 28-day cycle with more than 75% of planned doses, excluding doses missed because of related toxicity, or if they discontinued because of a related DLT. The actual number evaluable and the DLT count by dose are not reported in the registry record. The endpoint result, and any conclusion about a recommended dose, are therefore not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a dose-finding endpoint count?

The primary measure is a count of participants who met the registry’s DLT definition during the first 28-day cycle. A count is a straightforward summary of how many evaluable participants met specified criteria. Interpreting it requires the corresponding evaluable denominator: the count alone cannot show how common the event was among participants who could be assessed. The registry record gives the rules for evaluability, but the actual evaluable counts and primary outcome counts are not reported in the registry record.

The DLT definition combines clinical toxicity criteria with treatment-delivery criteria. It identifies certain severe events and also treats specified dosing interruptions or cycle delays because of related toxicity as dose-limiting. This reflects the purpose of dose finding: tolerability is relevant not only to whether a particular toxicity occurs, but also to whether treatment can be delivered as planned. The listed criteria use NCI-CTCAE version 4.0 and require the stated relationship to study drug for the specified events.

Why does the nonrandomized design matter?

Random assignment can help balance measured and unmeasured participant characteristics between groups. This study was nonrandomized, so such balance cannot be assumed. The registry record does not describe the assignment process. Consequently, comparisons across the dose levels are descriptive unless supported by an appropriate analysis and its assumptions. No such statistical analysis is reported in the registry record. Even a numerical difference between dose groups would not automatically demonstrate that dose alone caused the difference.

The study was also unmasked. Masking can reduce the influence of knowledge about treatment assignment on outcome assessment or reporting, depending on the outcome and procedures. The record states that masking was absent but does not describe any additional safeguards for outcome assessment. The DLT definition includes objective criteria as well as clinical judgments, so the absence of masking is relevant context rather than proof of bias.

How should uncertainty be considered?

In general, a confidence interval describes the range of estimates compatible with the observed data under the statistical model used. It helps readers judge precision, which is especially important when counts are limited. The registry record does not report a confidence interval or other inferential estimate for the primary DLT outcome. Because the primary counts and evaluable denominators are not reported, the precision of the dose-finding result cannot be assessed from this record.

For count data, the denominator and the definition of the analysis population matter alongside the numerator. Here, the DLT-evaluable population excludes participants who did not meet the stated completion and exposure rule unless they discontinued because of a related DLT. That rule is relevant to interpretation: participants who are not evaluable under the definition cannot simply be treated as having no DLT. The record does not report how many participants were excluded from this population or how any other missing endpoint information was handled.

What do the sample-size illustrations represent?

General sample-size calculations can illustrate the number of participants per arm needed to detect a chosen effect under specified assumptions. In this case, the stated illustration assumptions are a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the target effect set as a fraction of the observed effect. Such calculations are planning illustrations, not observed power and not evidence that the study was designed with those assumptions. The registry record does not report the study’s own sample-size justification or design assumptions. No sample-size values are needed to interpret the recorded primary outcome, which is not reported in the registry record.

In general, over-dispersion occurs when count variability is greater than a model assumes; ignoring it can make uncertainty appear too small. That concept is relevant to some analyses of counts, but the registry record does not report a count-model analysis or a method addressing over-dispersion. It would be inappropriate to assume such a method was used.

What is the role of the pharmacokinetic hypothesis?

The study summary states an objective to characterize ridaforolimus pharmacokinetics and a hypothesis about geometric mean Day-5 exposure over 24 hours at a safe and tolerated dose relative to an adult benchmark. This is a different type of question from counting DLTs: it concerns drug concentration over time rather than the frequency of participants meeting toxicity criteria. The detailed pharmacokinetic results, analysis population, and statistical method are not reported in the registry record. The stated hypothesis should therefore be understood as an aim, not a confirmed finding.

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("Ridaforolimus 22 mg/m^2", "Ridaforolimus 28 mg/m^2", "Ridaforolimus 33 mg/m^2")
n      <- c(4, 3, 13)
events <- c(0, 0, 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  Ridaforolimus 22 mg/m^2  4  0  0.0  0.0  60.2  0.0  49.0  0.5  52.2
ARM  Ridaforolimus 28 mg/m^2  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Ridaforolimus 33 mg/m^2  13  1  7.7  0.2  36.0  1.4  33.3  1.8  33.9

11. Multiplicity, Missing Data and Analysis Populations

The registry lists two outcome measures, while the study summary describes both a DLT dose-finding objective and a pharmacokinetic objective. Testing or interpreting multiple outcomes can raise multiplicity concerns because the chance of a misleading positive finding can increase when many statistical questions are considered. In general, a prespecified hierarchy or adjustment can address some multiplicity concerns. The registry record does not report a multiplicity strategy, a hierarchy for interpreting outcomes, or statistical analyses for these questions.

Missing-data handling for the primary endpoint is also not reported in the registry record. The DLT-evaluable population has a stated eligibility rule: completion of the first 28-day cycle with adequate exposure, or discontinuation because of a related DLT. This defines who is evaluable, but it does not explain how missing toxicity assessments, incomplete records, or other departures from the assessment schedule were handled. The actual number evaluable is not reported in the registry record.

The registry reports enrollment of 20, but enrollment does not establish the denominator for the primary endpoint. The number in each dose group who met the DLT-evaluable criteria, and the number with a recorded outcome, are not reported in the registry record. No imputation method or sensitivity analysis is reported.

The same caution applies to pharmacokinetic information: the registry summary describes the objective and hypothesis, but the detailed analysis population and any handling of missing measurements are not reported in the registry record. Without these details and the outcome results, the effects of missingness or multiple outcome assessments cannot be evaluated.

12. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: neoplasm progression (33.3%), headache (33.3%), vomiting (25.0%), device related sepsis (25.0%), oral herpes (25.0%).

The registry reports serious adverse events, other adverse events, and deaths separately for the ridaforolimus dose groups. For serious adverse events, the listed groups have 4 participants at risk with 3 affected at 22 mg/m^2, 3 at risk with 2 affected at 28 mg/m^2, and 13 at risk with 7 affected at 33 mg/m^2. For other adverse events, the corresponding counts are 4 at risk and 4 affected, 3 at risk and 3 affected, and 13 at risk and 13 affected. The registry lists 1 death in each group.

These are descriptive registry counts. They should not be read as a randomized comparison: allocation was nonrandomized, and the record does not provide an adjusted analysis or uncertainty estimates for these summaries. Nor do these counts establish that an event was caused by ridaforolimus. The record does not report a cause or timing for the deaths.

The listed serious-event terms include neoplasm progression and headache at 33.3%, and vomiting, device related sepsis, oral herpes, and convulsion at 25.0%. The registry information does not clarify the dose-group distribution for these terms. Serious adverse events should also not be equated with DLTs; the primary DLT endpoint has its own timing, attribution, and event criteria, and its results are not reported in the registry record.

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

This registry record describes an early-phase, nonrandomized study designed to investigate ridaforolimus dose and pharmacokinetics in pediatric participants with advanced solid tumors. It gives the dose levels, treatment schedule, first-cycle DLT definition, DLT-evaluable population rule, and selected adverse-event counts. Those details help explain what the investigators intended to measure and how the primary endpoint was defined.

The record does not report the primary DLT counts, the number evaluable at each dose, or the resulting recommended dose. It also does not report the detailed pharmacokinetic findings needed to assess the stated Day-5 exposure hypothesis. Consequently, the registry information cannot establish whether the DLT pattern was dose-dependent, what maximum tolerated dose was identified, or whether the adult exposure benchmark was exceeded.

The safety counts describe participants recorded as affected in each group, but they are not a controlled estimate of comparative risk. The nonrandomized design limits causal interpretation, and the record does not provide adjusted comparisons or confidence intervals. The listed deaths do not have reported causes or timing in the registry information, so no explanation for them should be inferred.

These limitations do not erase the descriptive value of a dose-finding study. Rather, they set boundaries on what the registry record supports. A study objective or hypothesis is not a result; an adverse-event count is not the same as a DLT outcome; and a planning illustration is not observed power. The conclusions available from the record are therefore about design, endpoint definitions, and reported safety summaries—not about a confirmed dose recommendation or treatment effect.

14. Why This Trial Matters Statistically

Early-phase studies ask questions that differ from those of a randomized efficacy trial. Here, the central statistical task was to observe dose-limiting toxicities across dose levels and use those observations, alongside pharmacokinetic characterization, to inform a pediatric dose. The endpoint’s timing and evaluability rules are therefore essential: they define which toxicity observations are intended to contribute to dose finding.

The study also illustrates why registry interpretation must distinguish planned hypotheses from posted results. The summary gives a DLT dose-dependence hypothesis and a pharmacokinetic benchmark hypothesis, but the primary endpoint result and detailed pharmacokinetic results are not reported in the registry record. Without those results, readers cannot assess whether the study objectives were met or how precise any dose-finding conclusion might be.

Nonrandomized dose groups require particular care. Group counts can be useful descriptive information, but they do not have the protections of a randomized comparison. Differences may reflect group composition or other factors, and the registry record does not report an analysis that separates those possibilities. The safety summaries also show why endpoint definitions should not be collapsed: serious adverse events, other adverse events, deaths, and DLTs answer related but distinct questions.

Finally, this record makes transparent the importance of reporting denominators, missing-data methods, and statistical analyses alongside outcomes. Enrollment alone does not tell readers how many participants were evaluable for the primary endpoint. When those results and methods are absent, the scientifically responsible interpretation is limited to what is documented, rather than filling gaps with assumptions.

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 principal limitation for interpreting the study’s dose-finding objective is that the primary DLT result is not reported in the registry record. The actual DLT counts and evaluable denominators are unavailable in the record, preventing assessment of the toxicity pattern by dose or the precision of that pattern.

The study was nonrandomized and unmasked. The registry does not describe the dose-allocation process, so comparability among dose groups cannot be assumed. It also does not report adjusted dose comparisons or other statistical analyses. The analysis count is zero.

The record describes a pharmacokinetic objective and hypothesis but does not report detailed results, the analysis population, or the method used. It also does not report a sample-size justification, multiplicity plan, interim-analysis plan, or broader missing-data methods. These omissions limit assessment of the planned inferential framework.

Safety information is descriptive and does not include uncertainty estimates or reported causes and timing for deaths. The record does not clarify the dose-group distribution of the listed serious adverse-event terms. Finally, the reason for termination is not reported in the registry record. These limitations restrict interpretation; they do not establish why the study ended or what its unreported results would have shown.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study of Ridaforolimus in Pediatric Participants With Advanced Solid Tumors (MK-8669-056) — NCT01431534.
• Registry record last updated 2019-03-01; status last verified 2019-02.
• Results first posted 2019-03-01.
• 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

This was a Phase I, nonrandomized, unmasked, parallel study of oral ridaforolimus in pediatric participants with advanced solid tumors. The registry lists enrollment of 20, three dose groups, and a terminated status. The primary outcome was the number of participants experiencing a DLT during Cycle 1, defined as 28 days, in a population meeting specified evaluability criteria.

The study summary also describes pharmacokinetic characterization and a Day-5 exposure hypothesis. The primary DLT results and detailed pharmacokinetic findings are not reported in the registry record. Descriptive safety counts are available for serious adverse events, other adverse events, and deaths, but the nonrandomized design does not support treating the dose groups as a controlled comparison. The reason for termination and the study’s sample-size justification are not reported in the registry record.