A Study of Robatumumab (SCH 717454, MK-7454) in Combination With Different Treatment Regimens in Pediatric Participants With Advanced Solid Tumors (P05883, MK-7454-006): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of Robatumumab (SCH 717454, MK-7454) in Combination With Different Treatment Regimens in Pediatric Participants With Advanced Solid Tumors (P05883, MK-7454-006) (NCT00960063), a non-randomized phase 1 study. The primary outcome is Number of Participants With Dose Limiting Toxicities.

2. Clinical Question

3. Trial Design

This was a Phase 1/1B, open-label, non-randomized, dose-escalation study of robatumumab combined with chemotherapy in pediatric participants with advanced solid tumors. The registry reports a parallel study model, but the treatment regimens were not randomized comparisons. The study began on 2009-11-11, had a primary completion date of 2010-12-22, and is listed as terminated. Enrollment was 4.

Three combinations were described: temozolomide plus irinotecan; vincristine plus doxorubicin and cyclophosphamide; and ifosfamide plus etoposide. Robatumumab was included in each regimen, at 10 mg/kg or 20 mg/kg on Day 1 of each 3-week cycle. The registry also describes the chemotherapy schedules and doses. These regimen descriptions establish what was planned for each group; they do not show which doses each participant received or how treatment proceeded in practice.

Because allocation was non-randomized and the regimens differed, the groups should not be read as treatment and control arms in a comparative efficacy trial. The registry record does not report how treatment assignment was made, the dose-escalation rules, or the number of participants treated in each regimen for the primary endpoint. It also does not report the reasons for termination.

The stated study purpose was to evaluate safety, tolerability, and dose finding. The primary endpoint was the number of participants with dose-limiting toxicities. Secondary outcomes included best overall response using RECIST, pharmacokinetic measures of robatumumab, plasma IGF-I and IGF-II levels, and anti-robatumumab antibodies. These listed objectives describe what the study set out to assess; they are not results. No analysis results are listed 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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All Treated Set was defined as all participants who received ≥1 dose of robatumumab or chemotherapy.

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 With Dose Limiting Toxicities, measured over Up to ~30 days after last dose of study drug (Up to ~10.3 months).

The primary endpoint was the number of participants with dose-limiting toxicities, measured in participants. A dose-limiting toxicity was defined using specified adverse events considered possibly or probably related to robatumumab or its interaction with the assigned chemotherapy regimen. The definition included particular forms of neutropenia and thrombocytopenia, as well as other adverse events of Grade 3 or higher that were not ameliorated by supportive or symptomatic measures. The registry specifies NCI-CTCAE version 4.0 for grading adverse events.

The endpoint was assessed up to approximately 30 days after the last dose of study drug, with the registry also describing the period as up to approximately 10.3 months. In a dose-finding study, counting participants who meet a predefined toxicity threshold can help characterize tolerability and inform decisions about doses for further study. That general purpose does not make the count a complete summary of safety: it focuses on events meeting the stated definition, within the stated observation period.

The registry record does not report the observed primary endpoint count. It therefore does not show how many treated participants experienced a dose-limiting toxicity, nor does it give a rate or uncertainty interval for that outcome. The definition and assessment window are available, but the result needed to interpret the primary endpoint is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The statistical interpretation starts with the study question and design. This was a non-randomized, open-label, dose-escalation study with three different chemotherapy combinations. Its primary focus was safety and dose finding. It was not designed, in the information recorded, as a randomized comparison between a treatment and a control. That distinction matters: random assignment can help balance measured and unmeasured participant characteristics across comparison groups, while a non-randomized design does not provide that protection. General statistical principle: differences between non-randomized groups can reflect both treatment and group composition.

What does a participant count convey?

The primary endpoint is a count of participants with dose-limiting toxicities. A count is a direct description of how many people met the endpoint definition, but its interpretation depends on the number of participants assessed and the way missing or unevaluable observations were handled. The registry defines the All Treated Set as participants who received at least one dose of robatumumab or chemotherapy. It does not report the primary endpoint count or the number contributing to that endpoint. Consequently, neither the observed count nor its precision can be assessed from the registry record.

For a binary outcome such as whether a participant experienced an event, analysts may describe both the count and the proportion of the relevant analysis population. General statistical principle: a proportion needs a clear denominator, and uncertainty is important when the number of observations is small. A confidence interval expresses a range of values compatible with the observed data under a statistical model; it is not a guarantee that the true value lies in that range. No primary endpoint proportion or confidence interval is reported in the registry record.

Why are the regimens not direct comparators?

The study lists three combination regimens, and allocation was non-randomized. One group received temozolomide and irinotecan with robatumumab, another received vincristine, doxorubicin, and cyclophosphamide with robatumumab, and another received ifosfamide and etoposide with robatumumab. These are different combinations, not alternative levels of a single randomized intervention. General statistical principle: comparing outcomes across groups with different treatments and non-random assignment cannot isolate the effect of one drug unless the design and analysis address confounding. The registry record does not report an adjusted comparative analysis.

The open-label nature also means treatment was not masked. For objective events, lack of masking may be less influential than for subjective assessments, but assessment and reporting can still be affected by knowledge of treatment. This is a general consideration, not evidence that bias occurred in this study. The registry does not report procedures used to limit or assess such effects.

What does dose escalation imply statistically?

Dose escalation is commonly used in early-phase research to examine tolerability at different dose levels. General statistical principle: observations from an escalation process are shaped by the rules used to move between doses, the sequence of enrollment, and the toxicity criteria. Those rules are essential for interpreting dose-finding results. The registry describes the study as dose escalation and lists robatumumab doses of 10 mg/kg or 20 mg/kg, but the escalation algorithm, dose-specific participant counts, and decisions made during escalation are not reported in the registry record. No particular escalation method should be inferred.

The registry’s definition of dose-limiting toxicity is a protocol-defined endpoint. It includes specified blood-count events and other adverse events at a stated severity level, with conditions relating to duration, recovery, fever, infection, transfusion, or treatment delay. Such a definition makes an endpoint more operational than an unrestricted count of all adverse events. It also means that events not meeting the definition may still be clinically relevant safety observations, while not counting as dose-limiting toxicity under this endpoint.

How should planning illustrations be interpreted?

Sample-size calculations are planning tools that depend on assumptions about the effect to detect, significance level, allocation, and statistical approximation. The planning illustration described for this study uses a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect expressed as a fraction of the observed effect. General statistical principle: changing these assumptions changes the planning result, and a planning calculation does not establish the probability that a completed study will produce a statistically significant result.

Those assumptions do not describe the actual design of this trial. The study had three non-randomized regimens, and the registry cautions that they are not like-for-like control groups. Any sample-size illustration based on two equal arms is therefore hypothetical planning information, not evidence that the trial used that allocation or was powered for a randomized comparison. Sample-size illustrations are not observed power. The registry record does not report the trial’s own sample-size justification.

What can be concluded from the posted analyses?

The record lists secondary outcomes, including best overall response by RECIST, maximum observed concentration, time to maximum concentration, area-under-the-curve measures, plasma IGF-I and IGF-II, and anti-robatumumab antibodies. Listing an outcome is not the same as reporting its analysis. The registry record contains no listed analysis results, so there are no reported estimates, confidence intervals, or hypothesis tests for these outcomes to interpret.

General statistical principle: estimates and uncertainty should be considered together, and a result should be interpreted in light of the study design, analysis population, endpoint definition, and missing data. Here, the missing primary endpoint result and absence of listed analysis results substantially limit statistical interpretation. No p-value, adjusted effect estimate, or precision measure should be inferred from the study description or safety counts.

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("Temozolomide+Irinotecan+Robatumumab", "Ifosfamide+Etoposide+Robatumumab")
n      <- c(1, 3)
events <- c(1, 3)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Temozolomide+Irinotecan+Robatumumab  1  1  100.0  2.5  100.0  20.7  100.0  15.8  98.7
ARM  Ifosfamide+Etoposide+Robatumumab  3  3  100.0  29.2  100.0  43.9  100.0  39.8  99.4

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists several secondary outcomes in addition to the primary dose-limiting toxicity endpoint. These include response, multiple pharmacokinetic measures, IGF-I and IGF-II levels, and anti-robatumumab antibodies. When multiple outcomes are examined, the chance of at least one apparently notable finding can increase if each is tested separately. General statistical principle: a prespecified multiplicity strategy can help define how to interpret multiple tests. The registry record does not report a multiplicity adjustment or a hierarchy for interpreting secondary outcomes, so no such plan should be assumed.

The record defines the All Treated Set as all participants who received at least one dose of robatumumab or chemotherapy. It does not report the number analyzed for the primary endpoint or for the secondary outcomes, and does not explain how participants with incomplete measurements were handled. Missing-data methods and reasons for missing observations are not reported in the registry record. Without this information, the impact of incomplete follow-up or unavailable measurements cannot be assessed.

The record also does not report a statistical analysis plan, interim analyses, or a sample-size justification. The planning assumptions described for the sample-size illustration are not a substitute for a reported trial analysis plan. In particular, they do not establish how outcomes were analyzed in this non-randomized study or how multiple outcomes were handled. These omissions limit assessment of the analysis choices, but do not by themselves establish that a particular bias occurred.

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: febrile neutropenia (100.0%), chills (33.3%), pyrexia (33.3%), lobar pneumonia (33.3%), transfusion reaction (33.3%).

The registry’s adverse-event listing gives group-level counts for participants at risk and affected, and separately lists selected serious adverse-event terms with percentages. For the temozolomide, irinotecan, and robatumumab regimen, the serious-event listing reports 1 at risk and 0 affected; the other-event listing reports 1 at risk and 1 affected. The vincristine, doxorubicin, cyclophosphamide, and robatumumab group has zero listed in these count fields. For the ifosfamide, etoposide, and robatumumab regimen, the listing reports 3 at risk and 3 affected for both serious and other adverse events.

The serious-event terms include febrile neutropenia at 100.0%, with chills, pyrexia, lobar pneumonia, transfusion reaction, and decreased white blood cell count each listed at 33.3%. The registry record does not report the denominator or detailed term-level counting rules for these percentages. They should not be treated as percentages of all enrolled participants or as directly comparable rates across regimens without that context.

Serious adverse events and dose-limiting toxicities are distinct categories. The endpoint definition for dose-limiting toxicity includes particular severity, duration, relationship, and treatment-course criteria. The adverse-event listing alone cannot supply the missing primary endpoint result. With limited enrollment and no reported analysis details, these figures are descriptive safety information, not precise estimates of risk.

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

The registry record establishes that this was an early-phase, non-randomized study of robatumumab combined with three chemotherapy regimens in pediatric participants with advanced solid tumors. It records enrollment of 4 and describes the intended safety, tolerability, and dose-finding objectives. It also specifies the primary dose-limiting toxicity endpoint and its adverse-event criteria. These design details clarify the question the study was intended to address.

The record does not report the primary endpoint result or analysis results for the listed secondary outcomes. It therefore does not show how many participants experienced a dose-limiting toxicity, what the response findings were, or what the pharmacokinetic and biomarker results showed. A missing result cannot be interpreted as a zero count or as evidence that an outcome did not occur. The posted safety counts and serious-event terms offer descriptive information, but they do not replace the endpoint result.

The design also limits comparative interpretation. Participants were not randomized, and the chemotherapy combinations differed. The groups are not a like-for-like control comparison, so differences across them cannot establish that robatumumab caused a difference in safety or response. The small enrollment further means that any group-level observations would have limited precision, although the registry does not report estimates or intervals with which to quantify that uncertainty.

More generally, an early-phase safety and dose-finding study addresses a different question from a trial designed to estimate comparative benefit. General statistical principle: a safety signal, an endpoint count, a response outcome, and a causal treatment effect are different forms of evidence. The registry description and safety listing do not support a conclusion about whether any regimen is effective, nor do they support a treatment recommendation. They document the study’s purpose and some recorded adverse-event information, while leaving the principal outcome results unavailable in the registry record.

14. Why This Trial Matters Statistically

This trial illustrates why study design and outcome reporting need to be read together. Its stated purpose was safety, tolerability, and dose finding for robatumumab with chemotherapy, and the primary endpoint was a defined count of participants with dose-limiting toxicities. The endpoint definition is detailed, but the result is not reported in the registry record. A clearly specified measure cannot be interpreted without its observed value and the population contributing to it.

The three chemotherapy regimens also show why a list of arms does not automatically create a comparative trial. Allocation was non-randomized, and the combinations differed. The registry explicitly says that the arms are not a like-for-like control comparison. General statistical principle: treatment-group labels alone do not make a valid causal contrast; the assignment process and comparability of groups matter.

The record also separates safety reporting from primary endpoint reporting. Adverse-event counts and terms can convey information about events recorded in the study, but they do not establish the number meeting a specific dose-limiting toxicity definition. Likewise, listing secondary outcomes does not reveal their findings. Keeping these categories distinct prevents descriptive safety information from being mistaken for a complete trial result.

Finally, the study’s limited enrollment and absent analysis results make precision and generalizability difficult to evaluate. The registry record does not report confidence intervals, analysis methods, missing-data handling, or a sample-size justification. These are not details that can be reconstructed from the study title or endpoint definition. The case therefore demonstrates a central statistical lesson: design, endpoint, analysis population, uncertainty, and reporting completeness jointly determine what a clinical study can support.

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 endpoint result is not reported in the registry record. Enrollment is listed as 4, but the record does not give the primary endpoint analysis count or the distribution of participants across the three regimens for that outcome. The listed All Treated Set definition identifies who could be included, but does not establish how many contributed to a particular analysis.

Non-randomized allocation and distinct chemotherapy combinations prevent a like-for-like comparison across groups. The registry does not report how participants were assigned to regimens, how dose escalation was conducted, or whether dose-specific results were analyzed. The open-label design is also a limitation to consider, although the record does not show whether knowledge of treatment affected event assessment.

Although safety counts and serious-event terms are listed, denominator and term-level counting details for the percentages are not reported in the registry record. The primary endpoint definition and serious adverse-event listings should not be treated as interchangeable. Reasons for termination are not reported in the registry record.

Analysis methods, missing-data handling, interim analyses, multiplicity procedures, and a sample-size justification are not reported in the registry record. Results for the listed secondary outcomes are also not reported. These limitations prevent assessment of outcome precision, robustness, and the extent to which incomplete observations may have influenced results. They describe gaps in the registry record, not proof that the study lacked procedures that were not recorded there.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study of Robatumumab (SCH 717454, MK-7454) in Combination With Different Treatment Regimens in Pediatric Participants With Advanced Solid Tumors (P05883, MK-7454-006) — NCT00960063.
• Registry record last updated 2018-08-27; status last verified 2018-07.
• Results first posted 2016-02-10.
• 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 registry record describes a Phase 1/1B, open-label, non-randomized dose-escalation study of robatumumab combined with chemotherapy in pediatric participants with advanced solid tumors. The three regimens paired robatumumab with temozolomide and irinotecan; vincristine, doxorubicin, and cyclophosphamide; or ifosfamide and etoposide. Enrollment was 4. The study is listed as terminated, with a start date of 2009-11-11 and a primary completion date of 2010-12-22.

The primary endpoint was the number of participants with dose-limiting toxicities, using defined adverse-event criteria. The primary endpoint result and results for the listed secondary outcomes are not reported in the registry record. Some group-level adverse-event counts and selected serious-event terms are listed, but they do not establish the missing primary endpoint result or permit a randomized comparison among regimens.