High-Dose 131I-MIBG Therapy Combined With Vincristine and Five Days of Irinotecan for Resistant/Relapsed Neuroblastoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for High-Dose 131I-MIBG Therapy Combined With Vincristine and Five Days of Irinotecan for Resistant/Relapsed Neuroblastoma (NCT01313936), a non-randomized phase 1 study. The primary outcome is Number of Participants With Dose-limiting Toxicity as a Measure of Tolerability.

2. Clinical Question

Other listed outcomes address therapeutic response, changes in diarrhea, and changes in standardized uptake values on FDG-PET scans. These outcomes broaden the questions recorded for the study, but the primary endpoint is the tolerability measure. Results for these secondary outcomes are not reported in the registry record.

3. Trial Design

This was a completed phase 1 pilot study with non-randomized allocation, no masking, and a parallel model. The registry lists University of California, San Francisco as the sponsor. The study began in 2011-03, reached primary completion in 2014-05, and has completed status. Enrollment is listed as 32.

The study focused on high-dose 131I-MIBG combined with vincristine and five days of irinotecan for children and young adults with resistant or relapsed high-risk neuroblastoma. The stated schedule was a one-week schedule. The brief summary identifies 15 mCi/kg and 18 mCi/kg as the 131I-MIBG doses under evaluation.

The arm descriptions refer to an initial safety cohort of 3-6 patients at 15 mCi/kg and a subsequent cohort of 3-6 patients at 18 mCi/kg, with the same doses of vincristine and irinotecan. Separately, the posted adverse-event figures list 6 participants at risk in the 15 mCi/kg group and 26 in the 18 mCi/kg group. The registry record does not explain the relationship between the cohort descriptions, the enrollment figure, and these adverse-event group counts. They should be read as the distinct information recorded for the design and safety summaries, not reconciled by assumption.

Because allocation was non-randomized and the study had no masking, the groups do not constitute a randomized, blinded comparison. The registry record does not report a control treatment, a randomization procedure, or a masking procedure. It also does not report the protocol details needed to determine whether dose assignment depended on prior safety observations or other eligibility criteria. The design is best understood as a pilot assessment of tolerability across the described dose cohorts, rather than as a definitive comparative-effectiveness trial.

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

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 Toxicity as a Measure of Tolerability, measured over 6 weeks.

The primary endpoint is the number of participants with dose-limiting toxicity, described as a measure of tolerability. Its timeframe is 6 weeks. The registry states that the endpoint addresses whether 15 mCi/kg and 18 mCi/kg of 131I-MIBG are tolerable when combined with irinotecan and vincristine on a 5-day schedule in children and young adults with high-risk refractory or relapsed neuroblastoma.

A participant count is an event-count outcome: it records how many participants meet the endpoint definition, rather than measuring an average change on a continuous scale. In general, dose-limiting toxicity is useful in an early-phase study because it focuses attention on treatment-related harms that constrain dose selection. It can help characterize tolerability in the setting and timeframe specified by the study. The registry record does not report the operational definition of dose-limiting toxicity, the grading criteria, or the rules for deciding whether an event qualified.

The primary endpoint result itself is not reported in the registry record. The posted serious and other adverse-event counts do not substitute for that result: the registry does not state that those event categories are identical to the dose-limiting-toxicity definition. Without the endpoint count and its definition, the primary tolerability question cannot be answered from the record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The study is recorded as phase 1, non-randomized, unmasked, and parallel. These descriptors concern different aspects of design. Phase 1 identifies the study stage; non-randomized describes how participants were allocated; unmasked means the registry records no masking; and parallel indicates that the treatment groups were followed as separate arms rather than as a crossover. The registry record does not report a detailed statistical analysis plan, so the design labels should not be taken as evidence of specific modeling or testing choices.

What does a participant count measure?

The primary endpoint is a count of participants with dose-limiting toxicity during 6 weeks. In general, a binary participant-level endpoint classifies each participant according to whether the specified event occurred, then reports the number meeting that criterion. This differs from counting every episode if one participant could experience repeated events. The registry describes a number of participants, but does not report the endpoint definition or clarify how repeated events, attribution, or incomplete observation were handled.

In general, a count is easier to interpret when its denominator, outcome definition, and observation period are clear. The registry specifies the timeframe but does not report the primary endpoint count or the detailed criteria for classifying dose-limiting toxicity. The safety summary gives at-risk and affected counts for serious and other adverse events, but those categories are not stated to be interchangeable with the primary endpoint. They must remain separate measures unless the registry explicitly links them.

Why does non-random allocation matter?

In general, randomization helps balance measured and unmeasured characteristics across treatment groups, on average. With non-random allocation, group differences can reflect participant characteristics, treatment assignment decisions, timing, or other factors as well as dose. Here, the registry says the arms are not a like-for-like control comparison. Consequently, a numerical difference between their posted counts should not be interpreted as a causal dose effect. A statistical adjustment could sometimes address measured differences, but the registry record does not report an adjusted analysis or the variables that such an analysis would use.

The cohort descriptions identify a 15 mCi/kg group followed by an 18 mCi/kg group, and describe safety cohorts of 3-6 patients. This establishes how the registry characterizes the cohorts, but it does not establish a particular escalation rule, stopping rule, or dose-selection algorithm. Those protocol details are not reported in the registry record. The adverse-event summary's at-risk counts differ from the cohort sizes described in the arm text; the record does not explain the discrepancy, so no reconciliation should be assumed.

How should uncertainty be understood?

In general, an estimate is more informative when accompanied by an uncertainty interval and a clearly stated analysis method. A confidence interval describes uncertainty in an estimate under the model and sampling assumptions used. It does not guarantee that the interval captures the true value, and its interpretation depends on the study design and outcome definition. No confidence interval for the primary endpoint is reported in the registry record. Nor does the record report a test statistic or p-value for that endpoint.

For event counts, small amounts of information can make estimates imprecise. General methods for proportions or event counts may use different assumptions, and the appropriate approach depends on how the endpoint is defined and how participants were observed. The registry does not report an analysis method for the primary endpoint, so a particular model or inferential procedure cannot be attributed to this study.

What do the planning illustrations represent?

Any sample-size planning illustrations associated with the results are not the trial's observed power and are not evidence that the study was designed around those values. The stated illustration assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is specified as a fraction of the observed effect. For non-time-to-event outcomes, the illustrations are expressed as participants per arm for 80% power or participants per arm for 90% power; time-to-event planning uses total events. These are planning calculations, not observed trial findings. The registry record does not report that these assumptions formed part of the original design or statistical plan.

More generally, a sample-size calculation depends on an assumed effect, variability or event rate, allocation, and analysis method. If an assumed effect comes from a small pilot, it may be unstable. A planning figure therefore does not establish that a future study will attain its intended power, nor does it describe the precision of the current study's results. No sample-size justification or prospective statistical plan is reported in the registry record.

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("15 mCi/kg of 131I-MIBG", "18 mCi/kg of 131I-MIBG")
n      <- c(6, 26)
events <- c(0, 0)
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  15 mCi/kg of 131I-MIBG  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  18 mCi/kg of 131I-MIBG  26  0  0.0  0.0  13.2  0.0  12.9  0.1  12.8

11. Multiplicity, Missing Data and Analysis Populations

The registry lists therapeutic response, changes in diarrhea, and changes in standardized uptake values on FDG-PET scans as secondary outcomes, in addition to the primary dose-limiting-toxicity endpoint. There are 4 outcome measures recorded, but the registry record does not report results for the secondary outcomes or a statistical plan for testing them.

In general, assessing several outcomes or performing several tests increases the chance of finding at least one apparently notable result by chance. A prespecified multiplicity strategy can clarify which outcomes are confirmatory and how interpretation should account for multiple comparisons. The registry record does not report whether multiplicity was addressed, whether any outcomes were designated exploratory, or whether a hierarchy of testing was planned. No claim about adjustment or lack of adjustment can be made beyond that absence of reporting.

Missing-data procedures and analysis populations are also not reported in the registry record. The record does not describe how participants with incomplete follow-up, missing outcome assessments, or treatment discontinuation were handled. It does not identify an intention-to-treat, per-protocol, safety, or other analysis population for the primary endpoint. The adverse-event summary does give participants at risk for its listed groups, but that alone does not define the analysis population for dose-limiting toxicity or other outcomes.

These omissions limit interpretation even when event counts are available. Without endpoint definitions, analysis populations, and missing-data rules, readers cannot determine whether all enrolled participants contributed to each outcome or whether the reported groups represent different subsets. Those details are not reported in the registry record.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: dehydration (7.7%).

The registry's adverse-event summary lists serious adverse events in 0 of 6 participants at risk in the 15 mCi/kg group and 2 of 26 participants at risk in the 18 mCi/kg group. For other adverse events, it lists 0 of 6 and 2 of 26, respectively. These are registry counts, not estimates from a randomized comparison. The record cautions that the arms are not a like-for-like control comparison.

The listed serious adverse-event term is dehydration at 7.7%. The record does not provide enough context to determine how this percentage is defined or how it corresponds to the participant counts. It also does not report event timing, severity grading details, attribution, recurrence, or the criteria used for classifying seriousness in the information. The listed term should not be treated as a complete account of all safety outcomes.

Serious adverse events and dose-limiting toxicity are not necessarily the same endpoint. The registry record does not state that every serious event met the dose-limiting-toxicity definition, or that every dose-limiting toxicity would appear in the serious-event count. The primary endpoint result remains unreported. Thus the safety figures describe the posted adverse-event summary but cannot answer the primary tolerability question by themselves.

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

The record establishes that this completed phase 1 pilot evaluated 131I-MIBG at 15 mCi/kg and 18 mCi/kg with vincristine and irinotecan in children and young adults with high-risk refractory or relapsed neuroblastoma. Its primary objective concerned dose-limiting toxicity over 6 weeks. The registry also records serious and other adverse-event counts for the two groups and lists dehydration at 7.7% among serious adverse-event terms.

The posted information does not report the number of participants with dose-limiting toxicity. It therefore does not answer the stated primary endpoint question in a way that permits readers to judge the observed frequency of that outcome. The serious and other adverse-event counts cannot fill this gap because the registry does not equate those categories with dose-limiting toxicity.

The record also does not report outcome results for therapeutic response, changes in diarrhea, or changes in standardized uptake values on FDG-PET scans. No inferential results, confidence intervals, or detailed analysis plan are reported for the primary endpoint. Consequently, the posted record does not establish the precision of any treatment-effect estimate or support a statistical comparison of efficacy across the dose groups.

Even if the group counts appear different, the non-randomized design means they should not be interpreted as a causal estimate of the effect of dose. The registry explicitly notes that the arms are not a like-for-like control comparison. Differences in participant characteristics, assignment, or follow-up could contribute to observed group counts, and the record does not provide the information needed to assess these possibilities.

In general, a pilot study can inform how a treatment combination is evaluated in a later study, but its role depends on the outcomes and methods actually reported. The registry record documents the study's purpose and design, yet its missing primary result and limited analysis detail constrain what can be concluded statistically. These limits describe the information available in the record, not a medical recommendation.

14. Why This Trial Matters Statistically

This trial is statistically notable because its central question is about tolerability at two specified 131I-MIBG doses, while the registry record does not report the primary dose-limiting-toxicity result. That distinction is important: a trial's stated objective and its posted results are not the same thing. Design details alone cannot establish how often the primary outcome occurred.

The study is also a useful example of why group labels do not automatically imply a valid comparison. Its arms represent non-randomized dose cohorts, and the registry cautions that they are not a like-for-like control comparison. In general, comparing raw counts across groups without random allocation can conflate treatment differences with differences in who entered each group or how follow-up occurred. A descriptive contrast is not necessarily a causal effect.

The recorded serious-event counts are informative as registry summaries, but their interpretation depends on clear endpoint definitions and denominators. The separate primary endpoint is dose-limiting toxicity, and the record does not establish that its definition matches the serious-event category. Distinguishing related but non-identical outcomes is essential when reading a safety-focused study.

Finally, the registry record identifies secondary questions and adverse-event terms but does not report a statistical analysis plan, missing-data procedures, or results for the primary and secondary endpoints. In general, reporting those elements helps readers judge multiplicity, uncertainty, and the possibility that outcome availability affected interpretation. The absence of these details means the record can orient readers to the study's design and aims, but offers limited basis for statistical conclusions about its outcomes.

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 important trial-specific limitation in the registry record is that the primary endpoint result is not reported. The study's main tolerability question concerns participants with dose-limiting toxicity over 6 weeks, but the record does not give that count. Detailed criteria for identifying a dose-limiting toxicity are also not reported, limiting assessment of what would have qualified as an event.

The posted safety group counts do not align transparently with the arm descriptions. The 15 mCi/kg and 18 mCi/kg cohort descriptions each refer to 3-6 patients, while the adverse-event summary lists 6 and 26 participants at risk, respectively. The registry does not explain this difference. The figures should not be combined or interpreted as if the record resolved the discrepancy.

Non-randomized allocation and the registry's explicit warning that the arms are not a like-for-like control comparison limit comparative interpretation. No masking was recorded. The registry does not report baseline characteristics, group-assignment details, or adjustment methods that could help readers assess comparability.

Results for the listed secondary outcomes are not reported in the registry record. Nor are confidence intervals, test results, analysis populations, missing-data procedures, multiplicity methods, or a detailed statistical plan. The serious adverse-event listing identifies dehydration at 7.7%, but the record does not provide context sufficient to connect that percentage to participant counts or to the primary endpoint. These limitations leave the posted record more useful for identifying study aims and design than for evaluating outcome precision or comparative effects.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: High-Dose 131I-MIBG Therapy Combined With Vincristine and Five Days of Irinotecan for Resistant/Relapsed Neuroblastoma — NCT01313936.
• Registry record last updated 2019-04-29; status last verified 2019-01.
• Results first posted 2015-08-07.
• 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 a completed, non-randomized, unmasked phase 1 pilot with parallel groups, sponsored by University of California, San Francisco. Enrollment is listed as 32. The study evaluated 15 mCi/kg and 18 mCi/kg of 131I-MIBG with vincristine and five days of irinotecan for children and young adults with high-risk refractory or relapsed neuroblastoma.

The primary endpoint was the number of participants with dose-limiting toxicity over 6 weeks. Its result is not reported in the registry record. The adverse-event summary lists serious and other event counts of 0 among 6 at risk in the 15 mCi/kg group and 2 among 26 at risk in the 18 mCi/kg group; dehydration is listed at 7.7% among serious adverse-event terms. The registry cautions that the non-randomized arms are not a like-for-like control comparison.

Secondary outcomes include therapeutic response, changes in diarrhea, and changes in standardized uptake values on FDG-PET scans. Their results, as well as detailed statistical and missing-data methods, are not reported in the registry record.