TPI 287 in Patients With Refractory or Recurrent Neuroblastoma or Medulloblastoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for TPI 287 in Patients With Refractory or Recurrent Neuroblastoma or Medulloblastoma (NCT00867568), a na phase 1 study. The primary outcome is Number of Participants With Adverse Events as a Measure of Safety and Tolerability.

2. Clinical Question

The study also describes exploratory safety and tolerability evaluation of TPI 287 with temozolomide. Tumor response is identified as an additional interest, rather than the primary objective. The registry lists secondary outcomes for overall response, progression-free survival, and pharmacokinetic measures, including Tmax, Cmax, and AUC. Numerical results for those secondary outcomes are not reported in the registry record.

This is a dose and safety question, not a randomized comparison of treatments. Without a concurrent control group, the record cannot separate observed events from the effects of the underlying disease, other care, or other influences. Nor can it establish a comparative treatment effect. The available adverse-event counts describe participants in the study group; they do not answer how the same population would have fared under a different treatment.

3. Trial Design

NCT00867568 is a completed phase 1 trial titled TPI 287 in Patients With Refractory or Recurrent Neuroblastoma or Medulloblastoma. The registry lists a start date of 2009-03 and a primary completion date of 2011-09. Enrollment was 18 participants. The trial is recorded as a single-group study, with allocation marked as not applicable and masking listed as none.

The intervention listing names TPI 287. The official title and primary outcome description refer to study of TPI 287 as a single agent and exploration of its safety and tolerability in combination with temozolomide. The registry record does not give arm descriptions or explain which participants, if any, received the combination, how treatment was assigned, or the dosing schedule. Those details are not reported in the registry record.

The primary outcome is the number of participants with adverse events as a measure of safety and tolerability, with a timeframe of 2 years. The stated primary objective also includes determining the maximum tolerated dose. The registry’s secondary-outcome listings include overall response, progression-free survival, and pharmacokinetic measures. Numerical results for these secondary outcomes are not reported in the registry record.

The single-group, unmasked structure is relevant to interpretation. Event counts can describe what was recorded among participants, but there is no concurrent control group for a like-for-like comparison. The registry does not report a randomization procedure, masking procedures, dose-escalation details, cohort structure, or a protocol for attributing adverse events. These design details should not be inferred from the phase designation or the study title.

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:

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 Adverse Events as a Measure of Safety and Tolerability, measured over 2 years.

The primary endpoint is the number of participants with adverse events, used to assess safety and tolerability. The registry gives a timeframe of 2 years and describes the primary objective as determining safety, tolerability, and the maximum tolerated dose of TPI 287 as a single agent, while collecting exploratory safety and tolerability data for combination with temozolomide.

Counting participants with events gives a direct description of how many people in the study were recorded as experiencing an event. In general, safety outcomes are important in an early-phase study because they help characterize tolerability and inform dose evaluation. A participant count does not by itself describe event severity, timing, duration, recurrence, or whether an event was judged related to treatment. Those details are not reported in the registry record for the primary outcome.

The registry’s adverse-event summary lists 18 participants at risk, 3 with serious adverse events, and 14 with other adverse events. These are reported categories; the record does not establish that they are mutually exclusive. The maximum tolerated dose is part of the stated objective, but a numerical dose result is not reported in the registry record. The posted count therefore gives a limited safety description and does not, on its own, provide a complete account of dose tolerability.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a phase 1, single-group trial with no masking and no allocation to a concurrent comparison arm. Its primary endpoint is a participant count: the number of participants with adverse events. This is a binary outcome at the participant level for a defined event category: a participant is counted as having or not having the event. The registry’s summary reports counts of participants at risk and participants with serious or other adverse events.

What does a participant count convey?

A count communicates the number of people recorded in an outcome category. It is not the same as a count of all individual event episodes, because a person may experience multiple events. The registry record does not explain whether the posted counts represent first events, all reported events, or a particular event-aggregation rule. It also does not state whether serious and other adverse-event categories overlap. For that reason, the counts should be read as reported categories rather than combined into a new total.

In general, a participant count is easiest to interpret alongside its denominator, outcome definition, and observation period. The registry gives 18 participants at risk for the adverse-event summary and a 2-year timeframe for the primary outcome. It does not report further details about the analysis population, participant-level follow-up, event definitions, or handling of incomplete observations. Those missing details limit assessment of how completely the counts capture events over the stated period.

Why is uncertainty relevant?

In general, an observed count from a study is subject to sampling variability: another group of similar participants could yield a different count. A confidence interval is one way to express uncertainty around an estimated quantity. No confidence interval or other uncertainty interval for the adverse-event results is reported in the registry record. The posted counts therefore describe this study group without showing a model-based range of plausible event frequencies.

A small study can be useful for describing early safety experience, while still producing uncertain estimates of event frequency. That general point is especially relevant when interpreting uncommon or serious event categories: the absence of a reported event, or a low observed count, would not by itself establish that the risk is absent or precisely known. No additional event rates should be calculated from the posted counts for this interpretation.

What can a single-group design establish?

As a general statistical point, a concurrent control group helps distinguish outcomes associated with one treatment strategy from outcomes that might also occur under another strategy. This study is recorded as single group, with allocation marked not applicable. Its adverse-event counts can describe events recorded among its participants, but they do not provide a randomized or otherwise like-for-like estimate of a difference between treatment strategies. The record does not report a formal comparative analysis.

The absence of masking is also relevant in general. Knowledge of treatment assignment can affect reporting, observation, or assessment, depending on the outcome and procedures. The registry does not describe the event-collection or adjudication procedures, so the extent of any such influence cannot be assessed from the record. This is a limitation of interpretation, not evidence that the posted counts are inaccurate.

How should the planning illustration be understood?

The registry’s planning assumptions describe a calculation framework using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The stated effect to detect is a fraction of an observed effect. These are assumptions for a planning illustration, not a description of the trial’s single-group design. The record gives no participant-per-arm planning results in the statistical details available for this analysis, and no observed treatment effect is reported from which to interpret such a calculation.

In general, sample-size calculations depend on the outcome, the assumed effect, variability, significance level, allocation, and statistical method. A planning calculation is not an estimate of what the study actually demonstrated. It is also not observed power. For time-to-event outcomes, the stated planning framework refers to a total number of events; for other outcomes, it refers to participants per arm. Those conventions do not turn this single-group trial into a two-arm comparison.

What analyses are missing?

The registry lists no inferential analyses. It does not report confidence intervals, hypothesis tests, adjusted estimates, an analysis population definition, or methods for missing data. It does not give a statistical procedure for the maximum tolerated dose, even though that is part of the stated primary objective. Details about dose escalation, interim review, and stopping rules are not reported in the registry record. Without these methods, the dose objective cannot be reconstructed from the adverse-event counts.

General statistical interpretation should therefore remain descriptive: identify the study group, report the recorded counts and named terms as they appear, and acknowledge that uncertainty and comparative effects are not quantified. The registry record supports that limited reading, but not causal, comparative, or dose-finding conclusions beyond what it explicitly reports.

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("TPI 287")
n      <- c(18)
events <- c(14)
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  TPI 287  18  14  77.8  52.4  93.6  54.8  91.0  54.4  90.9

11. Multiplicity, Missing Data and Analysis Populations

The registry lists several secondary outcomes in addition to the primary safety endpoint: overall response, progression-free survival, and pharmacokinetic measures including Tmax, Cmax, and AUC. It does not report numerical results for these outcomes. The registry also lists six outcome measures, but no detailed analysis results are reported. Readers therefore cannot assess whether the secondary outcomes were analyzed, how many comparisons were made, or how results were interpreted in relation to one another.

Multiplicity is a general statistical concern when many outcomes or comparisons are examined. The chance of obtaining at least one apparently notable result can be affected by the number of analyses and by whether adjustments or a prespecified hierarchy are used. The registry record does not report a multiplicity strategy, a statistical analysis plan, or which secondary outcomes were designated for confirmatory versus exploratory interpretation. No adjustment should be assumed.

Missing-data handling is also not reported in the registry record. The record does not state whether all participants completed the 2-year outcome timeframe, how incomplete follow-up was treated, or whether participants with missing outcome information were excluded or otherwise handled. It does not define the analysis population for the primary or secondary outcomes. These omissions make it difficult to judge how the reported counts relate to the full enrolled group and whether observation time was comparable across participants.

The primary outcome description names adverse events and the maximum tolerated dose objective, but the registry does not report detailed rules for event coding, attribution, or dose evaluation. Without those details, the count is interpretable as a reported safety summary, not as a fully specified analysis with known missing-data and multiplicity procedures.

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: seizure (5.6%), hemorrhagic cystitis (5.6%), progression of disease resulting in death (5.6%).

The registry’s adverse-event summary reports 18 participants at risk, with 3 participants recorded in the serious adverse-event category and 14 in the other adverse-event category. These are participant counts, not necessarily counts of individual event episodes. The record does not state whether a participant could appear in both categories, so the counts should not be added together.

The serious-event terms listed are seizure, hemorrhagic cystitis, and progression of disease resulting in death, each at 5.6%. These percentages are quoted as registered; they should not be read as proof that the events were caused by TPI 287. The registry does not provide event-level narratives, timing, duration, severity grading, relatedness assessments, or the number of participants associated with each term as a count.

The term progression of disease resulting in death appears among the serious-event terms, but a total number of deaths is not reported in the registry record. The listed event term and the overall serious-event count are different kinds of information and should not be used to infer details that the record does not give.

In general, safety summaries depend on the event definitions, observation period, completeness of follow-up, and rules for judging seriousness and treatment relatedness. Those procedures are not described in the registry record. The posted figures should therefore be read as a limited account of reported adverse events within the study group.

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

The registry record documents a phase 1 study of TPI 287 in a group of 18 participants with refractory or recurrent neuroblastoma or medulloblastoma. It reports adverse-event counts, including 3 participants with serious adverse events and 14 with other adverse events, and lists three serious-event terms with a reported value of 5.6% each. These are descriptive findings in the enrolled group.

The findings do not establish that TPI 287 caused any particular event. The registry provides no concurrent control group, and it does not report event-level details or treatment-relatedness assessments. The figures also do not establish a difference in safety compared with another treatment, because the trial is single group and has no like-for-like comparator.

The stated objective includes determining the maximum tolerated dose. A dose result and the dose-escalation methods are not reported in the registry record, so the posted safety counts alone cannot establish what dose was tolerated or how that decision was made. The record also lists response, progression-free survival, and pharmacokinetic outcomes, but numerical results for those measures are not reported.

More generally, a result in a small, non-comparative early-phase study is not a definitive estimate of safety or efficacy for a broader population. Uncertainty intervals and analysis details are not reported, and the record does not describe completeness of follow-up or missing-data handling. The available information therefore supports a narrow description of reported adverse events, not a conclusion that a treatment works or does not work.

The combination with temozolomide is discussed as an exploratory safety objective, while the intervention listing names TPI 287. The registry does not clarify whether or how the combination was administered. It would be inappropriate to infer a combination result from the study title or objective language alone.

14. Why This Trial Matters Statistically

Statistically, this trial illustrates the distinction between describing events and estimating a treatment effect. A single-group safety summary can identify adverse events recorded among participants and can contribute to the early characterization of tolerability. It cannot provide a randomized comparison with an alternative treatment when no concurrent comparator is listed.

The distinction matters especially for the stated maximum tolerated dose objective. Dose evaluation depends on the dose levels administered, how participants were assigned to them, the rules for escalation or stopping, and how events informed the decision. The registry record does not report those procedural details or a numerical maximum tolerated dose. The objective is clear, but the evidence needed to reconstruct its statistical evaluation is not available in the record.

The trial also demonstrates why counts need context. The adverse-event summary gives participants at risk and participants with serious and other events, while the registry does not state whether categories overlap or describe event-level timing and attribution. The named serious-event terms add detail, but they do not replace a complete account of coding, observation, and follow-up.

Finally, the registry lists clinically relevant secondary outcomes, but provides no numerical results for them and no inferential analyses. A list of endpoints is not itself evidence about their outcomes. Keeping the primary safety objective separate from exploratory response and pharmacokinetic questions helps prevent over-reading an incomplete outcome record. The statistical lesson is to match conclusions to the design, endpoint, and level of detail actually recorded.

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 registry record contains limited information about implementation and analysis. It does not report the dosing schedule, dose levels, escalation procedure, cohort structure, stopping rules, or the method used to determine the maximum tolerated dose. These omissions prevent readers from evaluating the dose-finding process or understanding how individual adverse events informed dose decisions.

The intervention listing names TPI 287, while the title and primary objective also refer to exploratory evaluation with temozolomide. Arm descriptions are blank, and the record does not explain which participants received which regimen or how combination treatment was administered. The actual exposure to the combination is therefore not clear from the registry record.

The record does not report participant-level event details, event timing, duration, severity grading, attribution, or procedures for event adjudication. It also does not state whether serious and other adverse-event categories overlap. Follow-up completeness, missing-data handling, and the analysis population are not described. These gaps limit interpretation of the adverse-event counts as estimates over the stated 2-year timeframe.

Numerical results for the listed secondary outcomes are not reported, and no inferential analyses are listed. The registry does not provide confidence intervals, hypothesis tests, a statistical analysis plan, or a multiplicity approach. The lack of a concurrent comparator and the absence of masking further mean that the safety counts cannot estimate comparative effects. These are limitations of what can be concluded from the registry record, rather than proof that any unreported procedure was or was not performed.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: TPI 287 in Patients With Refractory or Recurrent Neuroblastoma or Medulloblastoma — NCT00867568.
• Registry record last updated 2024-08-06; status last verified 2024-08.
• Results first posted 2016-10-28.
• 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

NCT00867568 is a completed phase 1, single-group, unmasked study of TPI 287 in patients with refractory or recurrent neuroblastoma or medulloblastoma. The registry reports enrollment of 18 participants and gives a primary outcome timeframe of 2 years. The primary objective concerns safety, tolerability, and maximum tolerated dose, with exploratory safety evaluation of TPI 287 in combination with temozolomide.

The adverse-event summary reports 3 participants with serious adverse events and 14 with other adverse events among 18 at risk. Seizure, hemorrhagic cystitis, and progression of disease resulting in death are each listed at 5.6%. Numerical results for response, progression-free survival, pharmacokinetic outcomes, and maximum tolerated dose are not reported in the registry record. The available counts are descriptive and do not provide a controlled comparison or establish causation.