Study Evaluating the Safety and Efficacy of Eribulin Mesilate in Combination With Irinotecan Hydrochloride in Children With Refractory or Recurrent Solid Tumors: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study Evaluating the Safety and Efficacy of Eribulin Mesilate in Combination With Irinotecan Hydrochloride in Children With Refractory or Recurrent Solid Tumors (NCT03245450), a na phase 1, phase 2 study. The primary outcome is Phase 2: Objective Response Rate (ORR).

2. Clinical Question

3. Trial Design

This was a phase 1/2, single-group study of eribulin mesilate in combination with irinotecan hydrochloride in children with refractory or recurrent solid tumors. The registry records an enrollment of 40, a start date of 2018-03-05, primary completion on 2021-05-17, and a completed status. Allocation is listed as NA and masking as none. There was no randomized control arm, so the design does not support a direct comparison of the combination with an alternative treatment.

The phase 1 part was intended to determine the maximum tolerated dose and Recommended Phase 2 Dose of the combination. The phase 1 population description excludes central nervous system tumors. The registry lists Schedule A dose groups with eribulin mesilate 1.4 mg/m^2 and irinotecan 20 mg/m^2 or 40 mg/m^2, and Schedule B groups with eribulin mesilate 1.4 mg/m^2 and irinotecan 100 mg/m^2 or 125 mg/m^2. The arm description states that eribulin was given by intravenous infusion on Days 1 and 8 of each 21-day cycle in Schedules A and B. Further administration details for irinotecan, including the complete Schedule B description, are not reported in the registry record.

The phase 2 part assessed objective response rate and duration of response in rhabdomyosarcoma, non-rhabdomyosarcoma soft tissue sarcoma, and Ewing sarcoma cohorts. The listed phase 2 dose was eribulin mesilate 1.4 mg/m^2 with irinotecan 40 mg/m^2. The registry also lists safety and pharmacokinetic outcomes, including measures of plasma concentration and drug disposition. The actual dose selected for phase 2, the duration-of-response results, and the pharmacokinetic results are 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.

Before assignment: A total of 46 participants were screened, out of which 13 participants were treated in the Phase 1 and 27 participants were treated in Phase 2 (9 participants each in the relapsed/refractory rhabdomyosarcoma \[RMS\], non-rhabdomyosarcoma soft tissue sarcoma \[NRSTS\], and Ewing sarcoma \[EWS\] cohorts).

Only the first 6 of 7 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Dose Evaluable Set (DES) for Phase 1 included all the participants who completed Cycle 1 treatment and were evaluated for DLTs and those who discontinued treatment during Cycle 1 due to DLTs.

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.

Population: Full analysis set included all participants who received at least 1 dose of either study drug.

Only the first 6 of 8 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Phase 2: Objective Response Rate (ORR), measured over From date of first dose of study drug until disease progression, development of unacceptable toxicity, withdrawal of consent, or up to approximately 2 years 4 months.

The phase 2 primary endpoint was objective response rate (ORR), expressed as the percentage of participants whose best overall response was a confirmed complete response or confirmed partial response. Responses were assessed by investigators using RECIST version 1.1. Under the registry definition, complete response meant disappearance of all target and non-target lesions, with pathological lesions having a short axis < 10 mm. Partial response required at least a 30% decrease in the sum of diameters of target lesions compared with baseline.

ORR is a binary outcome at the participant level: each participant either meets the response definition or does not. Reporting the percentage gives a compact measure of the frequency of confirmed tumor shrinkage according to the stated criteria. The registry identifies a 90% confidence interval as the uncertainty measure for this endpoint. A confidence interval communicates how imprecise an estimated response percentage may be; it does not guarantee that the true response percentage lies within any one calculated interval.

The endpoint timeframe ran from the first dose until disease progression, unacceptable toxicity, withdrawal of consent, or up to approximately 2 years 4 months. The phase 2 aim also included duration of response, which concerns how long a response lasts, but the registry record does not report its result. The ORR estimate and its confidence interval are not reported in the registry record either, so the endpoint definition is available without a posted numerical response result.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the response percentage represent?

In general, a response rate for a binary endpoint is the proportion of assessed participants who meet a prespecified definition. In this study, the definition counted a participant as a responder only when the best overall response was a confirmed complete response or partial response according to investigator assessment under RECIST version 1.1. A participant who did not meet either response category would not count as a responder under that definition. The registry record does not report the number of responders or the phase 2 ORR estimate, so a numerical rate cannot be interpreted.

The distinction between a response definition and a response result matters. A prespecified measurement rule explains what is being counted; it does not tell the reader how many participants met that rule. Here, the registry specifies disappearance of target and non-target lesions for complete response, including the pathological-lesion short-axis condition of < 10 mm. It defines partial response as at least a 30% decrease in the sum of diameters of target lesions relative to baseline. It also specifies confirmation of response. These criteria make the outcome more reproducible than an unstructured judgment, although the record does not give detailed procedures for handling missing measurements or independent review.

How should the confidence interval be understood?

The registry identifies a 90% confidence interval for ORR. In general, a confidence interval expresses sampling uncertainty around an estimate. A wider interval indicates less precision than a narrower interval, while the point estimate alone does not show how uncertain the estimate is. The confidence level describes the long-run performance of the interval procedure under its assumptions; it is not a probability statement that the particular interval contains the true value. Because neither the ORR estimate nor the interval is reported in the registry record, the response estimate’s precision cannot be judged.

A response percentage is especially sensitive to the number of participants contributing information when the study groups are small. In general, each participant’s classification has a larger influence on a proportion in a small group than in a large group. This is one reason an interval is useful alongside a percentage. The registry defines the phase 2 full analysis set as participants who received at least 1 dose of either study drug, but does not report how many participants entered that set or how many had response assessments suitable for the primary analysis.

What does the single-group design allow?

In general, a single-group study can describe observed outcomes in the group receiving the study intervention. Without a concurrent control group, it cannot isolate the intervention’s contribution from other influences on outcome or estimate a comparative treatment effect. Randomization is commonly used to make treatment groups comparable in expectation, but this study is listed as single-group, with allocation NA and no masking. Therefore, any reported response or safety result would need to be read as a descriptive finding in the studied group, not as a randomized comparison.

The phase structure also reflects different questions. The phase 1 part sought to identify the maximum tolerated dose and Recommended Phase 2 Dose. The phase 2 part sought to assess ORR and duration of response in three disease cohorts. The registry record does not report the dose-finding method, decision rules, or results. It also does not report whether there were interim analyses, a formal statistical analysis plan, or a particular method for calculating the confidence interval. These methods are not reported in the registry record and should not be inferred from the phase labels alone.

How should safety and secondary outcomes be read?

The registry lists participant counts for serious adverse events, other adverse events, and deaths across the phase 1 dose groups and phase 2 cohorts. In general, event counts describe what was recorded in each group; they do not by themselves establish causality or compare risks fairly across treatments. The record has no randomized comparator. It also lists pharmacokinetic measures such as maximum observed plasma concentration, time to maximum concentration, half-life, total clearance, volume of distribution, and area under the concentration-time curve. These measures characterize drug exposure or disposition, but their analysis results are not reported in the registry record.

The record lists 15 outcome measures and 0 analyses. It names the ORR endpoint and a 90% confidence interval, but supplies no result estimate or interval. It is therefore not possible to verify the analytical method, reproduce an effect estimate, or judge the results against any threshold from the registry material. Any sample-size planning illustration should be understood as a planning calculation under stated assumptions, not as observed power; it does not fill the gap left by an unreported endpoint result.

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("Phase 2: RMS Cohort, Eribulin Mesilate 1.4 mg/m^2 ", "Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^", "Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 ")
n      <- c(9, 9, 9)
events <- c(1, 1, 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  Phase 2: RMS Cohort, Eribulin Mesilate 1.4 mg/m^2   9  1  11.1  0.3  48.2  2.0  43.5  2.5  44.5
ARM  Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^  9  1  11.1  0.3  48.2  2.0  43.5  2.5  44.5
ARM  Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2   9  1  11.1  0.3  48.2  2.0  43.5  2.5  44.5

11. Multiplicity, Missing Data and Analysis Populations

The study included distinct phase 1 and phase 2 aims, several phase 2 disease cohorts, and multiple secondary outcomes. The registry lists safety outcomes and pharmacokinetic outcomes alongside the phase 2 ORR and duration-of-response objectives. When several outcomes or cohorts are examined, the chance of finding an apparently notable result by chance can increase if many statistical tests are conducted. In general, multiplicity procedures can address that issue, but the registry record does not report whether any adjustment was planned or used. It also does not report an analysis plan or a hierarchy among the outcomes beyond identifying ORR as the phase 2 primary endpoint.

The primary population is defined as the full analysis set, including participants who received at least 1 dose of either study drug. The number included in that set, the number with evaluable response data, and the handling of participants without an assessment are not reported in the registry record. The record does not state whether missing response assessments were treated as nonresponse, excluded, imputed, or handled by another method. Each approach can affect a binary endpoint’s estimate, so the missing-data rule is important for interpretation.

The registry describes response as confirmed and assessed by investigators using RECIST version 1.1, but it does not report details such as the assessment schedule, the confirmation procedure, or how unevaluable lesions or assessments were handled. These omissions prevent a full evaluation of the endpoint implementation. No outcome analyses are listed in the registry record. Accordingly, it is not possible to determine which participants contributed to reported analyses, whether sensitivity analyses were conducted, or whether missingness differed across cohorts. These analysis 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.

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: pyrexia (50.0%), bacteraemia (33.3%), malignant neoplasm progression (33.3%), febrile neutropenia (11.1%), abdominal pain (11.1%).

The registry reports serious adverse-event and other adverse-event counts separately for the listed dose groups and disease cohorts. For serious adverse events, it records 1 participant among 3 at risk in the phase 1 Schedule A 20 mg/m^2 group, 3 among 4 in the Schedule A 40 mg/m^2 group, 0 among 3 in the Schedule B 100 mg/m^2 group, and 1 among 3 in the Schedule B 125 mg/m^2 group. In phase 2, the counts are 5 among 9 in the rhabdomyosarcoma cohort, 4 among 9 in the non-rhabdomyosarcoma soft tissue sarcoma cohort, and 3 among 9 in the Ewing sarcoma cohort. The registry lists other adverse events for all participants at risk in each of these groups.

Listed serious adverse-event terms include pyrexia at 50.0%, bacteraemia and malignant neoplasm progression at 33.3% each, and febrile neutropenia, abdominal pain, and device related infection at 11.1% each. The registry also records deaths by group, but does not establish in these figures that deaths were caused by study treatment. These descriptive figures do not show comparative risks, and the registry record does not report statistical comparisons or uncertainty intervals for them.

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

The registry record describes a completed phase 1/2 study of eribulin mesilate with irinotecan hydrochloride in children with refractory or recurrent solid tumors. Its phase 1 objective was dose finding; its phase 2 objective included response assessment in rhabdomyosarcoma, non-rhabdomyosarcoma soft tissue sarcoma, and Ewing sarcoma. The primary phase 2 endpoint was confirmed ORR by investigator assessment using RECIST version 1.1. These details explain the questions the study was designed to address, but they are not themselves evidence of an observed response result.

The primary ORR estimate and its 90% confidence interval are not reported in the registry record. The duration-of-response result and phase 1 dose-finding conclusions are also not reported. Consequently, the posted registry information does not establish how often participants responded, how precisely a response percentage was estimated, or which dose was selected based on the phase 1 findings. Descriptive safety counts are available, but they do not show whether the combination caused the listed events or deaths.

Even if a numerical ORR were available, a response percentage from this single-group design would describe outcomes in the treated study group under the stated assessment rules. With no randomized control group, it would not directly establish how outcomes compare with another treatment. A response measure also does not, by itself, describe how long a response lasts; that is a separate question addressed by duration of response.

In general, statistical interpretation depends on both the estimate and its uncertainty, as well as on who was included and how missing outcomes were handled. The registry defines the full analysis set but does not report its size, the number with evaluable responses, or the missing-data approach. The available record therefore supports understanding the study’s design, outcome definition, and reported safety counts, but it does not support a quantitative conclusion about the primary efficacy outcome.

14. Why This Trial Matters Statistically

This study is statistically notable for combining a dose-finding phase with a disease-cohort phase while using a single-group design. Those phases address different questions: determining a tolerable and recommended dose is not the same task as estimating response in specified disease cohorts. Keeping those aims distinct helps readers avoid treating dose selection and response assessment as interchangeable evidence.

The primary outcome is a participant-level binary measure based on confirmed response under RECIST version 1.1. That definition requires explicit lesion criteria, and the registry identifies a 90% confidence interval as the intended uncertainty measure. In general, presenting both a proportion and an interval helps readers assess the stability of an estimate rather than relying on a percentage alone. In this case, neither the ORR percentage nor its interval is reported in the registry record, so the intended statistical summary cannot be evaluated.

The single-group structure also places a clear boundary on interpretation. A descriptive response result, if reported, would not be a randomized comparison and could not identify a comparative treatment effect. The several disease cohorts and phase 1 dose groups further make it important to keep results tied to the group and phase in which they were observed, rather than pooling or comparing groups without an explicit analysis plan.

Finally, the record illustrates why statistical reporting needs more than endpoint names. Population counts, missing-data handling, analysis methods, uncertainty estimates, and results are all relevant to interpretation. The registry defines the endpoint and lists safety and pharmacokinetic outcomes, but does not report the primary result or analyses. The design and definitions are informative; the absence of outcome analyses limits what can be concluded statistically.

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 of the registry record for evaluating the primary question is the absence of the ORR result and its 90% confidence interval. The record also does not report duration of response or the phase 1 maximum tolerated dose and Recommended Phase 2 Dose conclusions. Thus the planned objectives can be described, but their numerical outcomes cannot be assessed from the registry record.

The single-group design has no randomized control group, so it cannot provide a direct treatment comparison. The study includes multiple phase 1 dose groups and phase 2 disease cohorts; the registry record does not report a formal method for comparing these groups. The arm description gives some dosing details but is incomplete, including the Schedule B irinotecan administration details. Further information about assessment timing, response confirmation procedures, and handling of unevaluable assessments is not reported in the registry record.

The full analysis set is defined, but its size and the number with evaluable response information are not reported. Missing-data rules, analysis methods, multiplicity procedures, and any interim analyses are not reported in the registry record. These omissions limit the ability to assess how the stated endpoint would be analyzed or how robust a result might be to missing assessments. The listed safety figures are descriptive and do not establish causality or comparative risk. The registry record does not report uncertainty estimates for those safety counts.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study Evaluating the Safety and Efficacy of Eribulin Mesilate in Combination With Irinotecan Hydrochloride in Children With Refractory or Recurrent Solid Tumors — NCT03245450.
• Registry record last updated 2022-06-28; status last verified 2021-06.
• Results first posted 2022-06-28.
• 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

The registry identifies NCT03245450 as a completed phase 1/2 single-group study sponsored by Eisai Inc. It evaluated eribulin mesilate with irinotecan hydrochloride in children with refractory or recurrent solid tumors. Registry enrollment is 40; the study started on 2018-03-05 and reached primary completion on 2021-05-17. There was no masking and no randomized comparator.

Phase 1 aimed to determine the maximum tolerated dose and Recommended Phase 2 Dose. Phase 2 assessed ORR and duration of response in rhabdomyosarcoma, non-rhabdomyosarcoma soft tissue sarcoma, and Ewing sarcoma. The primary endpoint was confirmed complete or partial response by investigator assessment using RECIST version 1.1. The registry lists safety and pharmacokinetic outcomes, but no analyses are listed. The primary response result, its confidence interval, and the phase 1 dose-finding conclusions are not reported in the registry record.