Study of Lenvatinib in Combination With Everolimus in Recurrent and Refractory Pediatric Solid Tumors, Including Central Nervous System Tumors: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Lenvatinib in Combination With Everolimus in Recurrent and Refractory Pediatric Solid Tumors, Including Central Nervous System Tumors (NCT03245151), a non-randomized phase 1, phase 2 study. The primary outcome is Phase 1: Number of Participants With Any Treatment-emergent Adverse Event (TEAE).

2. Clinical Question

3. Trial Design

This was a Phase 1/2, nonrandomized, unmasked, parallel study of lenvatinib combined with everolimus in pediatric participants with recurrent or refractory solid tumors, including central nervous system tumors. The registry record lists enrollment of 64 and a completed status. It records a start date of 2017-11-16 and primary completion on 2022-09-30.

Phase 1 used a rolling 6 design. Participants with recurrent or refractory solid tumors received escalating doses of the combination. The stated aims were to determine the maximum tolerated dose and recommended Phase 2 dose and to describe toxicities. The listed dose groups were lenvatinib 8 mg/m^2 with everolimus 3 mg/m^2, and lenvatinib 11 mg/m^2 with everolimus 3 mg/m^2. The Phase 1 treatment phase was described as one cycle of 28 days.

Phase 2 was described as using Simon's optimal 2-stage design, with separate cohorts for Ewing sarcoma, rhabdomyosarcoma, and HGG. Participants were to receive the RP2D determined in Phase 1. The described treatment period was four 28-day cycles, up to 16 weeks. The intended Phase 2 efficacy measure was ORR at Week 16.

Because allocation was nonrandomized, differences between groups cannot be interpreted as randomized treatment effects. The groups also represent different phases, doses, or tumor types, so they are not like-for-like controls. Further protocol details, including the specific dose-escalation decisions and stage rules, 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 86 participants were screened, out of which 64 were enrolled and 9 participants completed the study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: SAS included all participants who received at least one dose of study drug (Lenvatinib or Everolimus).

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: Safety Analysis Set (SAS) included all participants who received at least 1 dose of study drug (lenvatinib or everolimus).

6. Primary Endpoint

The registry lists the primary outcome as Phase 1: Number of Participants With Any Treatment-emergent Adverse Event (TEAE), measured over From date of first dose up to 28 days after the last dose of study treatment (Up to 17.5 months).

The listed primary endpoint is the number of Phase 1 participants with any treatment-emergent adverse event (TEAE). A TEAE was defined as an adverse event that appeared during treatment, reappeared during treatment after having been present before treatment and then stopped, or worsened in severity during treatment when continuous. An adverse event was defined as an untoward medical occurrence in a participant administered an investigational product.

The endpoint is a participant count, not a count of all event episodes. Its stated observation window ran from the first dose through 28 days after the last dose of study treatment, up to 17.5 months. The analysis population was the safety analysis set (SAS), defined as all participants who received at least one dose of lenvatinib or everolimus.

Counting participants with a TEAE is a descriptive safety measure: it records whether participants experienced at least one event during the specified window. It does not, by itself, convey an event's severity, duration, attribution to a particular study drug, or recurrence. The primary endpoint title does not establish that all safety counts elsewhere in the registry are combined into a single TEAE result. An overall Phase 1 count for this endpoint is not reported in the registry record in the registry record for this analysis.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the design say about comparisons?

General: Randomization helps make treatment groups comparable on average, so a difference in outcomes can be interpreted more credibly as an effect of treatment. This study is identified as nonrandomized and unmasked, with a parallel model. Its groups should therefore be read as separate dose or disease cohorts rather than as randomized treatment and control arms. Differences in recorded outcomes may reflect differences in participants, tumor types, treatment phase, dose, or other factors; the registry record does not provide an adjusted comparison that separates these influences.

The planned Phase 1 rolling 6 design concerns dose escalation and safety monitoring, while the planned Phase 2 Simon's optimal 2-stage design concerns evaluating activity in selected cohorts. These design descriptions identify the general approach, but the full decision rules, stopping boundaries, and implementation details are not reported in the registry record. The design names alone do not reveal which decisions were made during conduct of the trial.

What does a participant count represent?

The primary endpoint is a count of participants with at least one TEAE, not a measure of how many separate event episodes occurred. A participant-level count can be useful for describing how widely an event affected a group. It does not show whether one participant had multiple events, how long events lasted, or how severe each event was. The endpoint's definition includes events that newly appeared, reappeared, or worsened during treatment, within the stated observation period.

General: Counts are easiest to interpret alongside the number of participants assessed and a clear definition of the event. A count alone is not a rate adjusted for time at risk. Participants with different exposure durations may have different opportunities to experience an event. The registry record gives group-specific at-risk counts for the serious and other adverse-event summaries, but does not provide person-time analyses in the registry record for this analysis.

How should uncertainty be understood?

General: A confidence interval describes a range of values compatible with the observed data under a statistical model and gives information about precision. A narrow interval indicates greater precision than a wide interval, while neither guarantees that the model or study design is free from bias. No confidence intervals are reported in the registry record for the safety counts, so the precision of those counts cannot be quantified from the posted results.

General: A p-value addresses how incompatible observed data are with a specified null hypothesis under a statistical model. It does not measure the probability that a treatment works, nor does it establish causation. No p-values or inferential analyses are reported in the registry record for this analysis. With no randomized comparator and no reported adjusted analysis, the group counts are descriptive rather than tests of treatment differences.

What do the planning illustrations mean?

The sample-size assumptions describe planning illustrations computed from an observed effect, not the trial's own design. They specify a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is a stated fraction of the observed effect. For time-to-event outcomes, the planning convention is a total number of events; for other outcomes, it is participants per arm.

General: Such illustrations answer a hypothetical planning question: how many participants might be needed under the stated assumptions to detect a selected effect with a chosen power. They do not describe the number actually enrolled, the study's original design justification, or the chance that this completed study detected an effect. Sample-size calculations based on an observed effect are particularly dependent on that estimate and should not be read as observed power. Numerical planning outputs are not reported in the registry record for this analysis, and the registry record does not report the trial's own sample-size justification.

What can be inferred from the listed safety categories?

The registry separates serious adverse-event counts from counts labelled other adverse events. The registry entries do not give a complete category definition for “other,” so it should not automatically be treated as a precise synonym for non-serious events without consulting the full registry record. Nor should serious and other counts be added to create an overall TEAE count: the registry entries do not establish whether the categories are mutually exclusive at the participant level. The top serious-event terms are listed with percentages, but their denominator and calculation details are not reported in the registry record for this analysis.

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 1: Lenvatinib 8 mg/m^2 + Everolimus 3 mg/m^2", "Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^")
n      <- c(5, 18)
events <- c(5, 18)
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 1: Lenvatinib 8 mg/m^2 + Everolimus 3 mg/m^2  5  5  100.0  47.8  100.0  56.6  100.0  54.1  99.6
ARM  Phase 1: Lenvatinib 11 mg/m^2 + Everolimus 3 mg/m^  18  18  100.0  81.5  100.0  82.4  100.0  82.4  99.9

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 19 outcome measures, including ORR, disease control rate, clinical benefit rate, and duration of response in Phase 1 and Phase 2. The study description identifies ORR at Week 16 as the intended Phase 2 measure of antitumor activity. The registry entries available for this analysis report zero analyses, however, and do not provide estimates for these efficacy outcomes. A prespecified statistical analysis plan, the outcome hierarchy, and any approach to controlling multiplicity are not reported in the registry record.

Multiplicity matters when several outcomes, cohorts, or analyses are considered: the more opportunities there are to identify a result, the greater the chance of at least one apparently notable finding under repeated testing. General: Prespecifying a primary outcome and a multiplicity strategy can help readers distinguish confirmatory tests from exploratory results. Without the statistical plan and posted analyses, it is not possible to determine how endpoint testing was intended to be interpreted.

The primary safety endpoint population is described as the safety analysis set, including participants who received at least one dose of lenvatinib or everolimus. The registry entries do not report the analysis populations used for the listed secondary outcomes, how participants with missing assessments were handled, or whether imputation or sensitivity analyses were used. Missing-data methods, withdrawal handling, and rules for evaluating ORR or response duration are not reported in the registry record. These omissions limit assessment of how complete and comparable the outcome data were.

12. Safety Results

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

Deaths

Other (non-serious) adverse events

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

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pyrexia (30.0%), pain (20.0%), headache (20.0%), pleural effusion (20.0%), seizure (18.2%).

The safety summaries give, for each group, the number of participants at risk and the number affected by serious adverse events and other adverse events. For example, the Phase 1 group receiving lenvatinib 8 mg/m^2 plus everolimus 3 mg/m^2 had 5 participants at risk, with 2 affected by a serious adverse event and 5 affected by an other adverse event. The same format applies to the remaining dose and tumor-cohort groups.

These counts are descriptive and do not establish that an event was caused by either study drug. The record also lists the most frequent serious-event terms as Pyrexia (30.0%), Pain (20.0%), Headache (20.0%), Pleural effusion (20.0%), Seizure (18.2%), and Hypoxia (16.7%). The denominator and method used to calculate those percentages are not reported in the registry record for this analysis, so they should be read as registry-listed percentages rather than independently interpreted rates.

Deaths are listed by group, but causes, timing, and treatment attribution are not reported. Serious events, other events, and deaths are distinct safety summaries; the registry entries do not establish that their counts can be combined.

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

The posted information describes a completed, nonrandomized Phase 1/2 study of lenvatinib plus everolimus in pediatric participants with recurrent or refractory solid tumors. It documents the intended Phase 1 aims of dose selection and toxicity description, and the Phase 2 plan to estimate ORR at Week 16 in selected tumor cohorts. It also records group-level counts for serious and other adverse events and lists serious-event terms and deaths.

Those safety counts can show how many participants in each group were recorded as affected under the registry's categories. They cannot, on their own, establish whether the combination caused an event, how risk compares with another treatment, or whether groups differed because of treatment. The nonrandomized design and the distinct doses and tumor cohorts mean that direct comparisons require caution. No randomized control group is listed.

The information does not establish the magnitude or precision of antitumor activity. Although ORR was the planned Phase 2 activity measure and ORR is listed among the outcomes, efficacy estimates and analyses are not reported in the registry record for this analysis. Confidence intervals and p-values are also absent. The safety summaries do not substitute for those missing efficacy results.

The record lists deaths, but does not report cause, timing, or attribution in the registry record. Those numbers should not be interpreted as treatment-caused deaths. Likewise, the listed serious-event percentages lack reported denominator and calculation details in the registry record for this analysis. Overall, the posted data support a descriptive account of selected safety summaries and the study's design, not a definitive causal or comparative conclusion.

14. Why This Trial Matters Statistically

This trial illustrates how a multi-phase design can address different statistical questions within one study. Phase 1 was intended to identify a tolerable dose for further study and describe toxicities. Phase 2 was intended to estimate response in selected tumor cohorts using ORR at Week 16. Those aims require different interpretations: dose-finding and safety description are not the same as estimating comparative treatment benefit.

The study also highlights why design features matter when reading results. It is nonrandomized and includes separate dose groups and tumor cohorts. Counts can be informative about what was recorded in each group, but they do not form a like-for-like randomized comparison. Differences between groups may have multiple explanations, and the registry entries do not include an adjusted analysis that addresses them.

For clinical researchers and biostatisticians, the gap between a stated outcome and a reported analysis is important. The record identifies a primary Phase 1 safety endpoint and describes planned Phase 2 efficacy assessment, but the registry entries do not include efficacy estimates, confidence intervals, p-values, or details of missing-data and multiplicity methods. Readers can therefore assess the stated design and selected safety counts, while recognizing that the efficacy question remains unanswered by the information.

Finally, safety summaries require careful attention to denominators, definitions, and attribution. Participant counts are not event counts, and serious-event labels do not establish treatment causality. Clear reporting of analysis populations, observation time, uncertainty, and event classification is essential for turning descriptive safety data into an interpretable evidence base.

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 limitation for interpretation is the nonrandomized design. There is no randomized control group, and the reported groups differ by phase, dose, or tumor cohort. Their event counts cannot be treated as direct estimates of comparative treatment effects. The registry record also identifies no masking.

The primary endpoint is described as the Phase 1 number of participants with any TEAE, but an overall result for that endpoint is not reported in the registry record for this analysis. The posted safety information instead gives group-level counts for serious and other adverse events. The relationship between those categories and the overall primary endpoint is not fully described, and they should not be combined or assumed to be mutually exclusive.

The registry entries do not include efficacy estimates for the planned Phase 2 ORR endpoint, despite listing efficacy outcomes. No confidence intervals, p-values, or adjusted analyses are reported. The available information therefore does not establish efficacy or quantify the precision of the safety estimates. The denominator and calculation method for the listed serious-event percentages are also not reported in the registry record for this analysis.

Further limitations include the lack of reported detail on missing assessments, analysis populations for secondary outcomes, multiplicity handling, and the trial's sample-size justification. For deaths, cause, timing, and attribution are not reported in the registry record for this analysis. These limits restrict causal interpretation and make it difficult to assess the robustness or completeness of the posted results.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study of Lenvatinib in Combination With Everolimus in Recurrent and Refractory Pediatric Solid Tumors, Including Central Nervous System Tumors — NCT03245151.
• Registry record last updated 2023-08-30; status last verified 2022-11.
• Results first posted 2023-08-30.
• 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 Phase 1/2, nonrandomized, unmasked, parallel study sponsored by Eisai Inc. It lists enrollment of 64 and evaluates lenvatinib in combination with everolimus in pediatric participants with recurrent or refractory solid tumors, including CNS tumors. Phase 1 was intended for dose determination and toxicity description; Phase 2 was intended to estimate ORR at Week 16 in Ewing sarcoma, rhabdomyosarcoma, and HGG cohorts.

The listed primary endpoint is the number of Phase 1 participants with any TEAE, assessed from first dose through 28 days after the last dose, up to 17.5 months. The record includes group-level safety counts and serious-event terms. Efficacy analyses, uncertainty estimates, missing-data methods, and multiplicity procedures are not reported in the registry record for this analysis, so the posted information supports descriptive safety interpretation rather than a comparative or causal conclusion.