Study of MEK162 for Children With Low-Grade Gliomas: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of MEK162 for Children With Low-Grade Gliomas (NCT02285439), a non-randomized phase 1, phase 2 study. The primary outcome is Best Overall Response Rate (Strata 1 and 2).

2. Clinical Question

3. Trial Design

NCT02285439 was a Phase I–II, nonrandomized, unmasked, parallel-group study sponsored by Children's Hospital Los Angeles. The registry lists enrollment of 105 and a completed status. The recorded start date is 2016-05-04, and the primary completion date is 2022-11-02. These overall record details do not establish how many participants contributed to any particular endpoint analysis.

The Phase I component enrolled patients with recurrent, progressive, or refractory non-hematologic malignancies after standard up-front therapy. Its stated purpose was to define the maximum tolerated dose, dose-limiting toxicities, and toxicity profile of MEK162. The registry describes five Phase I dose levels in its adverse-event reporting.

Phase II treated children with recurrent tumors signaling through the Ras/Raf pathway in strata. Stratum 1 was for low-grade gliomas with a BRAF truncated fusion, including KIAA1549 and similar translocations. Stratum 2 was for children with NF1 and low-grade glioma. The description for Stratum 3 is incomplete in the registry record, so its eligibility details are not reported in the registry record. A separate surgical target-validation arm enrolled eligible Phase II participants when tumor biopsy or resection was clinically indicated. The stated purpose was to assess drug concentration and target inhibition in tumor samples.

Participants received MEK162 by mouth twice daily for up to 2 years according to the study summary. The study's nonrandomized structure means that dose levels and disease strata are not randomized treatment groups. Differences between them could reflect differences in eligibility or disease characteristics, so they do not by themselves estimate a causal treatment effect.

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.

Only the first 6 of 9 groups are shown.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Phase II Stratum 2 population n=22; Analysis population n=21. One patient enrolled to this stratum did not initiate treatment and was excluded from analysis.

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.

Only the first 6 of 10 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Best Overall Response Rate (Strata 1 and 2), measured over 48 weeks.

The primary endpoint was the best overall response rate for Phase II Strata 1 and 2. It was expressed as the percentage of participants who achieved at least a minor response during the first 12 cycles, nominally 48 weeks. A minor response was defined as a reduction of at least 25% in maximal two-dimensional measurements compared with baseline.

This is a binary response outcome: each participant either meets the stated response threshold within the assessment period or does not. A response rate can provide a concise description of the fraction meeting a prespecified imaging-based criterion. It does not, by itself, describe how long a response lasted, whether symptoms changed, or what happened after the specified assessment period.

The population note states that Phase II Stratum 2 had n=22 and that the analysis population had n=21. One participant enrolled to that stratum did not initiate treatment and was excluded from analysis. The registry record does not report the observed response count, percentage, or an uncertainty interval for the primary endpoint. It also does not provide the primary result for Stratum 1 in the record summarized for this endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What kind of outcome is the primary endpoint?

The primary endpoint is a binary outcome summarized as a response rate. For each participant in the relevant analysis population, the response definition classifies the outcome as meeting or not meeting the stated threshold during the specified assessment period. The registry defines the threshold as at least a 25% decrease in maximal two-dimensional measurements compared with baseline. The resulting percentage would describe the proportion classified as responders, but the registry record does not report that result.

In general, binary outcomes are often reported as counts and proportions, with a confidence interval to communicate uncertainty. The count indicates how many participants met the definition; the proportion relates that count to the analysis population. A confidence interval conveys how imprecise an estimate may be, given the observed data and method. No primary response count, rate, or confidence interval is reported in the registry record.

What does the assessment window define?

The response endpoint concerns the first 12 cycles, nominally 48 weeks. The window is part of the outcome definition: a response outside it would not be the same endpoint as a response documented within it. The registry record does not report additional response-assessment timing details, such as the schedule of scans, the handling of assessments after treatment discontinuation, or the criteria for resolving ambiguous measurements.

How does the study structure affect comparisons?

The study is nonrandomized and unmasked, with parallel groups. In general, randomization helps balance measured and unmeasured characteristics between assigned treatment groups. Without random allocation, groups can differ in their clinical features, eligibility, or treatment context before outcomes are observed. As a result, differences between the Phase I dose levels or Phase II strata cannot automatically be interpreted as treatment effects or dose effects. The registry record explicitly cautions that its arms are not a like-for-like control comparison.

Unmasked treatment can also affect how participants, clinicians, or assessors behave or interpret observations. That is a general methodological concern, not evidence that any particular assessment in this trial was biased. The registry record lists no masking and does not describe blinded response review.

What does the sample-size illustration represent?

The stated sample-size assumptions describe a planning illustration based on the observed effect, rather than the trial's own design justification. The illustration assumes a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; its target effect is a stated fraction of the observed effect. Such calculations are planning illustrations, not observed power. They do not establish that the trial was designed with those assumptions, and the registry record does not report the trial's own sample-size justification.

In general, a planning calculation estimates the sample size needed to detect an assumed effect under specified conditions. It depends on the assumed effect and method, and it is not a measure of the probability that a completed study's result is true. No sample-size illustration values or observed primary effect are reported in the registry record, so no numerical interpretation of a planning scenario is possible from this record.

What analysis details are unavailable?

The registry record does not report the statistical test or model used for the primary response outcome, the confidence-interval method, or a prespecified approach to missing response assessments. It also does not report interim analyses or the detailed statistical analysis plan. Those details matter because different analysis choices can affect how an estimate is calculated and interpreted. The record lists no analysis entries for the posted outcome information; that does not establish what analyses may have been conducted outside the registry record.

The endpoint is limited to a response classification during the stated window. General statistical interpretation should keep that scope separate from other outcomes, such as response duration, progression, survival, or quality of life. Those outcomes cannot be inferred from the binary response definition, and their relevant results are not 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("Phase II Stratum 1", "Phase II Stratum 2")
n      <- c(27, 21)
events <- c(15, 12)
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 II Stratum 1  27  15  55.6  35.3  74.5  37.3  72.4  37.2  72.5
ARM  Phase II Stratum 2  21  12  57.1  34.0  78.2  36.5  75.5  36.4  75.6

11. Multiplicity, Missing Data and Analysis Populations

The primary endpoint is named as best overall response rate for Strata 1 and 2, but the stated population detail is for Stratum 2: n=22 enrolled and n=21 analyzed. One participant who did not initiate treatment was excluded from that analysis. This is an explicitly described exclusion; the registry record does not explain how missing response assessments among analyzed participants were handled.

The study includes Phase I dose levels, multiple Phase II strata, and a surgical target-validation arm, alongside two listed outcome measures. When studies evaluate multiple groups or outcomes, the chance of at least one apparently unusual result can increase if many statistical tests are conducted. This is a general multiplicity concern. The registry record does not report a multiplicity adjustment, a hierarchy among outcomes beyond identifying the primary endpoint, or a detailed testing plan. Whether any adjustment was used is not reported in the registry record.

The record identifies no analysis entries for the posted outcome information, and it does not provide the primary response result. The statistical plan, handling of missing data, and reasons for any unreported endpoint results are not reported in the registry record. The Stratum 2 exclusion should not be generalized to other strata or outcomes; their analysis populations and missing-data handling are not specified in the information available.

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: vomiting (66.7%), ascites (33.3%), edema face (33.3%), bone infection (33.3%), infections and infestations - other, specify (33.3%).

The registry reports participants with serious adverse events and participants with other adverse events by group. These are counts, not percentages calculated. In Phase I Dose Levels 1 through 5, serious-event counts were 0 of 4, 2 of 3, 2 of 3, 3 of 3, and 4 of 6, respectively; other-event counts were 1 of 4, 2 of 3, 2 of 3, 1 of 3, and 6 of 6. In Phase II Strata 1 through 4, serious-event counts were 12 of 27, 6 of 22, 12 of 30, and 5 of 7; other-event counts were 19 of 27, 13 of 22, 20 of 30, and 7 of 7. The registry reports 0 deaths in each listed group.

The listed serious-event terms include Vomiting (66.7%), Ascites (33.3%), Edema face (33.3%), Bone infection (33.3%), Infections and infestations - Other, specify (33.3%), and Infective myositis (33.3%). The record does not provide enough detail to interpret these term percentages as comparative risks between groups. The groups are nonrandomized, and their sizes and clinical composition differ. These counts describe reported events; they do not establish that MEK162 caused them or permit a like-for-like safety comparison.

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

The registry record establishes that this was a completed Phase I–II study of MEK162 in children with low-grade gliomas and other tumors involving Ras/Raf/ERK pathway signaling. It describes an oral treatment schedule, dose-finding aims, Phase II disease strata, a surgical target-validation arm, a primary response definition, and adverse-event counts. These details clarify what the study set out to examine and how the primary response outcome was defined.

The record does not report the primary response count or rate. Therefore, it does not establish from the information available whether, or how often, participants met the stated imaging threshold. It also does not provide a confidence interval for that endpoint. The response result's magnitude and precision are not reported in the registry record.

Even if a response rate were reported, a single-arm or nonrandomized response result would describe outcomes among participants meeting the study's eligibility and analysis criteria. Without a randomized control comparison, it would not by itself show what would have happened under another treatment or without treatment. This is particularly important when comparing the study's dose levels or disease strata, which were not allocated by randomization.

The adverse-event counts describe participants reported with serious or other events in the listed groups. They do not, on their own, establish causation or comparative safety. The registry record also does not provide the full statistical analysis plan or details of how missing outcomes were handled. Accordingly, the record supports a description of study design and reported safety counts, but not a complete estimate of treatment effect, response durability, or comparative benefit and harm.

14. Why This Trial Matters Statistically

This trial is statistically notable for combining dose finding with disease-specific Phase II strata in a nonrandomized study. Those components address different questions. Dose finding focuses on dose-limiting toxicity, maximum tolerated dose, and toxicity profile, while the Phase II endpoint focuses on an imaging-based response definition. Keeping the aims separate helps prevent safety observations from being mistaken for response evidence or group differences from being treated as randomized comparisons.

The response endpoint is operationally defined by a measurement threshold and assessment period. Clear definitions support consistent classification, but an estimate still needs the observed response count, analysis population, and an uncertainty measure for interpretation. The registry record does not report the primary response result, so the endpoint's numerical evidence cannot be assessed from this record.

The registry also illustrates why population details matter. For Stratum 2, the record distinguishes participants enrolled from those included in the analysis and explains that one participant did not start treatment. Reporting such distinctions helps readers understand which population an estimate would describe. Further details about missing assessments and analysis choices are not reported in the registry record.

Finally, the trial's nonrandomized design shapes what its results could establish. Descriptive findings can characterize events and outcomes within groups, but differences across dose levels or strata can reflect different participant characteristics as well as treatment. The registry record's explicit warning against treating arms as like-for-like controls is important when reading any group-level figures.

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 does not report the primary response count, percentage, or confidence interval, limiting interpretation of the endpoint that is identified as primary. It also does not report the detailed statistical analysis plan, the statistical method used for the response analysis, or the approach to missing response assessments. These omissions prevent assessment of the precision and robustness of the primary estimate from the registry record.

The study is nonrandomized and unmasked. Its dose levels and disease strata are not comparable by design as randomized groups, so direct contrasts between them would be vulnerable to differences in eligibility and participant characteristics. The registry itself cautions that the arms are not a like-for-like control comparison. No randomized control group is identified in the record.

The primary population description is specific to Stratum 2. It reports n=22 enrolled and n=21 analyzed, with one participant excluded for not initiating treatment. The registry record does not state how incomplete outcome assessments were handled or provide equivalent analysis-population details for all other strata in the material.

The description for Phase II Stratum 3 is incomplete in the registry record, which limits interpretation of that stratum's eligibility. The adverse-event counts are descriptive; the record does not establish causation or provide a randomized safety comparison. The sample-size assumptions describe a planning illustration, not the trial's own design justification. The latter is not reported in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study of MEK162 for Children With Low-Grade Gliomas — NCT02285439.
• Registry record last updated 2025-10-07; status last verified 2025-09.
• Results first posted 2025-10-07.
• 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

NCT02285439 was a completed, nonrandomized, unmasked Phase I–II study sponsored by Children's Hospital Los Angeles. It studied MEK162 in children with low-grade gliomas and other tumors involving Ras/Raf/ERK pathway signaling. The record lists enrollment of 105, a start date of 2016-05-04, and a primary completion date of 2022-11-02.

The study's primary endpoint was the best overall response rate for Phase II Strata 1 and 2, based on achieving at least a minor response during the first 12 cycles, nominally 48 weeks. For Stratum 2, the record reports n=22 enrolled and n=21 analyzed, with one participant excluded for not initiating treatment. The primary response result and its precision are not reported in the registry record. Adverse-event counts are reported by Phase I dose level and Phase II stratum, but the nonrandomized design does not support treating those groups as like-for-like comparisons.