E6201 Plus Dabrafenib for the Treatment of Metastatic Melanoma Central Nervous System Metastases (CNS): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for E6201 Plus Dabrafenib for the Treatment of Metastatic Melanoma Central Nervous System Metastases (CNS) (NCT03332589), a non-randomized phase 1 study. The primary outcome is Intracranial Disease Overall Response Rate by RANO-BM.

2. Clinical Question

3. Trial Design

This was a Phase 1, non-randomized, unmasked, single-group study of E6201, including a monotherapy safety run-in and planned phases of E6201 plus dabrafenib. The study began on 2018-07-02, had a primary completion date of 2021-04-30, and is listed as terminated. The reason for termination is not reported in the registry record.

The brief summary described a planned enrollment of up to N=28-34 participants with melanoma metastasized to the CNS. Actual enrollment was 4. The primary outcome description states that no participants were enrolled in the combination safety run-in or expansion phases. The safety record lists 4 participants at risk in the E6201 monotherapy group and 0 in each combination group.

The monotherapy run-in described E6201 320 mg/m^2 administered intravenously over 2 hours twice weekly on Days 1, 4, 8, 11, 15 and 18, repeated every 28 days. Dose reductions for toxicity were described as 240 mg/m^2 and 160 mg/m^2 twice weekly. The combination description specified dose levels of E6201 with dabrafenib; the expansion description planned up to N=18 participants at the combined maximum tolerated dose.

These features define an early-phase safety study rather than a randomized efficacy comparison. With no participants in the combination phases and no reported primary analyses, the registry record cannot support a comparison between E6201 alone and the combination. Further details of the protocol, including the reason for termination, 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: The study was terminated before any participants were enrolled in the Combination or Expansion Phases.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The analysis population was the per-protocol set (PPS). The PPS included all participants in the full analysis set (FAS) who had a valid baseline and one or more post-treatment assessments for a specific measure. No participants were enrolled in the Combination Safety Run-In or Expansion Phases of the 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.

Population: No subjects were enrolled in the Combination Safety Run-In or Expansion Phases of the study.

6. Primary Endpoint

The registry lists the primary outcome as Intracranial Disease Overall Response Rate by RANO-BM, measured over At the end of Cycle 2 and every 2 cycles through 6 months following last dose of study drug (each cycle is 28 days) up to 1 year..

The primary endpoint was intracranial disease overall response rate by RANO-BM, recorded as a count of participants. It concerns response in CNS disease, rather than systemic disease outside the CNS. The registry describes response assessment using Response Assessment in Neuro-Oncology - Brain Metastases (RANO-BM); further details of the criteria applied are not reported in the registry record.

In general, an overall response rate describes how many participants meet a specified response definition during a stated assessment period. A count alone does not give the rate unless the relevant analysis denominator is also known. The registry describes the analysis population as the per-protocol set (PPS), defined from participants in the full analysis set (FAS) who had a valid baseline and one or more post-treatment assessments for the specific measure. The counts making up those analysis sets are not reported in the registry record.

Assessments were scheduled at the end of Cycle 2 and every 2 cycles through 6 months following the last dose of study drug, with follow-up up to 1 year. This endpoint is relevant to the study's CNS focus because it captures response in the brain metastases under assessment. However, no primary outcome result or analysis is reported in the registry record, so the endpoint definition cannot be paired with a reported response count or estimate.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a binary outcome recorded as a participant count: intracranial overall response by RANO-BM. A binary endpoint classifies each participant according to whether the specified response criterion was met. In general, a response rate relates the number meeting the criterion to the number assessed in the relevant population. A count without its denominator does not supply a rate, and a rate without an uncertainty measure does not show how precisely it is estimated.

What population was analyzed?

The primary outcome description identifies the per-protocol set (PPS) as the analysis population. It defines the PPS as participants in the full analysis set (FAS) who had a valid baseline and one or more post-treatment assessments for the measure. This definition means that a participant needed both baseline information and follow-up assessment to qualify for the PPS endpoint analysis. The registry does not report the number in the FAS, the number in the PPS, or the endpoint-specific response count. The method used to address participants without a valid assessment is not reported in the registry record.

What can a confidence interval add?

In general, a confidence interval gives a range of values compatible with the observed data under a specified statistical method. It helps communicate uncertainty around an estimate; it does not guarantee that the true value lies within a particular interval. No confidence interval for the primary response endpoint is reported in the registry record. Since the underlying response estimate is also not reported, its precision cannot be evaluated from this record.

What does the design imply for analysis?

The study is listed as non-randomized, unmasked, and single group. Random allocation can support a balanced comparison of treatment groups, while masking can reduce some opportunities for expectations to influence assessment. Those design features are absent. The planned monotherapy and combination phases do not create a valid head-to-head comparison in the posted data: the registry says no participants were enrolled in the combination safety run-in or expansion phases. No adjustment method or comparative analysis is reported.

How should the planning calculations be understood?

The stated planning assumptions describe a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is described as a stated fraction of the observed effect. These are planning assumptions, not a description of the actual trial design, which was single group and non-randomized. Any sample sizes derived under those assumptions are planning illustrations, not observed enrollment and not observed power. The registry record does not report the trial's own sample-size justification, and no trial-specific statistical plan is reported.

Why does over-dispersion matter in general?

Over-dispersion is a general issue when observed variability is greater than a statistical model assumes. If a model understates variability, standard errors can be too small and intervals can appear more precise than warranted. That concept does not supply an analysis for this study: the primary endpoint is recorded as participant counts, and no model or over-dispersion assessment is reported in the registry record.

The registry lists 6 outcome measures and 0 analyses. It does not report a primary endpoint estimate, a statistical test, a model, a confidence interval, or an adjusted analysis. Therefore, the statistical methods that were actually used to analyze the primary endpoint cannot be established from the posted record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 6 outcome measures, including intracranial disease duration of response, systemic disease overall response rate outside the CNS, progression-free survival, and overall survival. It identifies intracranial overall response rate by RANO-BM as the primary outcome. The record lists 0 analyses, so it does not report inferential results for the primary or secondary outcomes.

When several outcomes are tested, multiplicity can increase the chance of obtaining at least one apparently notable result by chance. In general, statistical plans may address this through a prespecified testing order or an adjustment to the significance threshold. No multiplicity method or testing hierarchy is reported in the registry record. There is also no reported interim-analysis plan or statistical analysis plan.

The primary outcome population was the PPS, defined as participants in the FAS who had a valid baseline and at least one post-treatment assessment for the specific measure. The registry does not report the number in either population, the number with missing assessments, or the reasons for missing data. The handling of missing outcome data, including any imputation or sensitivity analysis, is not reported in the registry record.

These omissions matter because the analyzed population and missing-data approach can affect how an endpoint estimate should be interpreted. With no analysis count or endpoint results, it is not possible to assess whether planned analyses were completed or how the secondary outcomes were evaluated.

11. 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: abdominal pain (25.0%), hypoxia (25.0%), sepsis (25.0%), confusional state (25.0%).

The safety record lists 4 participants at risk in the E6201 monotherapy safety run-in and 0 participants at risk in each E6201 plus dabrafenib group. In the monotherapy group, 3 participants were recorded as affected by serious adverse events, 4 by other adverse events, and 1 death was recorded. The registry does not report a causal attribution for the death or adverse events in the registry record for this record.

The serious adverse event terms listed were abdominal pain, hypoxia, sepsis, and confusional state, each reported as 25.0%. These are descriptive percentages for the monotherapy group. Participants can experience more than one event or event term, so the listed terms should not be assumed to represent mutually exclusive categories. The percentages also do not establish that the study drug caused the events.

In general, adverse-event counts describe what was recorded during the specified safety observation, not the probability of harm in other populations or under other treatment conditions. The record does not provide exposure-adjusted rates, event timing, severity details beyond the serious-event classification, or a causal assessment in the registry record. Because the combination groups had no participants at risk, the safety record cannot describe observed safety in those groups.

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

The registry record documents a Phase 1 study of E6201, with planned evaluation of E6201 plus dabrafenib, in CNS metastases from BRAF V600-mutated metastatic melanoma. It records 4 participants enrolled and a primary endpoint based on intracranial response by RANO-BM. These details establish the study's question and limited scale, but they do not provide an answer to the efficacy question: no primary outcome result or analysis is reported.

The absence of a reported response estimate does not mean that no participant responded, nor does it mean that every participant responded. It means the registry record does not report the endpoint result. The reason for termination is also not reported, so termination cannot be interpreted as evidence of benefit, lack of benefit, toxicity, or any particular operational issue.

The registry's safety entries describe events in the E6201 monotherapy group and record no participants in the combination phases. These entries are not comparative evidence. They do not establish that E6201 caused any listed event, and they cannot characterize safety for E6201 plus dabrafenib in this study because no participants were recorded in those groups.

In general, a single-group study can describe observed outcomes among participants treated in that group, but without a concurrent randomized comparator it cannot separate treatment effects from other explanations for those outcomes. Here, even a descriptive efficacy interpretation is unavailable because the primary response result is not reported. No estimate of treatment effect, confidence interval, or hypothesis test can be interpreted from the registry record.

The most supportable conclusion is therefore about the record itself: it documents a small, terminated, early-phase study with no reported primary efficacy analysis and no enrollment in its combination phases. It does not establish whether either regimen changed intracranial disease outcomes.

13. Why This Trial Matters Statistically

This study raises a statistically important distinction between a trial's planned question and the evidence available to answer it. The registry describes intracranial response as the primary endpoint and lists a planned enrollment of up to N=28-34 in the brief summary. Actual enrollment was 4, and the primary outcome description states that no participants entered the combination safety run-in or expansion phases. These differences between planned scope and recorded enrollment shape the limits of interpretation.

The study's focus on CNS metastases is reflected in its primary endpoint: intracranial response assessed using RANO-BM. Separately listed outcomes include systemic response outside the CNS, progression-free survival, overall survival, and intracranial duration of response. Distinguishing intracranial from systemic outcomes matters because they refer to different disease locations and clinical measurements; they should not be treated as interchangeable endpoints.

Statistically, the record also illustrates why design and analysis details matter. A non-randomized, unmasked, single-group study cannot provide a randomized comparison between E6201 alone and E6201 plus dabrafenib. The combination phases have no enrolled participants in the registry record, and no primary analyses are listed. Without an endpoint estimate, denominator, and uncertainty interval, the reader cannot assess the observed response pattern or its precision.

The safety entries are likewise limited to descriptive reporting, principally in the monotherapy group. They offer a record of adverse events and deaths, but not a comparative safety estimate or causal conclusion. The study is therefore statistically informative as an example of how trial status, enrollment, analysis population, and outcome reporting determine what can be learned from a registry entry.

14. 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.

Actual enrollment was 4, while the brief summary described planned enrollment of up to N=28-34. The registry lists no participants in the combination safety run-in or expansion phases, so the intended combination experience is not represented in the recorded study groups. The reason for termination is not reported in the registry record.

The primary endpoint is defined, but no response count, denominator, estimate, or uncertainty interval is reported. The number of participants in the FAS and PPS is also not reported. As a result, the endpoint's analysis population and precision cannot be independently characterized from the registry record.

The design was non-randomized, unmasked, and single group, with no like-for-like control comparison. No statistical analysis plan, multiplicity approach, interim-analysis plan, or missing-data method is reported. The registry lists 0 analyses. These limitations prevent evaluation of the planned inferential approach and leave the status of the secondary outcome analyses unclear.

Safety interpretation is also constrained. The combination groups had no participants at risk, and the record does not report causal attribution for the listed events. Further details on event timing, exposure, and missing safety assessments are not reported in the registry record. These limitations mean that the posted information is descriptive and incomplete for assessing efficacy or comparing safety across regimens.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: E6201 Plus Dabrafenib for the Treatment of Metastatic Melanoma Central Nervous System Metastases (CNS) — NCT03332589.
• Registry record last updated 2022-05-20; status last verified 2021-12.
• Results first posted 2022-05-20.
• 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.

18. Record Summary

NCT03332589 is a Phase 1, non-randomized, unmasked, single-group study of E6201, with planned combination phases using dabrafenib, for CNS metastases from BRAF V600-mutated metastatic melanoma. The study began on 2018-07-02, reached primary completion on 2021-04-30, and is listed as terminated. Actual enrollment was 4; the brief summary described planned enrollment of up to N=28-34.

The primary endpoint was intracranial overall response by RANO-BM, with a PPS analysis population defined by valid baseline and post-treatment assessment. The registry lists 0 analyses and does not report a primary efficacy result. No participants were enrolled in the combination safety run-in or expansion phases. The reason for termination and the trial's statistical analysis plan are not reported in the registry record.