Dabrafenib/Trametinib, BRAF or BRAF AND MEK Pre-op With BRAF and MEK Post-op, Phase IIB, Melanoma With Brain Mets,Biomarkers and Metabolites: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Dabrafenib/Trametinib, BRAF or BRAF AND MEK Pre-op With BRAF and MEK Post-op, Phase IIB, Melanoma With Brain Mets,Biomarkers and Metabolites (NCT01978236), a randomized phase 2 study. The primary outcome is Concentrations of Dabrafenib, Its Metabolites Hydroxy-, Carboxy- and Desmethyl-dabrafenib in Peripheral Blood (Plasma).

2. Clinical Question

The scientific focus was the distribution of dabrafenib, its metabolites, and, in the combination cohort, trametinib across brain metastases, extracranial metastases, and plasma. The primary endpoint recorded in the registry concerns concentrations of dabrafenib and its metabolites in peripheral blood. The study also listed secondary outcomes involving cerebrospinal fluid concentrations, MAPK pathway markers, radiographic tumor changes, intracranial lesion measurements, extracranial response, survival, and vital signs.

The study was intended to connect drug exposure in sampled tissues and blood with biological and radiographic measurements. Those aims do not make the primary endpoint a clinical outcome: a measured blood concentration describes exposure in the sampled participants and does not by itself establish a change in tumor size, symptoms, or survival. Results for the primary endpoint and the listed secondary outcomes are not reported in the registry record.

3. Trial Design

This was a phase 2, open-label, multicentre study sponsored by GlaxoSmithKline. Its stated population was people with resectable BRAF V600E or V600K mutation-positive melanoma metastatic to the brain. The record describes treatment before surgery and planned follow-up for survival and new anti-cancer therapy for up to two years, or until death or withdrawal from follow-up.

The study description outlines two cohorts. Cohort A was to receive oral dabrafenib 150 mg twice daily for 7 to 14 days before surgery. Cohort B was to receive dabrafenib at the same dose and schedule together with trametinib 2 mg once daily for 7 to 14 days before surgery. The brief summary describes up to 30 evaluable participants, with 15 planned in each cohort. The recorded enrollment is 6, and the status is terminated. The registry record does not report why the study was terminated or how participants were distributed between cohorts.

There is an important design-field inconsistency: allocation is listed as randomized, while the model is listed as single group. The study description presents cohorts with different treatment regimens, but the record does not explain how the allocation field relates to those cohorts or establish that a randomized between-cohort comparison was carried out. Masking is listed as none, consistent with the open-label description. The primary endpoint is a pharmacokinetic concentration measure, and the record does not report a primary comparative analysis. The detailed protocol, a sample-size justification, and the planned statistical analysis 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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Pharmacokinetic analysis set included all participants who provided at least one evaluable Pharmacokinetic concentration.

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 Concentrations of Dabrafenib, Its Metabolites Hydroxy-, Carboxy- and Desmethyl-dabrafenib in Peripheral Blood (Plasma), measured over Pre-surgery and post-surgery on Day 15.

The primary endpoint is the concentration of dabrafenib and its metabolites—hydroxy-, carboxy-, and desmethyl-dabrafenib—in peripheral blood plasma. Concentration is expressed in nanograms per milliliter. The listed timeframe is pre-surgery and post-surgery on Day 15. The endpoint description says that blood was collected on the day of surgical resection, with two samples before surgery and two after surgery, separated by one hour. The stated pharmacokinetic analysis set includes participants who contributed at least one evaluable pharmacokinetic concentration.

Concentration measurements are used to describe drug exposure in the sampled blood. They can help characterize the presence and level of a drug and its metabolites at particular sampling times. In this study, the broader scientific question also concerned drug levels and distribution in brain and extracranial metastases, plasma, and—in the combination cohort—trametinib. The primary endpoint identified in the registry, however, is the plasma concentration measure; it should not be confused with a measure of tumor response or clinical benefit.

Interpretation of concentration data depends on the actual measurements, their timing, and how participant-level observations are summarized. Those results, including estimates of concentration and their variability, are not reported in the registry record. The endpoint definition therefore indicates what was to be measured, but cannot establish what concentrations were observed.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a pharmacokinetic endpoint describe?

Pharmacokinetics concerns the presence and movement of a drug and its metabolites in the body. A plasma concentration is a measurement in blood at a specified sampling time. It is not a direct measure of concentration in a brain metastasis, even when the study also collects tissue samples. The registry’s broader objective concerns distribution across plasma and metastatic sites, while its named primary endpoint is plasma concentration of dabrafenib and its metabolites. The distinction matters because measurements from different compartments answer related, but not identical, questions.

The endpoint description specifies pre-surgery and post-surgery sampling on Day 15 and describes repeated blood draws on the day of resection. Repeated sampling can characterize concentrations at more than one point in the peri-operative period. To interpret such observations, an analysis would need to make clear how samples and participants are summarized, including how missing or unevaluable samples are handled. Those details and the actual concentration summaries are not reported in the registry record.

How should concentration data be summarized?

As a general statistical matter, a concentration endpoint may be summarized using a measure of central tendency and a measure of spread. The appropriate summary depends on the distribution of the measurements and the scientific question. Concentrations can be unevenly distributed, so the mean and standard deviation may not always describe typical values well; a median and range or other distribution-aware summaries may be informative. This is general guidance, not a description of the analysis used in this study. The registry record does not report which summaries were planned or calculated.

Repeated samples from the same participant are related observations. A statistical analysis that treats them as independent would not reflect that within-participant relationship. General approaches can account for repeated measurements or summarize them at prespecified time points, but the registry record does not identify the approach used. It also does not report whether concentration results were analyzed separately by cohort, combined, or compared across sampling times.

What can confidence intervals and tests add?

In general, a confidence interval expresses the uncertainty around an estimate under the assumptions of the analysis. A narrower interval indicates greater precision, while a wider interval indicates less precision; it does not by itself establish clinical importance. A hypothesis test, when planned and interpreted appropriately, addresses compatibility between the data and a specified statistical model. Neither a confidence interval nor a p-value can substitute for the result itself, and neither can correct limitations in design, measurement, or missing data.

No confidence intervals, p-values, or other inferential results for the primary concentration endpoint are reported in the registry record. The record identifies zero analyses. It is therefore not possible to describe the precision of an observed concentration estimate, whether any comparison was tested, or what model assumptions were used. The registry also does not report interim analyses or a detailed statistical analysis plan.

How does the trial structure affect interpretation?

The study narrative describes Cohort A receiving dabrafenib and Cohort B receiving dabrafenib plus trametinib. The registry fields separately list randomized allocation and a single-group model. These entries are not reconciled in the record. A randomized comparison requires clear information about assignment, the groups analyzed, and the planned contrast. Without that information and without posted analysis results, the cohort descriptions should not be treated as evidence of a valid randomized treatment comparison.

The planned enrollment was up to 30 evaluable participants, with 15 described for each cohort; recorded enrollment is 6. A small enrollment can limit the amount of information available and make estimates less precise, but the actual precision cannot be determined from enrollment alone. It depends on the number with evaluable observations and on the variability of the endpoint, neither of which is reported for the primary measure. Enrollment is not a measure of power after the fact and does not supply missing endpoint estimates.

The sample-size assumptions describe planning illustrations based on an observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. Such illustrations are hypothetical planning calculations and are not the trial’s own design justification or observed power. The record does not report a trial-specific sample-size justification, and no primary outcome effect is reported from which to interpret an illustration.

Why do distribution and model assumptions matter?

General statistical methods rely on assumptions about the data and how observations relate to each other. For concentration data, skewness, values below assay limits, and differences between participants can affect which summaries or models are suitable. In other outcome types, such as counts, over-dispersion means that variability exceeds what a simpler count model assumes; ignoring it can make uncertainty appear too small. These are general considerations, not claims that any particular feature occurred in this study. The registry record does not report assay limits, distribution checks, or model diagnostics.

When a study examines multiple outcomes, time points, or treatment contrasts, multiplicity can increase the chance of at least one apparently notable result by chance. A prespecified primary endpoint helps identify the central question, while secondary outcomes are usually interpreted with attention to whether they are exploratory and whether any adjustment was planned. The record lists 16 outcome measures, but does not describe a multiplicity strategy. No analysis results are posted, so there is no reported set of tests to evaluate for multiplicity.

For time-to-event outcomes such as survival, interpretation depends on follow-up, censoring, the definition of events, and the analysis method. The registry describes follow-up for survival and new anti-cancer therapy, but it does not provide event-time results or the statistical methods used for those outcomes. General statistical principles can explain what such analyses would require; they cannot fill in the unreported analysis plan or results for this trial.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 16 outcome measures, including the primary plasma concentration endpoint and secondary measures relating to cerebrospinal fluid, MAPK pathway markers, radiographic change, lesion measurements, extracranial response, survival, and vital signs. Considering many outcomes can complicate interpretation because a collection of separate tests may yield an apparently unusual result by chance. A prespecified hierarchy or multiplicity adjustment can help manage that issue. Whether either was planned or used is not reported in the registry record.

The record identifies zero analyses and contains no posted results for the listed outcomes. It does not report p-values, confidence intervals, or a testing strategy. Consequently, the multiplicity issue can be described as a limitation of the information available, but no claim can be made about how multiplicity affected a particular result.

Missing-data handling is also not reported. The primary endpoint description defines the pharmacokinetic analysis set as participants who provided at least one evaluable pharmacokinetic concentration. That definition does not state how many participants met it, how many samples were missing or unevaluable, or how incomplete sampling was handled in summaries. The registry record does not report reasons for missing measurements or any sensitivity analysis.

The record does not provide participant flow through the planned procedures or explain the relationship between planned evaluable enrollment and recorded enrollment. It also does not report analysis populations for the secondary outcomes. These gaps matter because the number enrolled is not necessarily the number contributing data to a given endpoint. Without endpoint-specific denominators and analysis details, readers cannot assess whether the observed participants represent the intended study population or how missing observations may have influenced estimates.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: nausea (33.3%), dysphagia (16.7%), vomiting (16.7%), chills (16.7%), pyrexia (16.7%).

The safety figures reported for Cohort A identify 6 participants at risk for serious adverse events, 4 with serious adverse events, 6 at risk for other adverse events, 6 with other adverse events, and 4 deaths. These are separate registry counts. The record does not explain the timing or cause of the deaths, or whether they were considered related to study treatment. An adverse event occurring during a study does not by itself establish that the treatment caused it.

The listed serious adverse-event terms include nausea at 33.3%; dysphagia, vomiting, chills, pyrexia, and granulomatous liver disease are each listed at 16.7%. These are the reported percentages associated with the terms. The record does not provide event-level details, severity grades, timing, or information about whether a participant could contribute more than one term. The terms should therefore be read as a registry summary, not as a complete clinical account.

The safety group reported is Cohort A; the record does not provide parallel safety counts for Cohort B. The small recorded enrollment and absence of fuller event details limit how broadly these counts can be interpreted. They describe the events recorded for this group and do not establish comparative safety between regimens.

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

The registry record documents a study designed to measure dabrafenib and metabolite concentrations around surgery in people with BRAF mutation-positive melanoma metastatic to the brain. It describes pre-operative treatment with dabrafenib alone or combined with trametinib, surgical sampling, and additional biological and clinical outcomes. These elements explain the study’s scientific rationale and the kinds of observations it aimed to collect.

What the record does not provide is the primary concentration result. It does not give the observed plasma levels, a summary of their variability, or an estimate of how precisely they were measured. It also does not report results for the secondary biological, radiographic, response, or survival outcomes. Thus, the endpoint definition cannot be read as evidence that a particular concentration was achieved or that a tumor or clinical outcome changed.

The trial description lists two treatment cohorts, but the registry fields conflict on whether the study was randomized or single-group. The record does not establish a primary comparison between the cohorts. Even if cohort-specific results were available, a comparison would require adequate details about assignment, analysis populations, and statistical methods. Those details and results are not reported.

Recorded enrollment was 6, compared with a plan described as up to 30 evaluable participants. This helps explain why the record should not be treated as a definitive comparative evaluation, but enrollment alone does not quantify bias or precision. The status is terminated, and the reason is not reported in the registry record.

The appropriate conclusion is limited: the registry describes a pharmacokinetic and correlative study and records its enrollment and selected safety data, but does not post the primary endpoint or other outcome analyses. It does not establish whether either regimen changed drug concentrations in tissue or blood, improved clinical outcomes, or differed from the other regimen.

13. Why This Trial Matters Statistically

This study raises a statistically distinctive question because the central measurement is drug concentration in relation to surgery and tissue sampling, rather than a conventional single clinical outcome. Interpreting such a design requires keeping compartments and time points distinct: plasma, cerebrospinal fluid, and metastatic tissue are not interchangeable sources of measurement. The primary endpoint is plasma concentration, while the broader stated aim includes distribution in brain and extracranial metastases.

The record also illustrates why design metadata should be checked against the study narrative. It lists randomized allocation but a single-group model, while the narrative describes two cohorts with different regimens. Without clarification, readers cannot confidently identify the intended comparison or treat the cohorts as randomized arms. This is not merely a naming issue: the design determines which estimands and statistical comparisons are justified.

Another important statistical issue is the gap between planned and recorded enrollment. The study description anticipates up to 30 evaluable participants, while the enrollment field records 6. Smaller datasets can yield imprecise estimates, especially when measurements vary, but the degree of uncertainty cannot be assessed without actual endpoint data and analysis denominators. Since the registry reports no analyses, there is no basis for estimating that precision.

Finally, the record demonstrates the difference between an outcome being specified and its result being available. A detailed endpoint definition can clarify what researchers intended to measure, but it cannot answer what they observed. For clinical researchers, this distinction is essential when interpreting registry records: design information, safety counts, and outcome results are different kinds of evidence and should not be conflated.

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.

The principal limitation is the absence of posted outcome analyses. The registry describes the primary pharmacokinetic endpoint and a broad set of secondary outcomes, but does not report their results. Without concentration estimates, variability, or endpoint-specific denominators, readers cannot assess the magnitude or precision of the measurements.

Recorded enrollment is 6, whereas the study description anticipates up to 30 evaluable participants. The record does not explain the difference, provide participant flow, or state how many people contributed evaluable data to each outcome. The status is terminated, but the reason for termination is not reported in the registry record. No reason should be inferred from the status alone.

The allocation and model fields are inconsistent with one another, and the record does not resolve the discrepancy. It also does not state whether a between-cohort contrast was planned or analyzed. The detailed protocol, sample-size justification, statistical analysis plan, interim-analysis information, and methods for handling missing data are not reported in the registry record.

Sampling details are described for plasma, but the record does not provide assay characteristics, concentration summaries, or information on unevaluable samples. Although the stated scientific aims include tissue distribution and other biological outcomes, results for those measures are not posted. The available safety summary is limited to Cohort A and lacks event-level timing, attribution, and parallel counts for Cohort B. Together, these limitations restrict both statistical interpretation and comparison across regimens.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Dabrafenib/Trametinib, BRAF or BRAF AND MEK Pre-op With BRAF and MEK Post-op, Phase IIB, Melanoma With Brain Mets,Biomarkers and Metabolites — NCT01978236.
• Registry record last updated 2018-08-17; status last verified 2018-07.
• Results first posted 2018-08-17.
• 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

NCT01978236 is a terminated phase 2, open-label study sponsored by GlaxoSmithKline. It concerns pre-operative dabrafenib alone or with trametinib in BRAF mutation-positive melanoma metastatic to the brain. The study description planned up to 30 evaluable participants across two cohorts; recorded enrollment is 6.

The primary endpoint measures plasma concentrations of dabrafenib and its metabolites around surgery. The registry lists 16 outcome measures and zero analyses. Primary and secondary outcome results are not reported in the registry record. Safety counts are reported for Cohort A, including serious and other adverse events and deaths, but the record does not provide a complete comparative safety analysis.

Allocation is listed as randomized while the model is listed as single group; the registry does not explain this inconsistency. The reason for termination, detailed statistical plan, missing-data methods, and sample-size justification are not reported.