Investigate Safety, Pharmacokinetics and Pharmacodynamics of GSK2118436 & GSK1120212: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Investigate Safety, Pharmacokinetics and Pharmacodynamics of GSK2118436 & GSK1120212 (NCT01072175), a non-randomized phase 2 study. The primary outcome is Part A: Maximum Plasma Concentration (Cmax) of a Single Dose of Dabrafenib Administered Alone and in Combination With Trametnib.

2. Clinical Question

3. Trial Design

The registry classifies the study as Phase 2, while its official title describes a Phase I/II study. It lists an open-label, dose-escalation investigation of GSK2118436 and GSK1120212, with 430 participants recorded as the enrollment. The study is marked completed. Its start date is 2010-03-26 and its primary completion date is 2012-05-31.

The study had four parts. Part A examined the effect of repeat trametinib doses on the pharmacokinetics of a single dabrafenib dose before evaluating combination regimens. The listed schedule included dabrafenib 75mg on Day 1, trametinib 2mg from Day 2 through Day 16, and both drugs on Day 15. Part B used dose escalation to identify a range of tolerated combinations. Part C evaluated different combinations in cohort expansion. Part D evaluated pharmacokinetics and safety for dabrafenib HPMC capsules alone and with trametinib.

The registry classifies overall allocation as non-randomized and masking as none. Some Part C arm labels nevertheless include the word “Randomized.” These descriptions do not establish that every part had the same allocation method, and the record does not resolve the difference between the overall classification and those arm labels. The study should not be treated as one randomized comparison. The posted record includes different doses, study parts, and treatment sequences rather than one uniform intervention and control.

The stated enrollment is a registry figure; the number analyzed for each endpoint is not reported in the registry record. The record also does not report a sample-size justification or a complete protocol-level statistical plan.

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 comprised of Parts A, B, and D, which constitute the Phase I part of the study, and Part C, which constitutes the randomized Phase II part of the study. Participants did not enroll in all parts of the study sequentially. Each part of the study was comprised of a separate population of participants.

Only the first 6 of 13 groups are shown.

Part A (Drug-Drug Interaction)

Reasons for not completing this period:

Part B (Dose Escalation and Expansion)

Reasons for not completing this period:

Part C (Phase II: Randomized Phase)

Reasons for not completing this period:

Part C (Phase II: Crossover Phase [CP])

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic (PK) Population: all participants who received at least one dose of either dabrafenib or trametinib and for whom a PK sample was obtained and analyzed

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 13 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Part A: Maximum Plasma Concentration (Cmax) of a Single Dose of Dabrafenib Administered Alone and in Combination With Trametnib, measured over Day 15.

The primary endpoint is the maximum plasma concentration (Cmax) of a single dose of dabrafenib administered alone and in combination with trametinib, assessed on Day 15. Cmax is the highest measured concentration in plasma over the sampling period. The endpoint description says blood was sampled before dosing and at 1, 2, 3, 4, 6, 8, 10, and 24 hours after dabrafenib administration. Cmax was determined from the concentration-time curve using standard non-compartmental analysis in WinNonlin.

The result is specified as a geometric least squares mean with a 95% confidence interval, in nanograms per milliliter. In general, pharmacokinetic measures such as Cmax describe drug exposure over a sampling period; they are not direct measures of clinical benefit. A geometric mean is useful for concentration measures that are analyzed on a multiplicative scale. The confidence interval conveys uncertainty around the estimated mean, rather than the range of individual participants’ concentrations.

The endpoint is relevant to the study’s stated pharmacokinetic question: whether the measured dabrafenib concentration differs when given with trametinib. However, the numerical Cmax estimates and confidence intervals are not reported in the registry record. The registry therefore defines what was measured, but does not permit assessment of the observed concentration estimates or their precision.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary analysis uses a pharmacokinetic outcome: Cmax, the maximum measured plasma concentration after dabrafenib administration. The endpoint description specifies a concentration-time profile with samples collected before dosing and at 1, 2, 3, 4, 6, 8, 10, and 24 hours. The maximum concentration is identified from that profile. This differs from an endpoint based on tumor response, survival, or symptoms: it describes drug concentration rather than a clinical outcome.

What does a geometric mean describe?

The registry reports Cmax as a geometric least squares mean. In general, a geometric mean is appropriate for data analyzed on a multiplicative scale, where relative changes are more meaningful than absolute changes. A least squares mean is an estimate from a statistical model or adjusted analysis. The registry record does not describe the model or any adjustment factors used for this estimate. It therefore supports identifying the intended summary measure, but not reconstructing the full analysis.

The endpoint includes a 95% confidence interval. In general, a confidence interval describes the uncertainty around an estimated quantity under the assumptions of the analysis. It is not a range expected to contain most individual participant values. Because neither the Cmax estimates nor the intervals are reported, their numerical precision cannot be evaluated from the registry record.

Why use non-compartmental analysis?

The endpoint description says Cmax was determined using standard non-compartmental analysis in WinNonlin. In general, non-compartmental methods summarize concentration-time data without requiring the analyst to specify a compartment-based model of how drug moves through the body. The registry record does not give further computational details, such as rules for handling missing samples or the precise analysis population for each treatment comparison.

How should the study structure affect comparisons?

The study includes multiple parts, regimens, and doses. In general, comparisons are easiest to interpret when groups are formed and analyzed under comparable conditions. Here, the registry classifies overall allocation as non-randomized, while some Part C arm labels describe randomized groups. This mixed description means the design should not be reduced to a single trial-wide randomized contrast. The record does not explain the allocation procedures for each part or clarify the relationship between the overall classification and the Part C labels.

Open-label means masking is listed as none. In general, lack of masking can affect outcomes that involve judgment or reporting. The primary endpoint is a laboratory concentration measure, but the registry record does not discuss whether knowledge of treatment could have influenced sample handling, endpoint assessment, or other study processes. No such influence should be assumed from the design label alone.

What can the planning illustrations tell readers?

The sample-size illustrations are described as planning calculations based on the observed effect, not as the study’s original design justification. Their assumptions include a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. They consider detecting a stated fraction of the observed effect. In general, such calculations illustrate how sample size depends on the effect size and the assumptions chosen. They do not show that a study had a particular probability of detecting an effect after it was completed; they are not observed power.

The stated convention differs by outcome type: time-to-event calculations give a total number of events, while other calculations give participants per arm. No calculated values or detailed endpoint-specific assumptions are reported in the registry record in the registry record for interpretation. The trial’s own sample-size justification is not reported in the registry record.

Why does over-dispersion matter?

In general, over-dispersion occurs when outcome variability is greater than a model assumes. If a method assumes less variability than the data contain, its uncertainty estimates can be too narrow. This concept can matter for outcomes such as counts, but the registry record does not specify an over-dispersion analysis for this study. It should therefore be treated only as general statistical context, not as a feature known to have affected the reported results.

The registry lists 57 outcome measures and 22 analyses. These totals indicate that the record contains many planned or reported assessments, but they do not describe how estimates were selected, adjusted, or prioritized. The statistical analysis plan, including any interim analysis methods, is not reported in the registry record. Without that information and the numerical endpoint results, the intended inferential framework cannot be fully assessed.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 57 outcome measures and 22 analyses, spanning pharmacokinetic, safety, and clinical activity assessments. Multiple outcomes can create multiplicity: when many statistical questions are examined, the chance of at least one apparently notable result can increase. In general, methods such as a prespecified hierarchy or adjustment of significance thresholds can address some multiplicity concerns. The registry record does not report whether any such method was planned or used, and it does not identify a complete testing hierarchy.

The record defines the primary pharmacokinetic endpoint but does not report numerical results for it. It also does not report the full statistical analysis plan, interim analysis procedures, or a sample-size justification. These omissions make it difficult to determine which analyses were confirmatory and how uncertainty across multiple outcomes was handled. The listed outcome and analysis counts alone cannot answer those questions.

The primary endpoint analysis population is defined as participants who received at least one dose of either drug and had a pharmacokinetic sample obtained and analyzed. The number included in that population is not reported in the registry record. The registry does not report how missing or unusable samples were handled, whether participants were excluded from particular analyses, or whether sensitivity analyses were conducted.

These limitations concern what can be established from the registry record, not proof that a particular method was or was not used. The missing-data approach and handling of multiplicity are not reported in the registry record.

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: pyrexia (41.0%), chills (40.0%), nausea (25.0%), alanine aminotransferase increased (20.0%), aspartate aminotransferase increased (20.0%).

The registry reports serious adverse events and other adverse events separately for each listed group. For each group, it gives the number at risk and the number affected; it also lists deaths. These are counts within distinct dose groups and study parts. For example, the Part A group receiving dabrafenib 75 mg plus trametinib 2 mg lists 8 at risk for serious events and 5 affected, and 2 deaths. The Part B group receiving dabrafenib 150 mg plus trametinib 2 mg lists 94 at risk for serious events and 55 affected, and 12 deaths. These examples describe registry entries, not comparative estimates.

Group sizes and regimens differ, and the record’s overall allocation classification is non-randomized. The counts should therefore not be read as a fair ranking of regimens or as evidence that one regimen caused more events. The registry also lists serious-event terms and percentages, including pyrexia at 41.0%, chills at 40.0%, nausea at 25.0%, alanine aminotransferase increased at 20.0%, aspartate aminotransferase increased at 20.0%, and blood alkaline phosphatase increased at 20.0%. The denominator context for these percentages is not reported in the registry record. The death counts are listed by group, but cause-specific information is not reported in the registry record.

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

The study’s design and endpoint definitions establish what investigators set out to examine: pharmacokinetics, safety, pharmacodynamics, and clinical activity for combinations of GSK2118436 and GSK1120212. The primary endpoint focuses on dabrafenib Cmax after a single dose alone and in combination with trametinib. The registry identifies the sampling schedule, analysis method, summary measure, confidence interval, and analysis-population definition.

Those details do not establish the primary result. Numerical Cmax estimates and confidence intervals are not reported in the registry record, so the magnitude, direction, and precision of the primary pharmacokinetic finding cannot be evaluated. The record also does not provide a numerical primary-endpoint comparison or a p-value. A defined outcome is not the same as a reported outcome.

The safety counts describe events recorded in groups receiving different regimens across different study parts. They are useful as a record of what was reported, but the group structure and overall non-randomized classification limit causal interpretation. The Part C arm labels include “Randomized,” yet the overall allocation field is non-randomized; the registry record does not resolve this difference. The counts should not be used alone to claim that a regimen caused or prevented an event.

The listed sample-size calculations are planning illustrations based on an observed effect and stated assumptions. They are not a record of the study’s original design rationale and are not observed power. The registry does not report the sample-size justification, complete analysis plan, multiplicity approach, or missing-data methods.

In short, the record supports a description of the study’s structure, endpoint methods, and listed safety counts. It does not provide enough primary outcome information to judge the measured pharmacokinetic effect, and it does not establish clinical efficacy or a causal safety comparison.

13. Why This Trial Matters Statistically

This study is statistically notable for combining several distinct aims within a multi-part design. Part A addressed pharmacokinetics in the context of concomitant dosing, Part B escalated doses to identify tolerated combinations, Part C expanded evaluation of combinations, and Part D assessed dabrafenib capsules alone and with trametinib. Such a structure can answer several development questions, but it also means that a single overall comparison would not represent every part’s purpose.

The primary endpoint illustrates the distinction between measuring drug exposure and measuring clinical outcomes. Cmax is a pharmacokinetic quantity derived from timed concentration samples. The registry describes how it was assessed, including the geometric least squares mean and 95% confidence interval, but does not report the estimates. That makes the distinction between an outcome definition and an interpretable result especially important.

The record also highlights why design labels need careful reading. Overall allocation is classified as non-randomized, while Part C group names contain a randomized label. Different parts may have different structures, but the registry does not reconcile these descriptions. Readers should avoid treating the complete study as one uniform randomized comparison.

Finally, the record lists many outcomes and analyses but does not report a complete multiplicity strategy, missing-data approach, or sample-size rationale. These omissions constrain how confidently the analysis plan can be reconstructed. The study is informative as a record of multi-part pharmacokinetic and safety investigation, while the absent primary numerical results limit statistical interpretation of its principal endpoint.

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 primary limitation for interpreting the main endpoint is that the Cmax estimates and their 95% confidence intervals are not reported in the registry record. The record defines the endpoint and analysis method, but without numerical results it is not possible to describe the observed concentration estimates or their precision. The primary-endpoint comparison p-value is also not reported in the registry record.

The design contains multiple study parts, dose levels, and treatment sequences. Overall allocation is classified as non-randomized, whereas some Part C arm labels include “Randomized.” The record does not explain how those descriptions fit together. This uncertainty makes it important not to treat all listed groups as a single controlled comparison.

The registry lists safety counts and deaths by group, but group sizes and regimens vary. The cause of deaths, detailed participant characteristics, and denominator context for the listed serious-event percentages are not reported in the registry record. The counts therefore have limited value for comparative or causal interpretation.

Additional limitations include the absence of a reported sample-size justification, complete statistical analysis plan, interim analysis details, multiplicity methods, and missing-data procedures. The number analyzed for each endpoint is not reported in the registry record. The record lists 57 outcome measures and 22 analyses, but those totals do not reveal which assessments were confirmatory or how selective reporting was addressed.

Finally, the registry identifies an open-label design and a pharmacokinetic analysis population, but does not give all operational details needed to evaluate sample availability, exclusions, or sensitivity to analysis choices. These limitations describe gaps in the registry record; they do not establish that the study failed to use methods that are simply not reported.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Investigate Safety, Pharmacokinetics and Pharmacodynamics of GSK2118436 & GSK1120212 — NCT01072175.
• Registry record last updated 2019-07-05; status last verified 2019-06.
• Results first posted 2013-11-21.
• 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

The registry describes a completed, open-label, multi-part study of GSK2118436 and GSK1120212 in BRAF-mutant metastatic melanoma. The registry classifies it as Phase 2 and non-randomized, with 430 participants recorded as the enrollment. Its parts addressed pharmacokinetics, dose escalation, cohort expansion, and safety and pharmacokinetics of dabrafenib capsules alone and in combination. The official title describes a Phase I/II study, and some Part C arm labels include “Randomized,” while overall allocation is classified as non-randomized.

The primary endpoint was dabrafenib Cmax on Day 15, summarized as a geometric least squares mean with a 95% confidence interval. The endpoint methods are described, but its numerical result is not reported in the registry record. The record also lists serious adverse events and deaths by group, though the differing groups and design limit direct comparisons. Sample-size rationale, multiplicity methods, missing-data procedures, and the complete analysis plan are not reported in the registry record.