An Open-Label Phase II Study of the Combination of GSK2118436 and GSK1120212 in Patients With Metastatic Melanoma Which is Refractory or Resistant to BRAF Inhibitor: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for An Open-Label Phase II Study of the Combination of GSK2118436 and GSK1120212 in Patients With Metastatic Melanoma Which is Refractory or Resistant to BRAF Inhibitor (NCT01619774), a na phase 2 study. The primary outcome is Overall Response Rate (ORR).

2. Clinical Question

3. Trial Design

This was an open-label phase II study of the combination of GSK2118436 and GSK1120212 in patients with metastatic melanoma refractory or resistant to a BRAF inhibitor. The sponsor was M.D. Anderson Cancer Center. The study is recorded as completed, with enrollment of 28. The registry lists a start date of 2012-09 and a primary completion date of 2015-08.

The design is recorded as single group, with allocation listed as NA and masking as none. All participants were assigned to the combination regimen; the record does not describe a separate control arm. The intervention description gives GSK1120212 2 mg by mouth once a day and GSK2118436 150 mg by mouth two times every day, once in the morning and once in the evening, about 12 hours apart. The registry summary identifies these drugs as trametinib and dabrafenib, respectively.

The primary outcome was overall response rate, defined as the percentage of participants with a confirmed complete response or partial response at any time under RECIST 1.1. Tumor response assessments were scheduled every 8 weeks, or every 2 cycles, up to 12 months. Progression-free survival was listed as a secondary outcome. The registry record lists three outcome measures, but the details of the other measures are not reported in the registry record.

Because the study had a single treatment group, its design can describe outcomes observed among participants receiving the combination but cannot establish a randomized treatment contrast. The open-label design means masking was absent. The registry record does not report a statistical analysis plan, a sample-size justification, or details of interim analyses. The actual primary response result and the progression-free survival result 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: Of the 28 participants screened, five (5) were not eligible following enrollment thus were excluded prior to treatment assignment.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Three of the 23 participants were not evaluable for response.

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 Overall Response Rate (ORR), measured over Evaluation every 8 weeks (2 cycles) up to 12 months.

Overall response rate measures the percentage of participants who have a confirmed complete response or partial response at any time during the specified assessment period. A complete response is defined by disappearance of all lesions, with pathological lymph nodes reduced in short axis to <10 mm. A partial response requires a >30% decrease in the sum of lesion diameters relative to the baseline sum. The endpoint therefore focuses on documented tumor shrinkage that meets a prespecified response category, rather than on any change in tumor size.

RECIST 1.1 also defines progressive disease and stable disease, which distinguish tumor growth from response and from changes that meet neither response nor progression criteria. The registry describes progression as a >20% increase in the sum of lesion diameters relative to the smallest sum on study, with an absolute increase of >5 mm; the appearance of one or more new lesions is also considered progression. Stable disease is neither sufficient shrinkage for partial response nor sufficient increase for progressive disease, using the smallest on-study sum as reference.

As a general statistical concept, an overall response rate can give a concise description of how often participants meet a defined tumor-response threshold. It does not by itself describe how long a response lasts or how long participants remain free of progression. The registry lists progression-free survival as a secondary outcome, but its estimate and analysis are not reported in the registry record. The observed overall response count and percentage are also not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes the primary endpoint and its assessment framework, but does not report the statistical methods used to analyze the trial outcomes. General statistical concepts can help explain what the stated endpoint would measure and what information is needed to interpret it.

What does overall response rate count?

Overall response rate is a binary outcome at the participant level: a participant either meets the endpoint definition by having a confirmed complete or partial response, or does not. The registry defines a response as a confirmed complete response or partial response at any time according to RECIST 1.1. The endpoint is reported as a percentage of participants. The actual number meeting the definition and the resulting percentage are not reported in the registry record.

RECIST 1.1 supplies operational categories for tumor change. Complete response requires disappearance of all lesions, with pathological lymph nodes reduced in short axis to <10 mm. Partial response requires a >30% reduction in the sum of lesion diameters compared with baseline. Progressive disease is defined by a >20% increase relative to the smallest on-study sum, together with an absolute increase of >5 mm; the appearance of one or more new lesions also qualifies. Stable disease is the category for changes that satisfy neither the partial-response nor progressive-disease definition. These categories aim to make response assessment more consistent, but they do not themselves provide the trial's observed response result.

Why does the analysis population matter?

A percentage depends on who is included in its denominator. The registry states that three of the 23 participants were not evaluable for response. It does not report the reason for this status, the handling of those participants, or a defined analysis population for the primary endpoint. Without that information, a reader cannot determine from the registry record how the response percentage was calculated or whether the evaluation set was defined before the results were known.

In general, missing or unevaluable outcomes can affect an endpoint when the participants without an outcome differ from those with an evaluable outcome. An analysis plan may specify how such cases are handled, but the plan and the handling used for this endpoint are not reported in the registry record. It would therefore be inappropriate to assume that participants with missing or unevaluable response assessments were counted as nonresponders, excluded, or handled in some other way.

What can a confidence interval add?

In general, a confidence interval describes the uncertainty around an estimated outcome under the assumptions of the analysis. For an overall response rate, it would help show how precisely the observed percentage was estimated. The registry record does not report a response estimate or confidence interval, so neither the observed value nor its precision can be assessed. A point estimate without an uncertainty measure can also be difficult to compare across studies, particularly when study populations and analysis methods differ.

Why does the single-group design matter?

The study is recorded as single group, with allocation listed as NA and masking as none. In general, random allocation to a comparator can support a direct treatment contrast by helping balance factors between groups. This trial does not provide such a comparison. Its design can describe outcomes among participants receiving the combination, but cannot establish how those outcomes differ from outcomes under another treatment. It also cannot identify the separate effect of either drug in the combination.

Open-label status means masking was absent. In general, lack of masking can affect outcomes involving judgment or participant reporting, although the registry does not describe any such effect in this trial. The response endpoint was based on RECIST 1.1 and scheduled assessments, but details of independent review, adjudication, or other safeguards are not reported in the registry record.

What is reported about planning and analysis?

The registry record does not report the trial's sample-size justification, statistical analysis plan, or interim analyses. A separate planning illustration is based on an observed effect and specifies a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and effects expressed as fractions of the observed effect. The illustration is not the trial's own design justification, and its assumptions do not turn this single-group trial into a two-arm comparison. Sample-size planning illustrations are not observed power.

The registry lists three outcome measures and zero analyses. The primary response result and progression-free survival result are not reported in the registry record. Consequently, the available record does not establish which inferential procedures were used, whether adjustment was made for multiple outcomes, or how time-to-event outcomes were analyzed. In general, a complete statistical interpretation needs the endpoint estimate, its uncertainty, the analysis population, and the prespecified analysis approach; these details are not available for the efficacy outcomes 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("GSK2118436 + GSK1120212")
n      <- c(20)
events <- c(2)
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  GSK2118436 + GSK1120212  20  2  10.0  1.2  31.7  2.8  30.1  3.0  30.4

11. Multiplicity, Missing Data and Analysis Populations

The registry identifies overall response rate as the primary outcome and progression-free survival as a secondary outcome. It lists three outcome measures, but details for the other measures are not reported in the registry record. The analysis plan, including any strategy for handling multiple outcomes or repeated assessments, is not reported in the registry record. It is therefore not possible to determine whether a multiplicity adjustment was planned or used.

Multiplicity matters in general when several outcomes, comparisons, or analysis opportunities are examined: interpreting each result as if it were the only planned test can overstate the strength of evidence. That general concern does not establish that any particular adjustment was needed or used in this study. The registry record does not describe interim analyses, and no interim-testing plan is reported.

The response outcome was scheduled for evaluation every 8 weeks, or every 2 cycles, up to 12 months. The endpoint definition allows a confirmed complete or partial response at any time. The record does not explain how assessments at different time points were incorporated into the reported analysis or whether confirmation requirements involved any additional rules beyond the endpoint description.

For missing outcome information, the registry states that three of the 23 participants were not evaluable for response. Reasons, assumptions about missingness, analysis-population rules, and sensitivity analyses are not reported in the registry record. The response denominator and the handling of these participants are also not reported. These details are necessary to understand whether the response estimate represents all participants, only those evaluable for response, or another defined group.

The registry record does not report a statistical analysis plan or the methods used for the primary or secondary outcomes. It also does not report the observed response result or progression-free survival analysis. Accordingly, multiplicity, missing-data handling, and the efficacy analysis population cannot be reconstructed from the registry record.

12. Safety Results

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

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: arthralgias (4.3%), decreased ejection fraction (4.3%), sinus tachycardia (4.3%), thromboembolic event (4.3%).

The serious adverse event data list 23 participants at risk and 2 participants with a serious adverse event in the GSK2118436 plus GSK1120212 group. Four serious adverse event terms are listed, each at 4.3%: arthralgias, decreased ejection fraction, sinus tachycardia, and thromboembolic event. These are descriptions of reported serious adverse events in the study group, not a comparison with another treatment group.

The record also lists 23 participants at risk for other adverse events and 23 affected. This is a separate summary from the serious adverse event count and should not be conflated with the serious-event figures. The registry does not provide additional detail in the listed details about the severity, duration, management, or relationship to treatment for each event. Deaths are not reported in the registry record.

In general, adverse-event percentages describe the frequency recorded under a particular study's definitions and observation procedures. They do not by themselves establish whether an event was caused by treatment. A single-group study also lacks a randomized comparator for estimating whether event frequency differs from another treatment. The safety figures should therefore be read as descriptive findings for the recorded study group, with the limitations of the available reporting.

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

This study was designed to describe the response and safety of GSK2118436 plus GSK1120212 among participants with metastatic melanoma refractory or resistant to a BRAF inhibitor. The primary outcome was defined as the percentage with a confirmed complete or partial response under RECIST 1.1. The registry record provides the endpoint definition, assessment schedule, and regimen, but does not report the observed response count or percentage. It therefore does not establish the size or precision of the primary response result.

Progression-free survival was listed as a secondary outcome, but its result is not reported in the registry record. The record also does not report an analysis plan, response confidence interval, or statistical method for the efficacy outcomes. The stated assessment schedule and response criteria clarify how the endpoint was intended to be evaluated; they should not be mistaken for results.

The design was open-label and single group. As a general principle, findings in a single group describe what occurred among participants who received the regimen, but do not provide a randomized estimate of the difference that would have occurred under another treatment. The design also cannot separate the contributions of the two drugs. No treatment comparison or causal effect can be inferred from the registry design alone.

The safety record reports two participants with serious adverse events among 23 at risk and lists four serious event terms, each at 4.3%. It also records 23 participants affected by other adverse events among 23 at risk. Those figures are descriptive; the registry record does not report deaths. Safety data without a comparator cannot determine how event frequency differs from another treatment, and event listings alone do not establish causation.

The study's registry record is useful for identifying its population, combination regimen, primary endpoint, and some safety counts. It does not supply the outcome information needed to quantify efficacy or assess its statistical precision. This is a limitation of the available record, not evidence that an outcome was either favorable or unfavorable.

14. Why This Trial Matters Statistically

The study illustrates why an endpoint definition and an outcome result are distinct pieces of information. Overall response rate is clearly defined using confirmed RECIST 1.1 categories, and assessments were scheduled every 8 weeks, or every 2 cycles, up to 12 months. Yet the registry record does not report the observed response count or percentage. A detailed definition helps readers understand what would count as response, but cannot substitute for the measured result.

The response population also matters. The record states that three of the 23 participants were not evaluable for response, while leaving the reasons and analysis handling unreported. This makes the denominator and interpretation of any response percentage especially important. In general, explicit analysis-population rules and transparent accounting of participants help readers judge whether an endpoint estimate answers the intended question.

The single-group, open-label design is another important statistical feature. It can describe outcomes among participants receiving the combination, but it does not support a randomized comparison with another treatment. This distinction prevents descriptive outcomes from being read as comparative evidence. The design also cannot separate the effects of dabrafenib and trametinib when they are given together.

Finally, the record includes some safety counts but does not report the primary efficacy estimate, its precision, the progression-free survival result, or the analysis plan. This contrast shows why statistical interpretation depends not only on event counts and endpoint definitions, but also on an analysis population, an estimate, and uncertainty information. The registry record supports a careful description of design and reporting, while leaving the principal efficacy findings unavailable.

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 main trial-specific limitation for interpreting efficacy is that the registry record does not report the primary overall response rate result. It gives the definition and assessment schedule, but not the observed response count, percentage, or confidence interval. The progression-free survival result is also not reported in the registry record, despite being listed as a secondary outcome.

The endpoint description states that three of the 23 participants were not evaluable for response, but does not give reasons or explain their handling in the analysis. The response denominator and analysis-population definition are not reported in the registry record. This limits interpretation of how the primary outcome would relate to all participants enrolled.

The study was open-label and single group, with allocation listed as NA. It therefore lacks a randomized comparator and cannot support a direct treatment contrast. Outcomes in this group cannot, by design alone, determine what would have occurred under another treatment. Because the two drugs were administered together, the study also cannot distinguish their separate contributions.

The registry record does not report a statistical analysis plan, sample-size justification, interim analyses, multiplicity strategy, missing-data methods, or efficacy analysis methods. It lists three outcome measures and zero analyses, but details of the other outcome measures are not reported in the registry record. The listed safety information is limited to participant counts and serious event terms; deaths, event duration, and treatment relationship are not reported in the registry record. These reporting gaps constrain both clinical and statistical interpretation.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: An Open-Label Phase II Study of the Combination of GSK2118436 and GSK1120212 in Patients With Metastatic Melanoma Which is Refractory or Resistant to BRAF Inhibitor — NCT01619774.
• Registry record last updated 2016-12-12; status last verified 2016-10.
• Results first posted 2016-12-12.
• 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

NCT01619774 is a completed, open-label, single-group phase II study sponsored by M.D. Anderson Cancer Center. It enrolled 28 participants with metastatic melanoma described as refractory or resistant to a BRAF inhibitor. The registry lists a start date of 2012-09 and a primary completion date of 2015-08.

The combination was GSK2118436, identified as dabrafenib, and GSK1120212, identified as trametinib. The primary endpoint was overall response rate by RECIST 1.1, assessed every 8 weeks, or every 2 cycles, up to 12 months. Progression-free survival was a listed secondary outcome.

The record states that three of the 23 participants were not evaluable for response. It does not report the primary response result, the progression-free survival result, or an efficacy analysis plan. Safety information includes 2 participants with a serious adverse event among 23 at risk and four serious event terms, each reported at 4.3%. The study had no randomized comparator.