Trametinib and Akt Inhibitor GSK2141795 in Treating Patients With Metastatic Triple-Negative Breast Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Trametinib and Akt Inhibitor GSK2141795 in Treating Patients With Metastatic Triple-Negative Breast Cancer (NCT01964924), a na phase 2 study. The primary outcome is Objective Response Rate (ORR), Defined as the Proportion of Patients Who Have Had a Partial Response (PR) or Complete Response (CR) (RECIST 1.1 Based) Within the First 6 Months After Initiation of Therapy With Trametinib.

2. Clinical Question

3. Trial Design

This was a phase II, single-arm study of trametinib followed by trametinib in combination with Akt inhibitor GSK2141795 in patients with advanced triple-negative breast cancer. The registry record lists enrollment of 37 and a completed status. It records the study start as 2013-10-02 and primary completion as 2017-01-20. These are record dates, not evidence about how long any individual participant was followed.

The design used a treatment sequence rather than randomized parallel groups. In Part 1, participants received trametinib orally once daily on days 1-28. Courses were to repeat every 28 days in the absence of disease progression or unacceptable toxicity. Participants experiencing progression continued to Part 2, where the record says they received trametinib as in Part 1 and also received GSK2141795. The description of Part 2 is truncated in the registry record, so its full schedule and treatment details are not reported there.

Because the study was single-group and unmasked, it was not designed as a blinded comparison against a control treatment. Part 1 and Part 2 do not form comparable treatment arms: Part 2 followed progression and therefore involved a different treatment stage and patient experience. Comparisons between their safety counts cannot establish that one regimen caused more or fewer events than the other.

The record lists laboratory biomarker analysis as an intervention in addition to the two drugs. It also lists secondary outcomes including clinical benefit rate, duration of objective response, adverse events, overall survival, and progression-free survival. Outcome definitions or results for these measures are not reported in the registry record beyond the listed outcome names. The study's detailed eligibility criteria, treatment discontinuation rules beyond the stated progression or toxicity conditions, and statistical analysis plan 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: Patients on Part 1: trametinib monotherapy until progression and then will continue on to Part 2: trametinib combined with GSK2141795.

Trametinib Monotherapy

Reasons for not completing this period:

Trametinib + GSK2141

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 Objective Response Rate (ORR), Defined as the Proportion of Patients Who Have Had a Partial Response (PR) or Complete Response (CR) (RECIST 1.1 Based) Within the First 6 Months After Initiation of Therapy With Trametinib, measured over 6 months.

The primary endpoint is objective response rate, defined in the title as the proportion of patients with a complete response or partial response within the first 6 months after initiation of trametinib. The registry record expresses the outcome as a count of participants and identifies the unit as participants. A response proportion is a binary-outcome summary: each participant is classified according to whether a qualifying response was observed during the defined assessment period.

The record describes complete response as disappearance of all target lesions and partial response as a decrease in the sum of the longest diameter of target lesions meeting the stated threshold. It says assessment was based on RECIST and MRI. There is an internal version discrepancy: the endpoint title specifies RECIST 1.1, while the detailed description refers to RECIST v1.0. The registry record does not clarify which version governed the endpoint assessment.

In general, objective response is used to describe tumor shrinkage meeting prespecified criteria, rather than relying only on subjective impressions. The endpoint is limited to the response definition and assessment window stated in the record; it does not by itself describe how long a response lasts, whether disease remained stable, or survival. The record lists duration of objective response and other outcomes separately. It does not report the primary endpoint's observed count or proportion, so the endpoint definition alone does not establish the study's observed response result.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a response proportion measure?

In general, a response proportion counts the participants meeting a defined response category over a stated assessment window and relates that count to the analysis population used for the endpoint. The primary endpoint in this record concerns complete or partial response within the first 6 months after trametinib initiation. The record lists the outcome unit as participants, but does not give the response count, the denominator used for an analysis, or an estimate of the proportion. Enrollment alone does not establish how many participants were evaluable for this endpoint.

In general, an estimate of a proportion is more informative when accompanied by an uncertainty interval. A confidence interval describes a range of values compatible with the data and statistical method under the interval's assumptions; it does not guarantee that the true value lies in that range. No confidence interval for the primary endpoint is reported in the registry record. Without a response estimate and its uncertainty, precision cannot be assessed from the endpoint entry.

Why does the endpoint definition matter?

In general, a prespecified response definition helps make assessments more consistent by setting criteria for what qualifies as complete or partial response. This record defines complete response as disappearance of all target lesions and partial response as meeting a specified decrease in the sum of the longest diameter of target lesions. It refers to RECIST 1.1 in the endpoint title but RECIST v1.0 in the detailed description. That discrepancy makes the exact version applied unclear from the registry record. The record says assessments were based on MRI, but does not report assessment timing, review procedures, or whether response was independently reviewed.

A response endpoint is distinct from a time-to-event outcome. In general, a response measure asks whether a defined event occurred within an assessment period, while progression-free survival or duration of response concerns time until a specified event or endpoint. The registry lists duration of objective response and progression-free survival separately, but their operational definitions and results are not reported in the registry record. The response endpoint should not be read as a measure of durability or survival.

What does the design imply for comparisons?

In general, random allocation can help make groups comparable at baseline, supporting a treatment comparison when the study is appropriately conducted and analyzed. This record lists allocation as not applicable, masking as none, and the model as single-group. There is no randomized comparator. Thus, the design does not provide a concurrent control group for separating treatment-associated changes from disease course, participant selection, assessment practices, or other influences.

Part 2 is not an independent control group. Participants entered that treatment stage after progression, and the listed regimen combined GSK2141795 with trametinib. The Part 1 and Part 2 safety counts therefore describe different stages of a sequence, not exchangeable groups assigned to different treatments. A direct causal contrast between their counts would not be justified by this design information.

How should the planning assumptions be read?

In general, a sample-size calculation uses assumptions about the effect to detect, variability or event frequency, significance level, power, allocation, and analysis method. A planning illustration can show how required sample size changes when the assumed target effect changes. It is not an observation from the trial, and it is not observed power. The record explicitly labels its sample-size assumptions as an illustration based on the observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It states that the effect to detect is a fraction of the observed effect.

Those assumptions are not a description of this study's design: the trial is single-group, whereas the illustration assumes equal allocation between two arms. The registry record does not report the numerical planning outputs or explain that they were used to design the study. It also does not report a sample-size justification, target power for the trial, or the statistical plan behind the primary endpoint. Any participant-per-arm planning values should therefore be treated only as hypothetical illustrations, not as an observed feature of this trial.

In general, over-dispersion matters when count data vary more than a model's assumed distribution allows; ignoring it can make uncertainty estimates too small. The primary endpoint is described as a participant count for a binary response outcome, and the record gives no dispersion parameter or outcome analysis. A count-data explanation cannot supply an unreported model or justify an assumption about the analysis actually used.

What does the registry's analysis entry establish?

The record lists zero analyses. This means no analysis entries are recorded in the registry information summarized for this study; it does not prove that investigators conducted no analyses outside the registry. The record does not report a statistical test, a model, covariate adjustment, handling of repeated assessments, or a confidence-interval method. These details should not be inferred from the endpoint definition or from the sample-size illustration.

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("Treatment (Trametinib, Akt Inhibitor GSK2141795)")
n      <- c(37)
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  Treatment (Trametinib, Akt Inhibitor GSK2141795)  37  2  5.4  0.7  18.2  1.5  17.7  1.7  17.7

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 12 outcome measures, including the primary objective response endpoint and secondary outcomes such as clinical benefit rate, duration of objective response, adverse events, overall survival, and progression-free survival. The record does not report how these outcomes were ordered for confirmatory testing, whether any outcome hierarchy was used, or whether adjustment for multiple comparisons was planned. Therefore, the interpretation of any hypothetical set of significance tests cannot be assessed from the registry record. The record lists zero analyses, so it contains no reported multiplicity-adjusted or unadjusted results to interpret.

In general, evaluating many outcomes can increase the chance of at least one apparently unusual result when each is assessed separately. A prespecified testing strategy can clarify which comparisons are confirmatory and how uncertainty should be interpreted. This is a general statistical consideration, not a description of the study's analysis plan; that plan is not reported in the registry record.

Missing-data methods and analysis populations are also not reported in the registry record. The primary endpoint specifies a 6-month assessment window, but the record does not say how participants without an assessment in that window were classified, how incomplete assessments were handled, or whether the analysis used all enrolled participants or an evaluable subset. Enrollment of 37 does not establish the denominator used for the primary endpoint.

The registry identifies safety counts for the two treatment parts, but does not describe the conventions used to handle participants who moved between parts, event recurrence, event duration, or exposure time. It also does not report whether the safety populations were defined by treatment received or by another rule. These omissions limit interpretation of both the response endpoint and the safety summaries. They do not establish that missing data or multiplicity were mishandled; they mean the relevant procedures are not reported in the registry record.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: neoplasms benign, malignant and unspecified (incl cysts and polyps) - other, specify (21.6%), death nos (21.1%), diarrhea (10.5%), sepsis (5.4%), dehydration (5.3%).

The registry record reports serious adverse events for each treatment part as counts of participants at risk and participants affected. In Part 1, 30 participants were affected among 37 at risk. In Part 2, 15 were affected among 19 at risk. Other adverse events were reported for 37 among 37 at risk in Part 1 and 19 among 19 at risk in Part 2. The record also gives 13 deaths in Part 1 and 12 in Part 2.

These are descriptive counts, not a comparison of treatment risk. Part 2 followed progression in Part 1 and is not a randomized control group. The record does not report exposure time, event-level recurrence, cause of death, or whether the same participant could contribute to multiple event categories. It also does not state that the deaths were caused by treatment. The listed serious-event terms and percentages are Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify at 21.6%, Death NOS at 21.1%, Diarrhea at 10.5%, Sepsis at 5.4%, Dehydration at 5.3%, and Dyspnea at 5.3%. Their specific percentage denominators are not reported in the registry record. Seriousness, event term, and treatment attribution are distinct concepts and should not be conflated.

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

The registry record establishes that a phase II, single-group study evaluated a sequence beginning with trametinib and continuing, after progression, with trametinib plus GSK2141795. It specifies an objective response endpoint within the first 6 months and lists additional clinical and safety outcomes. It also records adverse-event counts for each treatment part. These are useful descriptions of the study question, design, and recorded safety summaries.

The record does not report the primary response count or proportion, a confidence interval, or an analysis result. It therefore does not establish the frequency or precision of objective response in the study. The record's endpoint definition is not itself a result. The registry also does not report results for the listed secondary outcomes, so their names should not be mistaken for demonstrated findings.

The study has no randomized comparator, and its second treatment stage was entered after progression. As a result, its structure does not support a direct comparison of Part 1 and Part 2 as if they were parallel groups assigned to alternative regimens. Counts alone cannot isolate a treatment effect from differences in disease status, treatment stage, time at risk, or other factors. The registry record also does not provide enough detail to assess causal attribution for deaths or adverse-event terms.

In general, an endpoint can describe a specific clinical outcome without answering every broader question about treatment benefit, durability, survival, or safety. Objective response is not the same as duration of response or progression-free survival. Likewise, an event listed during a study is not automatically an event caused by study treatment. Interpretation should remain within the endpoint definitions and outcome information actually reported.

The record does not support advice about care or a conclusion that either regimen does or does not work. It supports describing the planned question and the counts that are recorded, while recognizing that the principal efficacy result and detailed analysis are not reported in the registry record.

14. Why This Trial Matters Statistically

Statistically, this study illustrates why design and endpoint information must be read together. The primary question is framed as a response proportion over a defined period, but the registry record does not report the response count or its uncertainty. Without those results, the endpoint cannot be used to quantify what was observed or how precisely it was estimated.

The single-group design also defines the limits of inference. With no randomized comparator, an observed outcome would describe the participants in the study, but the design would not by itself distinguish treatment-associated change from other explanations. The sequential structure adds another interpretive constraint: Part 2 is a progression-contingent treatment stage, not a baseline-comparable arm. That matters especially when reading safety counts across the two parts.

The registry contains listed secondary outcomes and safety summaries alongside an absent analysis entry. This highlights the difference between listing outcomes and reporting analyzable results. Definitions, denominators, missing-data handling, endpoint hierarchy, and uncertainty estimates are all important for understanding how evidence was generated and how strongly it supports an inference. Several of these details are not reported in the registry record.

The record also shows why consistency in endpoint specification matters: the primary endpoint title refers to RECIST 1.1, while the detailed description refers to RECIST v1.0. Clarification of the version and assessment procedures would help readers understand exactly how response was classified. Together, these features make the study statistically informative as an example of how a clinical question, treatment sequence, endpoint definition, and reporting completeness jointly shape interpretation.

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 primary limitation for interpreting efficacy is that the registry record does not report the objective response count, response proportion, confidence interval, or statistical test. It identifies a primary endpoint and timeframe, but not an observed result. The listed secondary outcomes likewise lack reported results and detailed analysis information.

The study was single-group, unmasked, and had no randomized comparator. Consequently, the design does not supply a concurrent control for estimating a treatment contrast. Part 2 followed progression in Part 1, making it a different stage of treatment rather than a comparable control group. The registry record does not report exposure-adjusted safety rates, event timing, or sufficient detail to compare risks across treatment parts.

The endpoint description contains a version inconsistency: RECIST 1.1 appears in the title, while RECIST v1.0 appears in the detailed description. The record does not resolve this or report assessment review procedures. The full Part 2 treatment description is truncated, and the GSK2141795 dosing schedule is not reported in the registry record.

Analysis populations, missing-data handling, multiplicity procedures, and the statistical analysis plan are not reported in the registry record. Nor does it provide the denominator and coding context for the listed serious-event term percentages. These limits do not show that the study procedures were inappropriate; they restrict what can be concluded from the registry information.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Trametinib and Akt Inhibitor GSK2141795 in Treating Patients With Metastatic Triple-Negative Breast Cancer — NCT01964924.
• Registry record last updated 2019-09-20; status last verified 2019-08.
• Results first posted 2019-09-20.
• 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.

19. Record Summary

NCT01964924 is a completed phase II, single-group study of trametinib followed, after progression, by trametinib plus Akt inhibitor GSK2141795 in advanced triple-negative breast cancer. The record lists enrollment of 37 and identifies objective response within the first 6 months as the primary endpoint. It lists secondary clinical and safety outcomes and reports adverse-event counts for Part 1 and Part 2.

The registry record does not report the primary response result, uncertainty estimates, or detailed statistical analyses. It lists zero analyses. The absence of a randomized comparator, the progression-contingent treatment sequence, and unreported analysis procedures limit interpretation of efficacy and comparisons between treatment parts. The record also contains an inconsistency between the RECIST version in the primary endpoint title and the version in its detailed description.