MEK Inhibitor MSC1936369B Plus FOLFIRI in Second Line K-Ras Mutated Metastatic Colorectal Cancer (mCRC): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for MEK Inhibitor MSC1936369B Plus FOLFIRI in Second Line K-Ras Mutated Metastatic Colorectal Cancer (mCRC) (NCT01085331), a randomized phase 1, phase 2 study. The primary outcome is Part 2 or Phase 2 Randomised Part: Progression Free Survival (PFS).

2. Clinical Question

The trial was designed in two parts. A safety run-in was intended to identify a dose of pimasertib to take forward with FOLFIRI. A randomized Phase 2 part was intended to assess antitumor activity against FOLFIRI with placebo. The primary endpoint assigned to that randomized part was progression-free survival (PFS), with progression documented by the investigator using radiological progression per RECIST v1.0.

That comparison was not carried out: the registry says the randomized part was not conducted and PFS was not evaluated. Therefore, the record does not answer whether the two planned regimens differed in PFS. It reports no randomized treatment comparison, PFS estimate, or result that can establish the size or direction of an effect. The available trial information instead describes the planned question and safety-run-in groups. The reason the randomized part was not conducted is not reported in the registry record.

3. Trial Design

The registry describes a Phase 1 and Phase 2 study with a safety run-in followed by a planned randomized part. The run-in was intended to determine the maximum tolerated dose and recommended Phase 2 dose of pimasertib with FOLFIRI. The brief description characterizes the Phase 1 portion as open-label, non-randomized dose escalation using a “3+3” cohort approach. In the safety data, the pimasertib-plus-FOLFIRI groups are listed at 45 mg and 60 mg.

The planned Phase 2 portion was described as randomized, double-blind, comparative, multicenter, exploratory, and placebo-controlled. It was intended to compare pimasertib plus FOLFIRI with placebo plus FOLFIRI as second-line treatment. Although the registry's overall design fields identify randomization, double masking, and a parallel model, the arm descriptions state that both Phase 2 arms were planned but not performed. The primary PFS endpoint therefore has no randomized-part result.

Enrollment is listed as 16. The safety record lists 10 participants at risk in the 45 mg pimasertib group and 6 in the 60 mg group. The record gives a start of 2010-03 and primary completion of 2012-04, and marks the study as terminated. The reason for termination, allocation procedures, masking procedures in the run-in, and the planned or actual recruitment by site are not reported in the registry record. The record does not establish that the Phase 2 allocation or masking took place; its arm descriptions explicitly say that those arms were not performed.

The distinction between planned and conducted components is important for interpreting this trial. A protocol may specify an intended randomized comparison, but that intention does not create comparative outcome data. The record contains safety-run-in information, but not an evaluated PFS comparison between the two planned Phase 2 groups.

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: Enrolled: 22 screened for eligibility; 6 were excluded (mainly non-fulfillment of inclusion or exclusion). 16 subjects were treated in a total of 4 centers (2 in Spain and 1 each in Belgium and Italy).

Overall Study

Analysis population for the primary outcome, as defined in the registry: The safety analysis set included all subjects who received at least one (non-zero) administration of the trial medication (any of the 3 FOLFIRI drugs and pimasertib).

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: The safety analysis set included all subjects who received at least one (non-zero) administration of the trial medication (any of the 3 FOLFIRI drugs and pimasertib).

6. Primary Endpoint

The registry lists the primary outcome as Part 2 or Phase 2 Randomised Part: Progression Free Survival (PFS), measured over From randomization up to first documented disease progression maximum up to 2 years.

The primary endpoint assigned to the randomized Phase 2 part was progression-free survival (PFS). The registry defines it as time in months from randomization to the first documented disease progression, as reported and documented by the investigator, or death from any cause. Progression was specified as radiological progression per RECIST v1.0. The stated timeframe was from randomization until first documented progression, with a maximum of up to 2 years.

In general, PFS is a time-to-event endpoint: it accounts for both whether an event occurs and how long it takes to occur. It is often used in trials where the question concerns the time until disease progression or death. Combining progression and death into an endpoint also means that either event can count as the outcome, rather than requiring progression to be observed first. These are general features of the endpoint, not findings from this study.

For this trial, the distinction between the endpoint definition and its evaluation is decisive. The randomized Phase 2 part was not conducted, and the registry states that PFS was not evaluated. No PFS event summaries, group estimates, treatment contrast, confidence interval, or hypothesis test are reported in the registry record. The endpoint definition describes what would have been measured; it is not evidence of a result.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a two-part design, but only the safety run-in has reported participant groups. The randomized Phase 2 comparison was planned and not performed. Statistical interpretation must therefore separate the intended methods from analyses that actually have results. The primary endpoint definition and planned allocation do not imply that an endpoint analysis took place.

What does a time-to-event endpoint measure?

In general, a time-to-event endpoint records the time until a defined event. For PFS in this trial, the event was the first documented disease progression or death from any cause, measured from randomization. The registry specified investigator-documented radiological progression per RECIST v1.0. This definition determines what counts as an event, but does not reveal how many events occurred or how long participants remained event-free. Since the randomized part was not conducted, the record reports no PFS analysis.

Time-to-event methods can account for participants whose event has not been observed by the end of follow-up. Such observations are often described as censored: the participant contributes information up to the last time their status is known, without being treated as having experienced the event. This is a general explanation. The censoring rules, follow-up procedures, and handling of incomplete PFS information for this study are not reported in the registry record. Because PFS was not evaluated, there are no reported censoring counts or group-level follow-up summaries to interpret.

What would a treatment estimate and confidence interval tell a reader?

In general, a treatment estimate describes the contrast between groups according to a specified statistical measure. A confidence interval conveys uncertainty around that estimate and helps readers judge its precision. A p-value, when reported, addresses compatibility of the data with a specified null hypothesis under the analysis assumptions; it does not measure the size or clinical importance of an effect. These concepts require an analyzed comparison and its results. The registry reports no PFS estimate, confidence interval, p-value, or other efficacy analysis for the planned randomized groups, so none of these quantities can be interpreted for PFS in this trial.

There is no reported statistical analysis plan for the PFS comparison, including the intended effect measure, model, adjustment variables, or rules for analysis populations. These details are not reported in the registry record. It would be inappropriate to assume that a particular time-to-event model or covariate adjustment was used merely because the endpoint was PFS.

Why is the safety run-in not a substitute for randomization?

The run-in lists pimasertib with FOLFIRI at 45 mg and 60 mg. Its stated purpose was dose and safety assessment, rather than the randomized comparison of pimasertib plus FOLFIRI against placebo plus FOLFIRI. In general, randomization helps make groups comparable with respect to both measured and unmeasured characteristics, on average. Without the planned randomized comparison, differences between the run-in groups cannot be interpreted as a controlled estimate of the effect of pimasertib versus placebo. The registry does not report that participants were randomized between the two run-in doses.

Safety counts are descriptive. They show how many participants in the listed groups had reported events, but by themselves do not establish whether an event was caused by a treatment or whether one regimen changes risk relative to another. A controlled safety comparison would require suitable comparison groups and clearly defined analysis methods. The planned placebo group was not performed, so it does not serve as a safety comparator in the reported results.

What can planning calculations establish?

In general, sample-size planning uses assumptions about the effect to be detected, variability or event rates, significance level, allocation, and target power. A planning calculation is not a result from enrolled participants and is not “observed power.” The record describes planning illustrations based on a fraction of an observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation; it also distinguishes event totals for time-to-event illustrations from participants per arm for other outcomes. However, the registry provides no evaluated PFS effect from the unperformed randomized part. No numerical planning result or observed PFS effect is reported in the registry record, so those assumptions cannot support an efficacy conclusion.

Over-dispersion is a general concern for count outcomes when variation exceeds what a simple model assumes; using a model that allows extra variation can affect uncertainty estimates. That concept does not establish anything about this study's PFS, and no count-outcome efficacy analysis is reported. The statistical model, if any, for the safety-run-in outcomes is not reported in the registry record.

Finally, the analysis population definitions and missing-data methods are not reported. For a randomized study, common choices might include analyzing participants according to assigned group or according to treatment received, but the record does not state an approach for this trial's planned comparison. Since the randomized part did not occur, there is no posted randomized analysis population to evaluate. General methodological possibilities should not be mistaken for the trial's methods.

10. Multiplicity, Missing Data and Analysis Populations

The registry identifies PFS as the primary endpoint for the planned randomized part, but that part was not conducted and the endpoint was not evaluated. It reports 17 outcome measures, including safety and pharmacokinetic measures for the run-in, but does not provide a statistical analysis plan explaining how multiple outcomes, time points, or comparisons were to be handled. The number of analyses listed is 0. Any multiplicity strategy, such as adjusting significance thresholds or specifying a hierarchy of tests, is not reported in the registry record.

In general, testing multiple outcomes or comparisons can increase the chance of finding at least one apparently unusual result even when no underlying effect exists. Prespecifying which outcomes are primary and how tests are organized helps readers interpret a family of results. That general issue does not permit conclusions about the actual plan: the approach to multiplicity is not reported, and there are no randomized efficacy analyses to assess.

Definitions for missing PFS information, censoring, and handling of participants with incomplete follow-up are not reported in the registry record. No analysis population for the randomized comparison is reported, including whether it would have followed assignment or treatment received. Since the randomized part was not performed, there are no group-level missing-data counts or analysis-population results to describe. The record also does not report missing-data procedures for the safety-run-in outcomes.

These gaps matter because endpoint definitions alone do not specify how incomplete observations are handled or which participants enter each analysis. No assumptions about missingness, imputation, censoring, or exclusion should be attributed to the trial without a reported method.

11. 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: mucosal inflammation (33.3%), enteritis (16.7%), general physical health deterioration (16.7%), pyrexia (16.7%), memory impairment (16.7%).

The registry reports two safety-run-in groups: pimasertib 45 mg plus FOLFIRI, with 10 participants at risk, and pimasertib 60 mg plus FOLFIRI, with 6 participants at risk. Serious treatment-emergent adverse events are reported for 4 participants in each group. Other treatment-emergent adverse events are reported for 10 participants in the 45 mg group and 6 in the 60 mg group. These are descriptive counts from the run-in groups, not results from the planned randomized comparison.

The registry also lists serious-event terms with percentages: mucosal inflammation, 33.3%; enteritis, 16.7%; general physical health deterioration, 16.7%; pyrexia, 16.7%; memory impairment, 16.7%; and diarrhoea, 10.0%. The denominator and details of term-level counting are not reported in the registry record. The percentages should therefore be treated as reported descriptions, not as a basis for reconstructing participant counts or comparing risks between groups.

In general, a serious adverse event is a distinct category from an event that is non-serious, and event counts do not by themselves establish causality. The registry does not report deaths for these groups in the available figures; death counts are not reported in the registry record. These safety summaries do not determine whether either regimen is beneficial or harmful relative to the unperformed placebo comparison.

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

The result that can be stated is limited: the registry records a safety run-in involving pimasertib plus FOLFIRI and describes a randomized Phase 2 comparison that was planned but not performed. PFS was the primary endpoint for that planned comparison, but the registry says it was not evaluated. Consequently, no comparative PFS result is available to indicate the direction, size, or precision of an effect.

The safety-run-in figures describe treatment-emergent adverse events in the listed pimasertib dose groups. They do not compare pimasertib plus FOLFIRI with placebo plus FOLFIRI. They also do not establish that an event was caused by treatment. The registry's serious-event term percentages are descriptive, and their denominator and counting details are not reported. Interpreting those percentages as a treatment contrast would go beyond the information recorded.

In general, a planned randomized trial can answer a comparative question only when the comparison is conducted and outcomes are analyzed. The intended randomization and masking are features of the planned Phase 2 design, not evidence that participants were assigned or that blinding occurred. The record marks both Phase 2 arms as planned, not performed. Thus, the trial's design description should not be mistaken for findings from those arms.

The record does not report why the study was terminated, nor does it report a statistical analysis plan, PFS results, or randomized analysis populations. It is therefore not possible to infer why the comparison did not proceed or what its results might have been. The absence of an efficacy result is not evidence that the regimens were equivalent, nor evidence that either was superior. It means the registry record does not provide an evaluated answer to the primary comparative question.

These limits are specific to the record's contents. They do not replace interpretation of other research; they define what conclusions can be drawn from this trial record alone.

13. Why This Trial Matters Statistically

This trial is statistically notable because its planned design and its reported evidence are materially different. The registry describes a randomized, double-blind, placebo-controlled Phase 2 comparison with PFS as the primary endpoint, but also states that the randomized part was not conducted. Statistical descriptions of the intended design cannot substitute for outcomes from that comparison.

The distinction matters for readers assessing both efficacy and safety. The recorded enrollment is 16, and the reported safety groups are the pimasertib dose groups from the run-in. They are not randomized pimasertib-versus-placebo groups. Without the planned comparator, the safety counts cannot be read as comparative risk estimates, and there is no randomized PFS estimate to interpret.

In general, trial design features such as randomization and masking support the credibility of comparisons when implemented. Their intended presence in a protocol does not guarantee implementation or produce an estimate on its own. Here, the registry explicitly identifies the Phase 2 arms as planned, not performed. That makes careful separation of protocol intent from reported evidence essential.

The record also illustrates why an endpoint definition is not an outcome result. PFS is defined with a starting point, event criteria, and assessment method, but no PFS analysis is reported. Without an estimate and its uncertainty, readers cannot assess either the magnitude or precision of the planned treatment comparison. The registry's termination status adds context, but the reason is not reported and should not be inferred.

For statistical interpretation, the most informative conclusion is therefore about the limits of available evidence: the intended comparative question remains unanswered in this record. The run-in safety data retain descriptive value, but they cannot be promoted into evidence from the unperformed randomized part.

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 main limitation is that the planned randomized Phase 2 part was not conducted. As a result, the primary endpoint, PFS, was not evaluated. There is no randomized comparison, treatment-effect estimate, confidence interval, or hypothesis test reported for the primary question.

The registry reports only the safety-run-in groups at pimasertib 45 mg and 60 mg with FOLFIRI. These groups do not include the planned placebo-plus-FOLFIRI comparator. The record does not report whether participants were randomized between the run-in doses, so the groups should not be treated as controlled dose comparisons. The group sizes in the safety record are limited to the listed participants at risk; further participant characteristics are not reported in the registry record.

The serious adverse-event term percentages are listed without a reported denominator or term-counting details. Death counts are not reported in the registry record. The statistical methods for the safety outcomes, the analysis populations, missing-data procedures, and multiplicity approach are also not reported. These omissions limit interpretation of both the safety summaries and the intended efficacy question.

The record marks the study as terminated, but the reason for termination is not reported. It also does not explain whether planned procedures changed, why the randomized part did not proceed, or how the termination decision was made. Those explanations should not be inferred from the status alone. The available information supports description of the study plan and run-in safety counts, but not a conclusion about comparative efficacy or why the full planned design was not completed.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: MEK Inhibitor MSC1936369B Plus FOLFIRI in Second Line K-Ras Mutated Metastatic Colorectal Cancer (mCRC) — NCT01085331.
• Registry record last updated 2016-10-19; status last verified 2016-08.
• Results first posted 2016-10-19.
• 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 Phase 1 safety run-in and a planned randomized Phase 2 comparison of pimasertib plus FOLFIRI against placebo plus FOLFIRI as second-line treatment for metastatic K-Ras mutated colorectal cancer. The planned primary endpoint was PFS, defined as time from randomization to documented progression or death from any cause.

The study is listed as terminated, with enrollment of 16, a start of 2010-03, and primary completion of 2012-04. The run-in safety record lists 10 participants at risk in the 45 mg pimasertib group and 6 in the 60 mg group. Both randomized Phase 2 arms are marked planned, not performed. The registry states that PFS was not evaluated. Therefore, the record contains no randomized efficacy comparison, and the reason for termination is not reported in the registry record.