Combination Trial of Pimasertib (MSC1936369B) With Temsirolimus: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Combination Trial of Pimasertib (MSC1936369B) With Temsirolimus (NCT01378377), a non-randomized phase 1 study. The primary outcome is Number of Subjects With Dose Limiting Toxicities (DLTs).

2. Clinical Question

3. Trial Design

This was a Phase I, nonrandomized, unmasked, parallel-group trial of pimasertib combined with temsirolimus in subjects with advanced solid tumors. The registry reports enrollment of 33 subjects. The listed groups received pimasertib 45 mg with temsirolimus 12.5 mg, pimasertib 45 mg with temsirolimus 25 mg, or pimasertib 75 mg with temsirolimus 25 mg. The study's stated purpose was to determine the maximum tolerated dose and recommended Phase 2 dose of the combination.

In a dose-escalation study, the central design task is to evaluate tolerability across planned dose levels and use those observations to guide selection of a dose for later investigation. That is a general description of the design type, not a claim about the exact escalation procedure used in this trial. The escalation rules, cohort-enrollment rules, and any stopping boundaries are not reported in the registry record. The registry also does not report a separate dose-selection analysis or the dose ultimately recommended.

The study began on 2011-05-27, and primary completion is recorded as 2012-02-23. Its status is terminated. The reason for termination is not reported in the registry record, so the status alone does not establish why enrollment or follow-up ended. The record does not specify whether termination followed a safety concern, a business decision, a recruitment issue, or another circumstance.

Because allocation was nonrandomized and there was no masking, the dose groups should be read as descriptive groups in a dose-escalation study, rather than as randomized treatment arms. Their outcomes may be affected by differences in who entered each group, the sequence in which dose levels were studied, and the amount of exposure participants received. The registry record does not provide enough information to determine how those factors were handled in the analysis. It also does not report an inferential comparison between dose 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: 46 screened for eligibility; 13 were excluded (mainly non-fulfillment of inclusion or exclusion criteria). 33 subjects were enrolled and treated in the study.

Overall Study

Analysis population for the primary outcome, as defined in the registry: The dose escalation analysis set included all the subjects who received at least 80% of the planned doses of each treatment (pimasertib and temsirolimus) in the first cycle of treatment or who experienced DLT during the first cycle of treatment regardless of the received amount of drug.

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 the subjects who received at least one administration of trial medication.

6. Primary Endpoint

The registry lists the primary outcome as Number of Subjects With Dose Limiting Toxicities (DLTs), measured over Up to 21 Days (within Cycle 1).

The primary endpoint was the number of subjects with dose-limiting toxicities during Cycle 1, within 21 days. A dose-limiting toxicity, or DLT, was defined using the NCI Common Terminology Criteria for Adverse Events, version 4.0, along with clinical judgment about whether a toxicity was related to the underlying disease or concomitant medications. The definition included toxicities considered serious enough that further escalation could expose subjects to unacceptable risk, specified severe nonhematologic and hematologic toxicities, treatment interruption lasting more than 2 weeks because of adverse events, and certain severe or life-threatening complications attributable to therapy.

The registry definition included exceptions for specified Grade 3 events, such as asymptomatic increases in liver function tests and short-duration diarrhea, nausea, or vomiting, as well as alopecia. It also specified duration criteria for Grade 4 neutropenia and febrile neutropenia. These details matter because a DLT is not simply any adverse event: it is an event meeting prespecified severity, duration, attribution, or clinical-significance criteria.

In general, DLTs are used in early dose-escalation research to characterize tolerability at candidate doses and support decisions about whether escalation should continue. This endpoint is an early safety and dose-selection measure, not a direct measure of clinical benefit. The registry record gives the endpoint definition and analysis-population rule, but does not report the number of subjects who experienced DLTs at each dose level or the dose-selection conclusion.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Interpreting early dose-escalation research requires attention to what was counted, who was included, and whether the design supports comparisons. The registry record identifies a binary primary endpoint: whether a subject experienced a dose-limiting toxicity during the specified first-cycle period. It also describes the dose-escalation analysis population and lists adverse-event outcomes. The record does not report the statistical procedures used to summarize or compare the primary endpoint results.

What does a binary endpoint represent?

A binary endpoint classifies each eligible subject into one of two categories for the outcome being studied, such as whether a DLT occurred or did not occur during the defined period. Counts are useful because they show how many people in a group met the event definition. In general, the count should be interpreted alongside the number of people assessed, the outcome definition, and the time window. A count alone does not convey how uncertain the underlying event rate may be, especially when group sizes are limited.

The registry defines the primary outcome as a number of subjects with DLTs, not as a continuous measure of toxicity severity or a time-to-event measure. It gives a DLT definition based on specified adverse-event criteria and clinical judgment. That definition determines which events qualify for the primary endpoint. A general statistical point is that a narrowly defined endpoint can improve consistency of classification, but interpretation still depends on complete and consistent assessment. The registry does not describe adjudication procedures or how disagreements about attribution were resolved.

Why does the analysis population matter?

The dose-escalation analysis set included subjects who received at least 80% of the planned doses of both study drugs in the first cycle, or who experienced a DLT in that cycle regardless of the amount of drug received. This rule includes people who had a DLT despite receiving less treatment, while requiring a minimum amount of planned treatment for those without a DLT to enter the analysis set. In general, such rules seek to make dose-level safety summaries more interpretable when exposure differs, while preserving the inclusion of early DLTs.

The registry does not report how many participants met this analysis-set definition at each dose, whether any participants were excluded, or how incomplete first-cycle assessments were handled. Enrollment of 33 subjects is not automatically the same as the number analyzed for the primary endpoint. The distinction between enrolled participants and participants in a defined analysis set is important whenever eligibility for analysis depends on treatment exposure or observed events.

What can dose-group counts establish?

Counts by dose group can describe the observed safety experience within the study. In general, they do not by themselves establish that a higher dose caused more events or that one dose is safer than another. Nonrandomized groups can differ in participant characteristics, treatment exposure, timing, or follow-up. Dose-escalation studies also assign dose levels according to a planned sequence rather than by random allocation. The registry explicitly identifies the study as nonrandomized and unmasked, and its record does not describe an adjustment method for these potential sources of difference.

The listed adverse-event counts concern subjects affected by serious adverse events and by other adverse events. These summaries are not interchangeable with the DLT endpoint. A serious adverse event is classified according to seriousness criteria, whereas a DLT follows the study's specified toxicity, duration, attribution, and clinical-significance definition. An event may be serious without meeting the DLT definition, and the available record does not identify which reported events were counted as DLTs.

What does a confidence interval mean?

In general, a confidence interval expresses uncertainty around an estimated quantity, such as an event proportion. It communicates a range of values compatible with the observed data under the method's assumptions. Wider intervals generally indicate less precision, while narrower intervals indicate greater precision. A confidence interval does not eliminate limitations in the design, resolve confounding in nonrandomized groups, or prove that a treatment effect is causal.

The registry record does not report confidence intervals for the primary DLT outcome or for the serious adverse-event summaries. It also does not report p-values or a statistical comparison between dose groups. Consequently, the posted counts can be described, but their inferential precision cannot be characterized from reported interval estimates.

How should planning illustrations be understood?

Sample-size planning illustrations are not trial results. The registry's stated illustration assumptions use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is specified as a fraction of the observed effect. For time-to-event outcomes, the described planning quantity is the total number of events, while other outcomes use participants per arm. These are planning conventions, not evidence that the trial used those assumptions to determine its enrollment.

In general, an illustration based on an observed effect asks how much data might be needed to detect an effect of a specified size under stated assumptions. It does not show the probability that the completed study detected an effect, and it is not observed power. The groups in this study were nonrandomized dose levels, whereas the planning description assumes equal allocation between two arms. Those assumptions should not be mistaken for the actual study design or for a causal comparison. Numerical sample-size outputs and a trial-specific sample-size justification are not reported in the registry record.

Why does over-dispersion matter?

Over-dispersion is a general issue for count data when observed variability exceeds what a simple statistical model assumes. It can lead to uncertainty estimates that are too small if the model does not account for the extra variability. The primary endpoint is reported as a count of subjects with an event, rather than as a recurrent-event total. The registry record does not report a model for the endpoint or whether over-dispersion was assessed. This concept is therefore relevant as general statistical context, not as a claim that over-dispersion affected this trial.

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("Pimasertib 45 mg+Temsirolimus 12.5 mg", "Pimasertib 45 mg+Temsirolimus 25 mg", "Pimasertib 75 mg+Temsirolimus 25 mg")
n      <- c(3, 17, 6)
events <- c(0, 7, 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  Pimasertib 45 mg+Temsirolimus 12.5 mg  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Pimasertib 45 mg+Temsirolimus 25 mg  17  7  41.2  18.4  67.1  21.6  64.0  21.5  64.3
ARM  Pimasertib 75 mg+Temsirolimus 25 mg  6  2  33.3  4.3  77.7  9.7  70.0  9.9  71.0

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 16 outcome measures and reports 0 analyses. The primary outcome is the number of subjects with DLTs during the first treatment cycle. Secondary outcomes include the number of subjects with treatment-emergent adverse events and pharmacokinetic measures for pimasertib and temsirolimus, including maximum plasma concentration, time to maximum concentration, and area under the concentration-time curve. The record does not report numerical results for these outcomes beyond the adverse-event summaries described in the safety information.

When a study evaluates multiple outcomes, testing each one can increase the chance of finding an apparently notable result by chance. In general, multiplicity procedures may control that risk, or the outcomes may be treated as descriptive. The registry does not report a multiplicity adjustment, a prespecified hierarchy for inferential testing, or a statistical analysis plan explaining how multiple outcomes were handled. It is not possible to determine from the posted record whether any multiplicity procedure was planned or used.

The primary endpoint analysis population is defined by first-cycle treatment exposure or occurrence of a DLT. The record does not report the number analyzed under that definition for each group, participant-level missingness, reasons for missing data, or any imputation method. Handling of incomplete treatment cycles, incomplete adverse-event reporting, and missing pharmacokinetic measurements is not reported in the registry record. These details matter because incomplete observation can affect both the number of people eligible for analysis and the interpretation of event counts.

The record does not report a per-protocol or intention-to-treat analysis for the primary endpoint, nor does it describe sensitivity analyses. The enrolled total and the group safety counts should not be treated as proof that all enrolled subjects contributed complete primary endpoint data. The amount of missing outcome data and its effect on the conclusions cannot be assessed from the registry information.

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: stomatitis (33.3%), back pain (33.3%), nausea (25.0%), vomiting (25.0%), abdominal pain lower (25.0%).

The serious adverse-event summaries report the number of subjects affected and the number at risk in each dose group. For pimasertib 45 mg plus temsirolimus 12.5 mg, the registry reports 3 of 4 subjects affected by serious adverse events. For pimasertib 45 mg plus temsirolimus 25 mg, it reports 17 of 23. For pimasertib 75 mg plus temsirolimus 25 mg, it reports 5 of 6. The corresponding counts for subjects affected by other adverse events are 4 of 4, 23 of 23, and 6 of 6.

These are descriptive counts, not randomized comparisons. The groups were not assigned by randomization, and their sizes differ. The counts do not establish that a dose caused more or fewer serious events, and they do not quantify the uncertainty around the observed results. The registry record does not report confidence intervals for these figures.

The most frequently listed serious adverse-event terms include stomatitis and back pain at 33.3% each, followed by nausea, vomiting, abdominal pain lower, and diarrhoea at 25.0% each. Event terms are not necessarily mutually exclusive: one subject may experience more than one type of event. These term-level percentages should not be added together or treated as the proportion with any serious adverse event. The registry does not report the individual-level overlap between terms. Serious adverse events are also distinct from the primary DLT endpoint, whose numerical results are not reported.

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

The record establishes the study's purpose and design: a nonrandomized Phase I dose-escalation trial of pimasertib combined with temsirolimus in advanced solid tumors, intended to inform the maximum tolerated dose and recommended Phase 2 dose. It also defines the primary DLT endpoint and the analysis population. These details explain what the trial set out to measure, but they do not reveal the observed DLT counts or the final dose-selection outcome.

The posted safety information shows that serious adverse events were reported in each of the listed groups, and that subjects in each group were also reported as affected by other adverse events. The event-term percentages identify the serious adverse-event terms most frequently listed in the registry summary. These summaries provide a description of reported safety observations, not a complete account of each participant's experience or an estimate of comparative risk.

The findings do not establish that the drug combination is effective, ineffective, safe, or unsafe. The registry record does not provide numerical results for the primary endpoint, efficacy outcomes, or the pharmacokinetic outcomes listed. The record also does not report a randomized comparator, so the study cannot support a randomized treatment-effect comparison between dose groups. Nor does the available information establish the reason the trial was terminated.

In general, a dose-escalation study provides early evidence to guide further research rather than a definitive estimate of clinical benefit. Even when dose-limiting toxicity counts are available, conclusions depend on the endpoint definition, number of participants assessed, extent of follow-up, and uncertainty around the estimates. In this case, the absence of reported primary endpoint results prevents an assessment of how the observed DLT experience informed dose selection. The registry status and safety summaries should therefore be read separately from conclusions about a recommended dose or later-phase performance.

14. Why This Trial Matters Statistically

This trial illustrates why the distinction between a study question and a reported result matters. Its stated aim was to identify the maximum tolerated dose and recommended Phase 2 dose of a drug combination. The registry describes a primary endpoint designed for that purpose: the number of subjects with DLTs during Cycle 1, within 21 days. Yet the numerical results for that endpoint are not reported in the registry record. A carefully specified endpoint cannot answer the dose-selection question for readers unless the observed data and analysis are also available.

The study also highlights the limits of interpreting nonrandomized dose groups. Dose-level summaries can be useful in early development, but they are not automatically comparative evidence. Participant characteristics, treatment exposure, and sequence of enrollment may differ across groups. The registry identifies nonrandomized allocation and does not report an inferential comparison or adjustment strategy. Statistical interpretation must therefore remain descriptive.

There is also a useful distinction between serious adverse events and DLTs. Serious-event summaries contribute safety information, while the DLT definition applies additional criteria related to severity, duration, attribution, and clinical significance. Treating those outcomes as interchangeable would change the question being answered. The registry's event-term percentages add detail, but do not replace DLT counts or disclose how specific events were classified for dose escalation.

Finally, the record demonstrates the importance of reporting analysis populations, missing data, and uncertainty. It defines an analysis-set rule, but does not report the number included in that set, missingness, confidence intervals, or the primary endpoint results. Without those details, the precision and completeness of the dose-level evidence cannot be evaluated. These reporting gaps constrain interpretation independently of the trial's enrollment and stated aims.

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 principal limitation for interpreting the study is that numerical results for the primary DLT endpoint are not reported in the registry record. The endpoint definition and analysis-population rule are available, but the number of subjects with DLTs at each dose level and the dose-selection conclusion are not. The record therefore does not permit an assessment of the central dose-escalation outcome.

The study was nonrandomized and unmasked. Its dose groups are not randomized controls, and differences between their safety counts cannot be interpreted as causal effects of changing dose. The registry does not report a method for adjusting group comparisons or an inferential analysis. The listed group sizes are 4, 23, and 6 subjects at risk for serious adverse events; the record does not provide uncertainty intervals for these summaries.

Although enrollment is reported as 33, the registry does not state how many subjects met the primary endpoint analysis-set definition in each group. That definition depends on first-cycle drug exposure or experiencing a DLT. Missing outcomes, incomplete exposure, reasons for exclusion, and missing-data handling are not reported. The extent to which the posted safety counts reflect complete observation cannot be assessed from the record.

The trial is marked terminated, but the reason is not reported in the registry record. No explanation should be inferred from that status. The record also does not report the statistical analysis plan, multiplicity approach, confidence intervals, p-values, escalation rules, or the trial's sample-size justification. The planning assumptions described for sample-size illustrations are not evidence of the study's actual design calculations. Together, these limitations mean the available record supports a description of the design and selected safety summaries, but not a full evaluation of the primary dose-selection findings.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Combination Trial of Pimasertib (MSC1936369B) With Temsirolimus — NCT01378377.
• Registry record last updated 2018-07-30; status last verified 2017-10.
• Results first posted 2018-07-30.
• 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

NCT01378377 is a Phase I, nonrandomized, unmasked, parallel-group trial of pimasertib with temsirolimus in advanced solid tumors. The registry reports enrollment of 33 subjects and lists three dose combinations: pimasertib 45 mg with temsirolimus 12.5 mg, pimasertib 45 mg with temsirolimus 25 mg, and pimasertib 75 mg with temsirolimus 25 mg. The stated purpose was to determine the maximum tolerated dose and recommended Phase 2 dose.

The primary endpoint was the number of subjects with DLTs in Cycle 1, within 21 days. The record defines the endpoint and analysis population, but does not report numerical primary endpoint results or a dose-selection conclusion. It provides serious and other adverse-event counts by group and selected serious-event terms. The trial status is terminated; the reason is not reported in the registry record.