Study of MK-8353 + Selumetinib in Advanced/Metastatic Solid Tumors (MK-8353-014): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of MK-8353 + Selumetinib in Advanced/Metastatic Solid Tumors (MK-8353-014) (NCT03745989), a na phase 1 study. The primary outcome is Number of Participants Experiencing Dose Limiting Toxicities.

2. Clinical Question

3. Trial Design

The registry identifies this as a Phase 1 study, and its official title describes it as Phase 1b. It was multicenter, worldwide, open-label, and used a sequential model. The study is marked completed. The record lists enrollment as 30, with a start date of 2019-02-22 and primary completion on 2021-03-19. Those registry figures describe the study record; they do not establish how many participants were evaluable for the primary endpoint or included in any particular analysis.

The intervention was a combination of MK-8353 and selumetinib. The regimen description specifies 4 days on followed by 3 days off, continuing until disease progression or discontinuation. Dose escalation was sequential and was to be based on pharmacokinetic and safety data. The listed safety groups pair MK-8353 50 mg with selumetinib 25 mg; MK-8353 100 mg with selumetinib 50 mg; and MK-8353 150 mg with selumetinib 75 mg. The arm description gives escalation ranges of 50 mg to 250 mg for MK-8353 and 25 mg to 75 mg for selumetinib. The registry record does not say that every dose in those ranges was administered.

Because the allocation is recorded as not applicable and the study was not randomized, the dose groups are not parallel randomized arms. They are sequential dose levels, and participant characteristics, exposure, or observation time could differ across them. The record does not report a control group, masking, or a comparative efficacy analysis. Its stated objectives were safety, tolerability, and exploratory efficacy. Pharmacokinetic outcomes were also listed, including measures of exposure and plasma concentration for both study drugs.

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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The analysis population included all participants who received at least 1 dose of study treatment who met the criteria for DLT evaluability (finished Cycle 1 without a DLT or experienced a DLT in Cycle 1).

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 Number of Participants Experiencing Dose Limiting Toxicities, measured over Cycle 1 (3-week Cycle) (Up to 3 weeks).

The primary endpoint is the number of participants experiencing dose-limiting toxicities during Cycle 1, described as a 3-week cycle. A dose-limiting toxicity was defined as a hematologic or non-hematologic toxicity of Grade 3 or higher according to NCI CTCAE v4.0. It counted only if the investigator assessed the toxicity as possibly, probably, or definitely related to study treatment administration. Thus, the endpoint is a count of participants meeting the protocol’s toxicity definition, not a general count of all adverse events or all symptoms.

In general, early-phase dose-escalation studies use dose-limiting toxicity information to characterize tolerability during a specified early treatment period and to inform decisions about dose levels. That rationale is general; the registry record does not report a dose-selection rule, a target toxicity rate, or the statistical procedure used to make escalation decisions. Nor does it report the primary endpoint count for any dose group.

The stated endpoint population included participants who received at least one dose and met the criteria for dose-limiting-toxicity evaluability. That definition included people who finished Cycle 1 without a dose-limiting toxicity and people who experienced one during Cycle 1. It does not indicate how participants who stopped early for another reason were treated for analysis; that detail is not reported in the registry record. As the result itself is absent, the endpoint definition can be interpreted, but the observed frequency cannot.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The record’s design and outcome definition determine what can be interpreted statistically. The study was open-label and sequential, with dose levels escalated in sequence. That structure is different from a randomized parallel-group trial: dose groups were not assigned concurrently by random allocation, and there is no like-for-like control group. Comparisons across these groups are therefore descriptive. They can show what was recorded at each listed dose level, but they cannot by themselves estimate what would have happened to the same participants under another dose or a control treatment.

What does the primary endpoint count?

The primary endpoint is a participant count. Each participant in the defined evaluable population would be classified according to whether a qualifying dose-limiting toxicity occurred during Cycle 1. The definition combines clinical grading and investigator assessment of treatment relationship: toxicity had to be Grade 3 or higher under NCI CTCAE v4.0 and assessed as possibly, probably, or definitely related to study treatment. This is a protocol-defined binary outcome at the participant level. It is not a measure of the total number of toxicity episodes, their duration, or their severity beyond the qualifying threshold.

In general, a count of participants with an event is often presented alongside the number assessed, because the denominator clarifies the population represented. For this endpoint, the record describes an evaluability rule but does not report the actual primary count or denominator by dose group. The serious and other adverse-event counts elsewhere in the record should not be substituted: those fields describe different safety summaries and do not provide the specified Cycle 1 endpoint result.

How should dose escalation affect interpretation?

Sequential escalation means that later dose groups are entered after earlier dose levels, with escalation based on pharmacokinetic and safety data according to the arm description. In general, this design is used to collect safety and exposure information across dose levels. It does not create randomized groups. Participants at different levels may have entered at different times or had different characteristics, but those details are not reported in the registry record. Consequently, a simple contrast between observed counts at two levels would mix dose differences with any other group differences and with variation from small group sizes. The record does not report a model that adjusts for such differences.

The registry lists pharmacokinetic outcomes including area under the plasma concentration-time curve and minimum and maximum observed plasma concentration for MK-8353 and selumetinib. These outcomes concern drug exposure or concentration, rather than clinical benefit. Their presence does not establish that a particular exposure was reached or associated with toxicity; the relevant results and analyses are not reported in the registry record.

What do the planning assumptions mean?

The planning illustration is described as using an effect based on the observed effect, with the target effect set to a stated fraction of that observed effect. Its stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. In general, a sample-size calculation estimates how many participants would be needed under specified assumptions to detect a defined effect at a chosen error rate and power. Such an illustration is a planning exercise, not evidence that the study had that power, and not an observed-power calculation. It also does not establish that this trial used those assumptions in its own design.

The registry record does not report the sample-size justification or the trial’s statistical design assumptions. It does not provide an observed primary endpoint effect in the registry record for interpretation, so the assumed effect and the resulting planning estimates cannot be independently assessed. The stated illustration’s equal-allocation assumption is also unlike the sequential dose-escalation structure described for this study. Any sample-size numbers generated under those assumptions should therefore be understood as hypothetical planning quantities, not as a reconstruction of the trial’s design or evidence about its findings.

Why do uncertainty and event counts matter?

In general, a confidence interval expresses uncertainty around an estimate: wider intervals indicate less precision, while narrower intervals indicate greater precision, conditional on the method and assumptions used. A count without an interval gives no direct account of that uncertainty. The registry record does not report a confidence interval for the primary endpoint, and no primary estimate is available to interpret. Small event counts can be particularly imprecise, but no additional precision measure should be inferred from the adverse-event counts alone.

In general, statistical tests and models also depend on the design, outcome definition, and analysis population. A test comparing randomized groups can support a different interpretation from a descriptive comparison of sequential dose levels. No test result or model-based primary endpoint analysis is reported in the registry record. The record also does not report an interim analysis plan, a dose-escalation algorithm, or a statistical analysis plan. Without those details and the primary result, the appropriate interpretation is limited to the stated design, endpoint definition, and descriptive safety entries.

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("MK-8353 50 mg + Selumetinib 25 mg", "MK-8353 100 mg + Selumetinib 50 mg", "MK-8353 150 mg + Selumetinib 75 mg")
n      <- c(3, 11, 14)
events <- c(0, 1, 7)
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  MK-8353 50 mg + Selumetinib 25 mg  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  MK-8353 100 mg + Selumetinib 50 mg  11  1  9.1  0.2  41.3  1.6  37.7  2.1  38.5
ARM  MK-8353 150 mg + Selumetinib 75 mg  14  7  50.0  23.0  77.0  26.8  73.2  26.6  73.4

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 9 outcome measures, including the primary dose-limiting-toxicity endpoint and secondary pharmacokinetic measures for MK-8353 and selumetinib. It does not report any analyses. No multiplicity adjustment, hierarchy for testing outcomes, or strategy for distinguishing confirmatory from exploratory analyses is reported in the registry record. The brief study description characterizes efficacy as exploratory, but it does not specify how multiple outcomes or dose levels were to be interpreted statistically.

In general, when a study evaluates multiple outcomes, doses, or comparisons, the chance of at least one apparently unusual result can increase if each is assessed separately. A prespecified testing strategy can clarify which results are primary and how uncertainty should be interpreted across several tests. That is general statistical context, not a description of the plan used in this study. The record does not report such a plan, so no claim can be made about control of multiplicity.

The record defines an analysis population for the primary endpoint: participants who received at least one dose and were evaluable for dose-limiting toxicity, either by finishing Cycle 1 without one or experiencing one during that cycle. It does not report how many participants met this definition, how missing or incomplete Cycle 1 assessments were handled, or whether participants who discontinued for reasons other than a dose-limiting toxicity were included or excluded. These details are not reported in the registry record.

Without a reported primary endpoint result, analysis population count, missing-data approach, or statistical plan, the primary outcome cannot be independently assessed for completeness or precision. The safety counts do not resolve these gaps, because their event definitions and analysis denominators are not established as identical to those for the primary endpoint.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: vomiting (13.3%), pneumonia (13.3%), anaemia (8.3%), ascites (8.3%), pneumonia aspiration (8.3%).

The safety entries are grouped by the listed dose combinations. For MK-8353 50 mg plus selumetinib 25 mg, the record lists serious adverse events in 0 of 3 participants at risk and other adverse events in 3 of 3. For MK-8353 100 mg plus selumetinib 50 mg, it lists serious events in 3 of 12 and other events in 11 of 12. For MK-8353 150 mg plus selumetinib 75 mg, it lists serious events in 4 of 15 and other events in 15 of 15. The registry separately lists deaths as 3, 8, and 6 across these dose groups, respectively.

These are descriptive safety counts, not randomized comparisons and not the primary dose-limiting-toxicity endpoint. The record’s primary definition is limited to qualifying toxicities in Cycle 1 with a specified severity and investigator-assessed relationship to treatment. The serious and other adverse-event fields do not establish that same definition or time window. Therefore, the counts should not be treated as counts of primary endpoint events.

The listed serious-event terms include vomiting and pneumonia at 13.3% each; anaemia, ascites, and pneumonia aspiration at 8.3% each; and diarrhoea at 6.7%. These registry percentages are descriptive. The record does not establish from these entries the relevant denominator, comparative risk, or causal relationship to study treatment. They should be read as reported safety summaries rather than evidence that the combination caused any particular event.

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

The record establishes that a Phase 1, open-label, sequential dose-escalation study of MK-8353 with selumetinib was conducted in participants with advanced or metastatic solid tumors. It specifies the planned treatment schedule, lists dose combinations in the safety groups, and defines the primary endpoint as the number of evaluable participants experiencing a dose-limiting toxicity during Cycle 1. Those details explain the study question and the intended interpretation of its main safety measure.

The record does not report the primary endpoint result. It therefore does not show how many participants met the dose-limiting-toxicity definition, how that count differed across dose levels, or how precisely any such estimate was known. The absence of that result also means the primary safety question cannot be answered from the registry record alone. The safety fields give other event counts and serious-event term percentages, but they are not substitutes for the endpoint result.

The listed dose groups are sequential, not randomized comparator arms. Their event counts do not isolate the effect of dose and should not be interpreted as evidence that one dose is safer or more harmful than another. Likewise, the registry’s descriptive adverse-event terms do not establish causality. The record does not report an efficacy result that would support a conclusion about tumor response or clinical benefit.

In general, early-phase dose-escalation studies can contribute information about safety, tolerability, and drug exposure at studied dose levels. That general role should not be mistaken for proof of efficacy or a controlled estimate of treatment effects. For this record, the available details establish the design and definitions, while the missing primary result and absence of reported analyses limit further interpretation. No conclusion about whether the treatment works or does not work follows from the information reported.

14. Why This Trial Matters Statistically

This study illustrates why the distinction between a trial’s design and its results matters. Its primary endpoint is clearly defined around qualifying toxicities in Cycle 1, but the registry record does not report the corresponding participant count. Knowing the definition alone does not reveal the observed frequency, and the separate adverse-event summaries cannot fill that gap because they refer to different safety fields.

The sequential dose-escalation structure also affects the kinds of comparisons that can be made. The listed dose groups are not randomized arms, so their counts are descriptive rather than controlled estimates of dose effects. This is a basic interpretive distinction for early-phase research: the information collected across dose levels can characterize observed safety and pharmacokinetic measures, but it does not automatically establish a causal contrast between levels.

The record also makes the difference between a planning calculation and a trial’s actual design important. Its sample-size assumptions describe an illustrative calculation based on an observed effect, equal allocation between two arms, a normal approximation, and a two-sided significance level of 0.05. Those assumptions do not match the sequential design as described and are not evidence of observed power or of the original design rationale. The registry does not report the sample-size justification or a statistical analysis plan.

For clinical researchers, these features underscore the need to read endpoint definitions, analysis populations, and reported estimates together. A toxicity definition tells readers what should count; an analysis population defines who contributes; and an estimate with uncertainty indicates what the observed data support. Here, key primary results and analysis details are not reported in the registry record, so statistical interpretation must remain correspondingly limited.

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 most consequential limitation for interpreting the primary question is that the registry record does not report the primary dose-limiting-toxicity result. It also does not report a primary estimate, confidence interval, or analysis by dose group. Although the outcome definition and evaluability criteria are given, the number of participants meeting those criteria is not reported in this material, nor is the number experiencing the defined event.

The design further limits comparisons. The study is open-label and sequential, with allocation listed as not applicable. Its dose groups are not randomized controls, and any differences in observed safety counts across them cannot be attributed to dose alone. The registry does not report participant characteristics by dose group, duration of exposure, or an adjusted comparative analysis. It also does not state whether every dose in the described escalation ranges was administered.

The safety entries do not remove these limitations. They are not identified as the primary Cycle 1 endpoint, and the registry does not report enough detail in this material to establish that the event definitions, follow-up windows, or analysis populations match the primary endpoint. The percentages attached to serious-event terms are reported, but the relevant denominator and causal interpretation are not established in the record.

Finally, the registry record does not report a statistical analysis plan, multiplicity strategy, interim analysis details, sample-size justification, or missing-data handling. These omissions limit assessment of how outcomes were selected, how uncertainty was managed, and how incomplete observations might affect the reported safety information. The completed status does not itself establish that all intended results are present in the registry.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study of MK-8353 + Selumetinib in Advanced/Metastatic Solid Tumors (MK-8353-014) — NCT03745989.
• Registry record last updated 2023-07-27; status last verified 2023-07.
• Results first posted 2023-01-25.
• 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

The registry record describes a completed, open-label, sequential Phase 1 study of MK-8353 combined with selumetinib in advanced or metastatic solid tumors. Its official title describes the study as Phase 1b. The regimen description specifies 4 days on and 3 days off, and the listed safety groups include three dose combinations. The primary endpoint is the number of evaluable participants with a qualifying dose-limiting toxicity during Cycle 1, defined as a 3-week cycle.

The record lists enrollment as 30 and includes pharmacokinetic secondary outcomes. It reports safety counts by dose group and percentages for selected serious adverse event terms. However, it does not report the primary endpoint result or any analyses. The sequential, nonrandomized design also means the dose groups are not like-for-like control arms. The registry record therefore supports an account of the design, endpoint definition, and descriptive safety entries, but not an estimate of the primary endpoint frequency or a controlled treatment comparison.