A Phase I Study of MK-2206 in Combination With Standard Chemotherapy in Participants With Locally Advanced or Metastatic Solid Tumors (MK-2206-003): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Phase I Study of MK-2206 in Combination With Standard Chemotherapy in Participants With Locally Advanced or Metastatic Solid Tumors (MK-2206-003) (NCT00848718), a non-randomized phase 1 study. The primary outcome is Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) During Cycle 1.

2. Clinical Question

In statistical terms, this is an early-phase investigation of safety and dose selection across different treatment combinations, rather than a randomized test of comparative efficacy. The key endpoint focuses on toxicities judged drug related by the investigator and meeting specified severity, duration, treatment-delay, or dose-modification criteria. The posted information also lists a secondary outcome concerning complete or partial tumor response, but does not report its results.

3. Trial Design

This was a Phase I, non-randomized, unmasked, parallel study. The registry record lists enrollment of 77 participants and a completed study status. The recorded study start was 2009-03-17, and primary completion was 2011-05-19. The stated study purpose was to compare the safety and tolerability of several MK-2206 dose levels when combined with chemotherapy or targeted therapy in participants with locally advanced or metastatic solid tumors.

The treatment combinations were MK-2206 with carboplatin plus paclitaxel, MK-2206 with docetaxel, and MK-2206 with erlotinib. The docetaxel combination included corticosteroid pretreatment. The posted safety information lists distinct dose groups within these combinations, including different MK-2206 schedules and partner-agent doses. Because allocation was non-randomized, participants were not assigned by chance to a common set of comparable treatment arms. Differences between groups may reflect their different dose combinations or other factors; the registry record does not support treating these groups as randomized controls.

The study description identifies dose escalation as part of the investigation and states an objective of defining a maximum tolerated dose for each of the three combinations. The detailed escalation rules, cohort decision procedure, and specific dose-selection algorithm are not reported in the registry record. The record also does not report whether interim analyses were planned or performed, or provide a full statistical analysis plan.

The primary endpoint was a count of participants with a qualifying dose-limiting toxicity during Cycle 1, up to 21 days. The endpoint population is described as participants who received one dose of study treatment. Although the registry record gives total enrollment, it does not report the number assessed for this endpoint or the observed count of participants with a dose-limiting toxicity. Those omissions prevent a direct assessment of the primary safety result from the information posted.

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.

Only the first 6 of 13 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All participants that have received one dose of study treatment

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: All participants who were allocated to receive treatment.

Only the first 6 of 14 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) During Cycle 1, measured over Cycle 1 (Up to 21 days).

The primary endpoint counts participants who experienced a dose-limiting toxicity during Cycle 1, with the timeframe specified as up to 21 days. A dose-limiting toxicity was defined through clinical criteria: the event had to be considered related to study drug by the investigator and meet the listed severity, duration, treatment-delay, or dose-change conditions. The definition uses National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. It includes specified severe blood-related and non-blood-related toxicities, certain infections, unresolved toxicity causing a treatment delay, persistent QTc increases, clinically significant bradycardia, and missed MK-2206 doses due to toxicity, with stated exceptions.

In general, an early-cycle dose-limiting toxicity endpoint is used in dose-escalation research to identify combinations and doses whose short-term toxicity may constrain further treatment. Counting participants with at least one qualifying event gives a participant-level summary, rather than a count of every occurrence. The stated study hypotheses included a dose-limiting toxicity rate of at most 30% and defining a maximum tolerated dose for each combination. These are objectives or hypotheses, not evidence that a particular rate or dose was achieved.

The registry record gives the endpoint definition and population but does not report the primary endpoint count or the corresponding denominator. It therefore does not show the observed dose-limiting toxicity rate, its precision, or how the result informed dose selection. The record also does not report a confidence interval or a statistical test for this endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical methods help distinguish what a study was designed to describe from what its results can establish. In this study, the design was non-randomized and the primary endpoint was a count of participants with a qualifying event. The registry record does not report a detailed analysis plan, confidence intervals, hypothesis tests, or analyses comparing the dose groups. The explanations below describe general statistical principles and how they relate to the information posted, without implying that an unreported method was used.

What does a participant count represent?

For a binary outcome such as whether a participant experienced a dose-limiting toxicity, each participant is classified as having or not having the event within the stated assessment period. A count reports how many participants had the event. To interpret that count as a rate, the denominator—the number of participants assessed—must also be available. Rates can make groups of different sizes easier to describe, but do not remove differences in treatment, selection, or follow-up. Here, the primary endpoint definition and intended population are stated, while the observed count and denominator are not reported in the registry record.

A confidence interval, in general, gives a range of values compatible with the observed data under a specified statistical method. It communicates uncertainty around an estimate; it is not a guarantee that the underlying value lies in the interval. No confidence interval for the primary endpoint or the posted adverse-event counts is reported in the registry record. Without the endpoint result and its denominator, its precision cannot be assessed from this information.

Why does non-randomized allocation matter?

Random allocation is a way to reduce systematic differences between treatment groups, on average. In a non-randomized study, group membership may be related to dose decisions, clinical circumstances, or other factors. The registry record does not provide enough information to describe the role of such factors in this study. Consequently, simple differences between the listed groups would not isolate the effect of a dose or combination. This is especially important because the groups involve different partner treatments, dose levels, and schedules. The record itself cautions that the arms are not a like-for-like control comparison.

In general, adjusting for measured characteristics can sometimes address certain imbalances, but only when the relevant data and an appropriate analysis are available. The registry record reports no posted analysis records, and does not describe an adjusted comparison. No causal or comparative conclusion should be inferred from the group counts alone.

How should dose-limiting toxicity be understood?

The primary endpoint is a prespecified clinical classification, not simply any adverse event. The definition requires investigator attribution to study drug and includes specific grades, durations, complications, treatment delays, and dose changes. Such criteria make the endpoint more relevant to early dose selection than a count of all symptoms or events. At the same time, an endpoint based on clinical judgment and listed thresholds depends on consistent assessment and recording. The registry record specifies the criteria but does not report information about adjudication, consistency checks, or how missing assessments were handled.

The study’s stated dose-limiting toxicity threshold and maximum-tolerated-dose objective describe what the investigators sought to evaluate. They do not substitute for the observed endpoint counts or a reported decision rule. The detailed escalation procedure and the analysis used to select a dose are not reported in the registry record, so the dose-selection process cannot be reconstructed from the posted description.

What do planning illustrations mean?

In general, sample-size calculations are planning tools: they describe the sample size associated with assumptions about an effect, allocation, significance level, and statistical method. They are not observed results and should not be described as observed power. The planning assumptions associated with the sample-size material specify a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and effects expressed as fractions of an observed effect. The material states that non-time-to-event planning quantities are participants per arm and that time-to-event quantities are total events.

Those assumptions do not describe the trial’s design. The study was non-randomized and comprised different dose groups and combinations, rather than a simple equal-allocation comparison between two like-for-like arms. The planning illustration is not a retrospective demonstration that the study had adequate power. The primary endpoint count and its denominator are not reported in the registry record, so the posted information does not permit the reader to evaluate how an assumed effect relates to the primary safety result.

More broadly, statistical interpretation depends on having a clearly defined endpoint, an analysis population, observed results, and an account of uncertainty. The registry record supplies the endpoint definition and the intended primary population, and it posts descriptive adverse-event counts. It does not report the primary result, inferential analyses, missing-data procedures, or the details needed to reproduce a dose-selection analysis. Statistical explanations should therefore remain descriptive and avoid claims that go beyond those the registry 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-2206 45 mg QOD+Carboplatin+Paclitaxel", "MK-2206 60 mg QOD+Carboplatin+Paclitaxel", "MK-2206 90 mg Q3W+Carboplatin+Paclitaxel", "MK-2206 135 mg Q3W+Carboplatin+Paclitaxel", "MK-2206 200 mg Q3W+Carboplatin+Paclitaxel", "MK-2206 45 mg QOD+Docetaxel 75 mg/m^2")
n      <- c(6, 9, 5, 5, 6, 5)
events <- c(1, 2, 1, 1, 2, 3)
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-2206 45 mg QOD+Carboplatin+Paclitaxel  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  MK-2206 60 mg QOD+Carboplatin+Paclitaxel  9  2  22.2  2.8  60.0  6.3  54.7  6.7  55.6
ARM  MK-2206 90 mg Q3W+Carboplatin+Paclitaxel  5  1  20.0  0.5  71.6  3.6  62.4  4.3  64.1
ARM  MK-2206 135 mg Q3W+Carboplatin+Paclitaxel  5  1  20.0  0.5  71.6  3.6  62.4  4.3  64.1
ARM  MK-2206 200 mg Q3W+Carboplatin+Paclitaxel  6  2  33.3  4.3  77.7  9.7  70.0  9.9  71.0
ARM  MK-2206 45 mg QOD+Docetaxel 75 mg/m^2  5  3  60.0  14.7  94.7  23.1  88.2  22.3  88.2

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists a primary dose-limiting toxicity endpoint and a secondary outcome counting participants with complete or partial tumor response. It also describes several treatment combinations and dose groups. When a study examines multiple endpoints, doses, or groups, multiplicity can arise: repeated statistical testing may increase the chance of a chance finding if results are interpreted as confirmatory. In general, a statistical analysis plan may explain which outcomes are primary, how comparisons are prioritized, and whether adjustments are used. Any multiplicity strategy is not reported in the registry record.

The record reports no posted analyses, hypothesis-test results, or confidence intervals. It therefore does not show whether any formal multiplicity adjustment was used or whether the outcomes were treated as descriptive. The study’s stated hypotheses include tolerability, a dose-limiting toxicity rate of at most 30%, plasma exposure and pharmacodynamics exceeding target thresholds, and defining a maximum tolerated dose. The result for each of these aims is not reported in the registry record.

Missing-data handling is also not reported in the registry record. The primary endpoint population is described as all participants who received one dose of study treatment, but the number assessed and the handling of participants without a complete Cycle 1 assessment are not stated. No imputation method, missingness assumption, or sensitivity analysis is described. The record also does not clarify whether the stated population was the population used for any analysis.

These gaps matter because a participant count is interpretable only in relation to who was assessed and how incomplete assessments were treated. The intended endpoint population is identifiable, but the actual analysis population and procedures for missing data cannot be established from the posted information. No conclusion about the impact of missing observations or multiplicity can be drawn.

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: febrile neutropenia (60.0%), pleural effusion (40.0%), retinal vein occlusion (33.3%), diarrhoea (33.3%), stomatitis (33.3%).

The registry record reports serious adverse events, other adverse events, and deaths by listed dose group. For each group, it gives the number of participants at risk and the number affected. These are descriptive participant counts, not randomized estimates of comparative safety. Group sizes and treatment combinations vary, so counts should be read in the context of each group rather than compared as if the participants had been randomly assigned to otherwise identical arms.

The serious-event counts range from one to eight affected participants across the listed groups, with group-specific denominators shown in the posted results. The other-adverse-event counts are also given by group. These counts do not tell how many total event episodes occurred, how long participants were followed, or how event risks compare under a common design. The record lists deaths in some groups, with one death in each such group, and zero in the other listed groups. The information posted does not establish the cause of those deaths.

The serious-event terms include febrile neutropenia at 60.0%, pleural effusion at 40.0%, and retinal vein occlusion, diarrhoea, stomatitis, and pyrexia at 33.3% each. The denominator and details underlying these term percentages are not reported in the registry record. Participants may also experience more than one event type in general, so term percentages should not be added or treated as mutually exclusive. A serious event is not automatically a dose-limiting toxicity; the primary endpoint applies its own criteria, including investigator attribution and Cycle 1 timing.

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

The posted information establishes that this completed Phase I study evaluated MK-2206 in combination with carboplatin plus paclitaxel, docetaxel, or erlotinib in participants with locally advanced or metastatic solid tumors. It identifies a Cycle 1 dose-limiting toxicity endpoint and states the study’s dose-selection and tolerability aims. It also provides descriptive adverse-event counts for the listed dose groups.

It does not establish whether the primary dose-limiting toxicity hypothesis was met. The registry record does not report the number of participants with a dose-limiting toxicity, the corresponding denominator, an estimated rate, or an uncertainty interval. It also does not report the plasma exposure, pharmacodynamic, or maximum-tolerated-dose results described among the study hypotheses. Tumor response is listed as a secondary outcome, but response results are not reported in the registry record.

The safety counts do not show that one dose or combination is safer than another. Allocation was non-randomized, groups differed in treatment and dose, and the record does not report a comparative analysis. The event counts and term percentages are useful as descriptions of what was recorded, but they do not by themselves establish that study treatment caused an event or that a treatment had a favorable or unfavorable overall effect.

In general, evidence about treatment effects requires suitable comparisons, clearly reported outcomes, and an assessment of uncertainty. This record is informative about the study question, design, endpoint definition, and posted safety summaries, but the absent primary results limit interpretation. It cannot support a conclusion about efficacy, comparative safety, or whether the study’s stated targets were achieved.

14. Why This Trial Matters Statistically

This trial illustrates a central statistical distinction in early-phase research: the aim is to characterize tolerability and support dose selection, not to provide a randomized estimate of comparative treatment benefit. The primary endpoint is framed around qualifying dose-limiting toxicities during Cycle 1, a clinically defined event that can inform whether a combination and dose warrant further study. The record makes the endpoint criteria and intended population explicit, which are important foundations for interpreting a safety outcome.

The design also shows why dose-group summaries need careful interpretation. A non-randomized parallel study may include several treatment combinations and dose schedules, but those groups do not automatically constitute valid controls for one another. Differences in adverse-event counts can reflect differences in participants, treatment components, dose, or other factors. Without a randomized comparison or a reported analysis addressing relevant differences, group counts remain descriptive.

Equally important, a well-defined endpoint does not replace a reported result. The registry record identifies the primary question and states hypotheses, including a dose-limiting toxicity rate of at most 30%, but does not provide the observed primary endpoint count or denominator. That gap prevents evaluation of the stated threshold and of the endpoint’s precision. A complete statistical account would also clarify the analysis population, missing assessments, and dose-selection procedure; these details are not reported in the registry record.

The study is therefore a useful example of reading registry records in layers: distinguish design from outcome, hypotheses from findings, and descriptive safety counts from comparative evidence. Those distinctions matter whenever multiple doses and combinations are considered, particularly when the posted information is incomplete.

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 important limitation for interpreting the primary question is that the registry record does not report the primary endpoint result. Although the endpoint definition, timeframe, and intended population are given, the number of participants with a dose-limiting toxicity and the number assessed are absent. The primary dose-limiting toxicity rate and its precision therefore cannot be evaluated.

The non-randomized design limits comparisons between dose groups. The groups include different combinations and dose schedules, and the record cautions that they are not like-for-like control arms. No comparative analysis is posted. The adverse-event counts should consequently be treated as descriptive rather than as evidence that one treatment combination or dose differs from another.

The registry record does not report detailed dose-escalation rules, the procedure used to select a maximum tolerated dose, interim analyses, or a full statistical analysis plan. It also does not report how missing endpoint assessments were handled or identify the actual analysis population beyond the stated intended population. Information about follow-up duration for the adverse-event summaries and the denominator used for the serious-event term percentages is not reported in the registry record.

The record lists tumor response as a secondary outcome but does not report response results. It also does not report results for the stated plasma exposure and pharmacodynamic aims. These omissions mean that the posted information cannot support conclusions about those outcomes or about overall treatment effects. The sample-size assumptions are planning illustrations rather than the trial’s design and should not be read as observed power or as a remedy for the missing endpoint results.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Phase I Study of MK-2206 in Combination With Standard Chemotherapy in Participants With Locally Advanced or Metastatic Solid Tumors (MK-2206-003) — NCT00848718.
• Registry record last updated 2019-11-12; status last verified 2019-11.
• Results first posted 2019-11-12.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

NCT00848718 is a completed Phase I, non-randomized, unmasked, parallel study of MK-2206 combinations in participants with locally advanced or metastatic solid tumors. The registry record lists enrollment of 77 participants, a start date of 2009-03-17, and primary completion on 2011-05-19. The three combination approaches were carboplatin plus paclitaxel, docetaxel, and erlotinib; the docetaxel combination included corticosteroid pretreatment.

The primary endpoint was the number of participants with a qualifying dose-limiting toxicity during Cycle 1, up to 21 days, among participants who received one dose of study treatment. The record describes the endpoint criteria and states hypotheses concerning tolerability, a dose-limiting toxicity rate of at most 30%, exposure and pharmacodynamic targets, and defining a maximum tolerated dose for each combination.

Posted safety information gives serious and other adverse-event counts and deaths by dose group. The primary endpoint result, tumor-response results, and detailed analysis procedures are not reported in the registry record. Because allocation was non-randomized and treatment groups differed, the posted group counts do not constitute a like-for-like comparison.