Safety and Pharmacokinetics of Cobimetinib in Pediatric and Young Adult Participants With Previously Treated Solid Tumors: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Pharmacokinetics of Cobimetinib in Pediatric and Young Adult Participants With Previously Treated Solid Tumors (NCT02639546), a non-randomized phase 1, phase 2 study. The primary outcome is Percentage of Participants With Dose-Limiting Toxicities (DLTs).

2. Clinical Question

The study’s stated aims included evaluating safety, tolerability, pharmacokinetics, and preliminary efficacy. The primary endpoint addresses an early safety question: whether participants experienced a specified toxicity during the DLT assessment period. It does not, by itself, describe every adverse event during follow-up or establish a comparative treatment effect.

The record describes a dose-escalation stage followed by an expansion stage at the recommended dose. Dose groups included different cobimetinib levels and formulations; these groups were not assigned by randomization. Consequently, differences among their observed event counts cannot be interpreted as randomized comparisons between doses or formulations.

The registry lists the recommended Phase II dose as a secondary outcome, but the result for that outcome is not reported in the registry record. The primary endpoint result is also not reported in the registry record. The record therefore identifies the clinical safety question but does not provide the posted endpoint estimate needed to answer it quantitatively.

3. Trial Design

This was a Phase I/II, multicenter, open-label, non-randomized study with a sequential model. Its stated structure had two stages: dose escalation and expansion at the recommended dose. Enrollment was 56, and the registry status is completed. The recorded study start was 2016-05-20, and primary completion was 2021-07-21.

During Phase I dose escalation, participants received cobimetinib in tablet or suspension form at listed dose levels. The tablet groups used 0.6 mg/kg, 0.8 mg/kg, or 1 mg/kg. Suspension groups used 0.6 mg/kg, 0.8 mg/kg, 1 mg/kg, or 1.33 mg/kg. The listed schedules were oral dosing once daily on Days 1 to 21 of each 28-day treatment cycle. The Phase II expansion group used suspension cobimetinib at 1 mg/kg on the same schedule.

Open-label means masking was not used, as also recorded in the registry. Non-randomized allocation means participants were not assigned randomly among the listed groups. Sequential dose escalation is a design structure in which dose groups are considered in sequence; the registry does not report the detailed escalation rules or decision criteria. It also does not report the specific method used to select the recommended Phase II dose.

The intervention was cobimetinib, with no separate control intervention identified. Although the dose groups allow the registry to describe experience at different doses and formulations, they do not create a randomized comparison. Cohort sizes differ, and the groups may also differ in when or why participants entered them. A comparison of their event counts would therefore be descriptive rather than a controlled estimate of dose effects.

The registry lists 21 outcome measures, including the primary DLT endpoint and secondary measures concerning response duration, overall survival, and pharmacokinetics. Results for those outcomes, apart from the adverse-event counts described in the record, are not reported in the registry record. The planned sample-size justification, detailed analysis plan, and any interim-analysis procedures are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: A total of 63 participants were screened, of which a total of 56 participants were enrolled. Tumor type was not a determinant of cohort assignment for the phase I portion of the study. The phase II portion of the study was restricted to participants with Low-Grade Glioma.

Only the first 6 of 8 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The safety evaluable population was defined as all participants who received at least one dose of study 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.

Only the first 6 of 9 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Dose-Limiting Toxicities (DLTs), measured over Baseline up until 30 days after the last dose of study drug (up to 5 years, 2 months).

The primary endpoint is the percentage of participants with dose-limiting toxicities. A DLT was defined as a cobimetinib-related adverse event occurring within the first 28 days of each administration of cobimetinib. The safety-evaluable population was defined as all participants who received at least one dose of study drug. The stated outcome timeframe extends from baseline until 30 days after the last dose, up to 5 years, 2 months.

As a binary endpoint, each participant is classified according to whether a qualifying DLT occurred. A percentage expresses the number of participants with the event relative to the endpoint’s relevant population. The registry record does not report the primary endpoint result, the number of participants included in that endpoint analysis, or an uncertainty interval. The total enrollment of 56 should not be assumed to equal the safety-evaluable population.

General statistical context: a DLT endpoint is useful in dose-escalation research because it focuses attention on defined toxicities during a specified assessment window. A clearly defined event and window make the endpoint more interpretable than an unspecified count of all adverse events. The DLT measure is nevertheless narrower than overall safety: it depends on the event definition, attribution to study drug, and assessment period. It cannot represent every later or non-qualifying adverse event.

The endpoint is a safety measure, not a measure of tumor response or survival. Response duration, overall survival, and pharmacokinetic outcomes appear among the registry’s other outcomes, but their results are not reported in the registry record. No conclusion about those outcomes follows from the DLT endpoint definition or the adverse-event counts alone.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a percentage endpoint represent?

The primary outcome is a binary participant-level measure: a participant either met the DLT definition during the relevant assessment or did not. General statistical context: a percentage summarizes the proportion of an analysis population with an event. Its interpretation depends on both the event definition and the denominator. Here, the record defines the safety-evaluable population as participants who received at least one dose, but does not report the primary endpoint numerator or denominator. The enrollment count alone cannot substitute for the endpoint analysis population.

In a complete report, an estimate of a proportion is commonly presented with an uncertainty interval. General statistical context: a confidence interval describes a range of values compatible with the observed data under the interval’s statistical assumptions. It helps readers distinguish a relatively precise estimate from one that is uncertain, especially when the number of participants is limited. No confidence interval for the primary endpoint is reported in the registry record, so its precision cannot be assessed from a posted primary result.

Why does the sequential design matter?

The trial used dose escalation followed by expansion, with no random allocation and no masking. General statistical context: dose-escalation studies organize exposure across dose groups to study safety and dosing, rather than to create the same kind of treatment-effect comparison as a randomized controlled trial. In a sequential design, groups may enter at different points in the study process. Their membership and sizes can differ, and the registry does not report detailed rules governing escalation or group selection.

For that reason, group-by-group counts can be described, but they should not be treated as causal comparisons. A difference in counts could reflect group size, participant characteristics, follow-up, or the sequence in which groups were enrolled, as well as dose. The record does not report an analysis that adjusts for such factors. The listed adverse-event counts should therefore remain descriptive.

How should DLT and serious-event data be distinguished?

The primary endpoint is based on DLTs, defined as cobimetinib-related adverse events occurring within the first 28 days of each administration of cobimetinib. The adverse-event group data separately report participants with serious adverse events and participants in another adverse-event field. Seriousness alone does not establish that an event qualifies as a DLT. The record does not give a cross-tabulation linking serious events to DLT status, so the serious-event counts cannot be used to reconstruct the primary endpoint.

General statistical context: event definitions can overlap without being identical. A serious event may fall outside an endpoint’s time window or attribution rule; an endpoint event may not meet a separate seriousness criterion. Readers need the endpoint definition and the corresponding participant-level analysis, rather than assuming one safety summary is a substitute for another.

What can be inferred from the posted analyses?

The registry lists zero analyses. No primary endpoint estimate, inferential test, confidence interval, or adjusted model is reported in the registry record. The absence of a posted analysis is not evidence that an event did or did not occur; it means the relevant quantitative result is not available in the record. The secondary outcome list does not itself establish that results were observed or analyzed.

The registry includes sample-size assumptions for planning illustrations based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. These assumptions describe an illustration, not the trial’s reported design justification. No calculated sample-size values are reported in the record, and the planned sample-size justification is not reported in the registry record. General statistical context: sample-size planning illustrations are prospective design calculations and are not observed power. They should not be used to claim that a completed study had a particular probability of detecting an effect.

What statistical information is missing?

The registry does not report the analysis method for the primary binary endpoint, the handling of missing endpoint data, any prespecified subgroup analyses, or a multiplicity strategy. It also does not report interim-analysis procedures, decision thresholds for escalation, or the detailed criteria used to choose the recommended Phase II dose. These omissions limit the ability to reconstruct how the study’s listed aims were translated into statistical decisions.

General statistical context: for a binary outcome, the choice of interval or test can affect how uncertainty is represented, particularly when sample sizes are small or event counts are sparse. No specific method should be attributed to this trial without a reported analysis plan. Similarly, multiple outcomes can increase the chance of at least one apparently notable finding if many tests are conducted; whether and how that issue was addressed is not reported in the registry record.

Pharmacokinetic outcomes such as maximum plasma concentration and time to maximum concentration require their own definitions, analysis populations, and summaries. The record lists these outcomes but does not report their results or methods. They cannot be inferred from the safety counts.

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("Phase I (Tablet) Cobimetinib (0.6 mg/kg)", "Phase I (Tablet) Cobimetinib (0.8 mg/kg)", "Phase I (Tablet) Cobimetinib (1 mg/kg)", "Phase I (Suspension) Cobimetinib (0.6 mg/kg)", "Phase I (Suspension) Cobimetinib (0.8 mg/kg)", "Phase I (Suspension) Cobimetinib (1 mg/kg)")
n      <- c(6, 6, 6, 6, 7, 8)
events <- c(0, 0, 2, 1, 0, 0)
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  Phase I (Tablet) Cobimetinib (0.6 mg/kg)  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Phase I (Tablet) Cobimetinib (0.8 mg/kg)  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Phase I (Tablet) Cobimetinib (1 mg/kg)  6  2  33.3  4.3  77.7  9.7  70.0  9.9  71.0
ARM  Phase I (Suspension) Cobimetinib (0.6 mg/kg)  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  Phase I (Suspension) Cobimetinib (0.8 mg/kg)  7  0  0.0  0.0  41.0  0.0  35.4  0.3  36.9
ARM  Phase I (Suspension) Cobimetinib (1 mg/kg)  8  0  0.0  0.0  36.9  0.0  32.4  0.3  33.6

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 21 outcome measures, including DLTs, response duration, overall survival, and pharmacokinetic outcomes. It does not report a multiplicity strategy, such as prioritization of outcomes, adjustment of inferential thresholds, or a distinction between confirmatory and exploratory tests. The registry also lists zero analyses, so no set of posted statistical tests is available to assess.

General statistical context: when researchers evaluate many outcomes or conduct multiple tests, the chance of obtaining at least one apparently notable result can increase. Methods for addressing multiplicity depend on the study’s objectives and prespecified analysis plan. Because that plan is not reported in the registry record, no adjustment or unadjusted testing approach should be assumed.

Handling of missing data is not reported in the registry record. The record does not describe how participants without a complete DLT assessment were treated, how missing outcome measurements were handled, or whether follow-up differed by group. These details matter because a percentage estimate depends on which participants are included and how incomplete information is treated.

The primary endpoint defines the safety-evaluable population as participants who received at least one dose of study drug. Enrollment was 56, but the number included in the primary endpoint analysis is not reported. No analysis population is described for the secondary outcomes in the information available. The stated safety population definition should not be assumed to apply to response, survival, or pharmacokinetic analyses.

Any further details about analysis populations, missing-data methods, multiplicity handling, or interim analyses are not reported in the registry record. Without those details and the primary endpoint result, the completeness and precision of the endpoint estimate cannot be assessed.

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: chorioretinopathy (20.0%), pyrexia (20.0%), catheter site infection (20.0%), paronychia (20.0%), vascular device infection (20.0%).

The adverse-event record lists serious-event counts by study group. In the Phase I tablet groups at 0.6 mg/kg, 0.8 mg/kg, and 1 mg/kg, 2 participants in each group had serious events, with 6 at risk in each group. In Phase I suspension groups, the counts were 2 participants among 6 at 0.6 mg/kg, 1 among 7 at 0.8 mg/kg, 2 among 8 at 1 mg/kg, and 2 among 5 at 1.33 mg/kg. In the Phase II suspension group at 1 mg/kg, 5 participants had serious events, with 12 at risk.

These counts describe serious events recorded in the groups; they are not the DLT endpoint result. The registry reports no deaths in any of the groups. Serious-event terms listed include chorioretinopathy, pyrexia, catheter site infection, paronychia, vascular device infection, and pericardial effusion, with the listed percentages of 20.0%, 20.0%, 20.0%, 20.0%, 20.0%, and 16.7%, respectively.

General statistical context: counts and percentages should be interpreted alongside their denominators and event definitions. Group sizes vary, and the groups were not randomized comparisons. The registry does not report uncertainty intervals for these counts or establish that the listed serious events met the DLT definition.

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

The record establishes that this was a completed Phase I/II study of cobimetinib with dose-escalation and expansion stages, and it gives the definition of the primary DLT endpoint. It also posts serious adverse-event counts by dose and formulation group. These details help describe what the study set out to assess and what safety information is present in the registry.

The record does not report the primary endpoint result. It therefore does not establish the percentage of participants who experienced DLTs or the precision of that percentage. The serious adverse-event counts cannot fill this gap because serious events and DLTs are not stated to be equivalent, and the record does not link the two classifications participant by participant.

The study was not randomized and had no identified control group. As a result, the group counts do not support a controlled comparison of doses or formulations. Differences in counts should not be presented as evidence of a dose effect. The record also does not report results for the listed response-duration, overall-survival, or pharmacokinetic outcomes, so the posted safety information does not support conclusions about those outcomes.

General statistical context: an observed count is a description of events in a particular study population. It does not, on its own, establish how frequently an event would occur in another population or what would have happened under a different treatment. Uncertainty, eligibility, follow-up, event definitions, and study design all affect interpretation.

The registry record therefore supports a limited reading: it documents the study structure, endpoint definition, and selected adverse-event counts. It does not provide a quantitative primary DLT finding, a randomized estimate of comparative safety, or reported evidence for efficacy. These are limits of the posted information, not evidence that an unreported outcome was favorable or unfavorable.

14. Why This Trial Matters Statistically

This trial illustrates a statistical distinction between a dose-escalation safety question and a comparative treatment question. The study’s sequential, non-randomized structure organized participants across cobimetinib dose levels and formulations. That structure can support descriptive reporting across groups, but it does not create the protections of random allocation for estimating differences between treatment groups.

The primary endpoint also illustrates why outcome definitions matter. DLTs were defined through event attribution and a specified assessment window. Serious adverse events were reported separately. Readers cannot safely substitute one category for the other, even though both concern safety. A precise endpoint definition is useful only when the matching event count and analysis population are also reported.

The registry lists a broad set of outcomes: safety, response duration, overall survival, and pharmacokinetic measures. Each answers a different question and may require a distinct analysis population and method. Without posted results and analysis details, the outcome list should be understood as a record of planned measures, not as evidence that each measure produced a result.

General statistical context: early-phase studies often have design goals that differ from confirmatory comparisons. Descriptive safety information can be important for understanding experience across dose groups, while causal claims generally require an appropriate comparison and analysis. Here, the non-randomized design and lack of a posted DLT estimate both matter when interpreting what can be concluded.

The record’s limitations are a useful reminder that enrollment, endpoint definitions, and adverse-event counts do not substitute for a complete statistical report. A reader needs the analysis population, outcome estimate, uncertainty, and relevant methods to assess how much information the results carry.

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 main limitation for interpreting the primary question is that the percentage of participants with DLTs is not reported in the registry record. The record defines the safety-evaluable population but does not state its size or the number of participants meeting the DLT definition. The total enrollment of 56 cannot be assumed to be the analysis denominator.

The listed serious adverse-event counts are not a replacement for the primary endpoint. The record does not report whether those events were cobimetinib-related, occurred within the DLT assessment window, or met the DLT definition. The serious-event term percentages are listed without a denominator in the information available for interpretation, limiting their direct comparison with the group-level counts.

The study was non-randomized, open-label, and sequential. There was no randomized control group, and the dose groups had different sizes. The record does not report methods to adjust for differences among groups, detailed escalation rules, or the criteria used to select the recommended Phase II dose. Consequently, the group counts should be treated descriptively rather than as dose-effect estimates.

The registry does not report the primary analysis method, confidence intervals, missing-data handling, multiplicity strategy, or interim-analysis procedures. It lists 21 outcome measures but provides no posted statistical analyses. Results for the listed secondary outcomes, including response, survival, and pharmacokinetic measures, are not reported in the registry record.

These limitations concern what can be interpreted from the registry record. They do not establish that an unreported analysis was not conducted, nor do they indicate what its result would have been.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety and Pharmacokinetics of Cobimetinib in Pediatric and Young Adult Participants With Previously Treated Solid Tumors — NCT02639546.
• Registry record last updated 2022-09-16; status last verified 2022-09.
• Results first posted 2022-03-31.
• 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

NCT02639546 is a completed Phase I/II, multicenter, open-label, non-randomized, sequential study of cobimetinib in pediatric and young adult participants with previously treated solid tumors. Enrollment was 56. The study included dose escalation and expansion, with oral cobimetinib given once daily on Days 1 to 21 of each 28-day treatment cycle across the listed dose groups.

The primary endpoint was the percentage of participants with DLTs, defined as cobimetinib-related adverse events occurring within the first 28 days of each administration. The primary result and the number analyzed are not reported in the registry record. Serious adverse-event counts are listed by group, but they are not interchangeable with the DLT endpoint and do not establish randomized comparisons.

The registry lists 21 outcome measures and zero analyses. Results for the listed secondary outcomes and details of the statistical analysis plan are not reported in the registry record.