Safety, Tolerability and Pharmacokinetics of Cobimetinib in Combination With Pictilisib in Patients With Locally Advanced or Metastatic Solid Tumors: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety, Tolerability and Pharmacokinetics of Cobimetinib in Combination With Pictilisib in Patients With Locally Advanced or Metastatic Solid Tumors (NCT00996892), a non-randomized phase 1 study. The primary outcome is Number of Participants With Dose-Limiting Toxicities (DLTs) During Dose Escalation Stages 1, 1A and 1B.

2. Clinical Question

3. Trial Design

This was a Phase Ib, open-label, multicenter study of cobimetinib plus pictilisib in locally advanced or metastatic solid tumors. The registry records the study as nonrandomized, unmasked, and single-group, with enrollment of 178 participants. The listed start was 2009-11 and primary completion was 2014-03. Its current status is terminated; the reason for termination is not reported in the registry record.

The study had dose-escalation stages followed by dose-expansion stages. Escalation cohorts evaluated different cobimetinib and pictilisib dose combinations and schedules. Expansion cohorts used doses identified during the corresponding escalation stage as a maximum tolerated dose or potential recommended Phase 2 dose. The regimen schedules were not identical across all stages: some used study drugs on Days 1 to 21 with Days 22 to 28 off, while other schedules included intermittent treatment days or a second treatment period within the cycle. Treatment duration and stopping rules are not fully reported in the registry record.

Because dose assignment was not randomized, the cohorts cannot be treated as balanced comparative arms. Differences across cohorts could reflect their different doses, schedules, enrollment periods, or participant composition; the registry record does not report a comparative analysis that separates these influences. This design is consistent with an early-phase focus on safety, tolerability, and pharmacokinetics rather than a controlled estimate of comparative clinical benefit.

The primary outcome was the number of participants with DLTs during dose escalation. Secondary outcomes included pharmacokinetic measures of cobimetinib, including Tmax, Cmax, AUC0-24, terminal half-life, and apparent clearance at specified cycle time points. The registry lists 99 outcome measures and no statistical analyses. It does not report a sample-size justification, a formal statistical analysis plan, or the reason the study was terminated.

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: Study was terminated before initiation of Stage 2B; hence Stage 2B cohorts were not applicable.

Only the first 6 of 20 groups are shown.

Dose-Escalation Stage 1

Reasons for not completing this period:

Dose-Escalation Stage 1A

Reasons for not completing this period:

Dose-Escalation Stage 1B

Reasons for not completing this period:

Expansion Stage 2

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety-evaluable population included all participants who received at least one dose of study drug. Here, number of participants analyzed = participants who were evaluable for this outcome.

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 enrolled participants.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Dose-Limiting Toxicities (DLTs) During Dose Escalation Stages 1, 1A and 1B, measured over Cohorts 1-3: Day 1 to Day 35, All other cohorts: Day 1 to Day 28.

The primary endpoint counts participants with dose-limiting toxicities during dose-escalation stages 1, 1A, and 1B. The assessment window was Day 1 to Day 35 for cohorts 1-3 and Day 1 to Day 28 for all other cohorts. The registry defines a DLT as a treatment-related toxicity meeting specified severity and duration criteria, with exceptions for certain events that resolved within stated time limits or were considered non-clinically significant. The definition includes qualifying non-hematologic or non-hepatic organ toxicities, febrile neutropenia, prolonged neutropenia or thrombocytopenia, severe anemia, prolonged liver-test abnormalities, and a specified lung diffusion-capacity change with an absolute decrease from baseline.

In general, a DLT endpoint is used in dose-escalation research to identify toxicities that constrain dose selection. It condenses a defined set of clinically assessed events into a participant count over a specified assessment period. It does not capture every possible adverse event, and it does not by itself describe longer-term safety, treatment benefit, or comparative effects. The registry says the safety-evaluable population included participants who received at least one dose; the number evaluated for this endpoint and the DLT count are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a count endpoint represent?

The primary outcome is a participant count: it records how many evaluable participants met the DLT definition during the assessment window. In general, a count is easier to interpret when its denominator and observation period are reported alongside it. A count alone does not tell the reader how frequently the event occurred relative to the number assessed. The registry defines the eligible safety population and the time window, but the primary count and outcome-specific denominator are not reported in the registry record.

The DLT definition is operational: it specifies which severities, durations, and clinical circumstances count. Operational definitions are important because they make a safety endpoint less dependent on an informal impression of toxicity. The exceptions also matter. Some events are excluded if they resolve within the stated period or meet the registry's specified clinical circumstances. The endpoint therefore represents the prespecified classification, not a count of all symptoms, laboratory changes, or adverse events.

Why are the dose cohorts not direct comparisons?

In general, randomization helps make treatment groups comparable by allocating participants without systematic selection into treatment arms. This study is recorded as nonrandomized and single-group. Its cohorts reflect different dose combinations and schedules in an escalation and expansion program, rather than randomly assigned alternatives. Accordingly, an apparent difference in event counts between cohorts cannot be interpreted as the effect of changing one drug dose while holding all else constant. The registry does not report a comparative model that would account for cohort differences.

Early-phase dose escalation also has a different statistical aim from a confirmatory trial. The focus is on describing safety and pharmacokinetic behavior across regimens and informing dose selection. Dose-expansion cohorts then provide additional experience at selected doses. This design does not, by itself, provide a controlled estimate of efficacy or a definitive safety comparison. The registry states that the study was designed to assess safety, tolerability, and pharmacokinetics; it does not report a formal statistical plan describing how dose decisions were made.

What do confidence intervals and hypothesis tests add?

As a general statistical explanation, a confidence interval describes the precision of an estimated quantity under a specified analysis. For a binary safety outcome, an interval around a proportion can show how much uncertainty remains when the number of observed events and the denominator are limited. A hypothesis test addresses compatibility with a stated null model, but its interpretation depends on the study design, analysis plan, and outcome being tested. Neither an interval nor a p-value resolves bias arising from nonrandomized comparisons.

No confidence intervals, p-values, or statistical analysis results are reported in the registry record for the primary endpoint. Therefore, precision cannot be assessed from an inferential estimate, and no hypothesis-test conclusion should be attributed to the study from this record.

How should pharmacokinetic outcomes be understood?

The listed secondary outcomes include Tmax, Cmax, and AUC0-24 for cobimetinib at specified cycle time points, as well as terminal half-life and apparent clearance. In general, pharmacokinetic measures describe aspects of drug concentration over time: the timing of a peak, the peak concentration, exposure over a stated interval, elimination behavior, or apparent clearance. They are not themselves clinical efficacy endpoints. The registry lists these measures but does not report their results, analysis methods, or the number of participants contributing to each measure.

What do the planning assumptions mean?

The registry's planning description characterizes sample-size calculations as illustrations based on an observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It also says the effect to detect is expressed as a stated fraction of the observed effect. These are planning assumptions, not a description of the trial's own design justification. In general, such calculations ask what sample size a hypothetical study might require under chosen assumptions; they do not describe the precision or power actually achieved in this nonrandomized, single-group dose-escalation study. They are not observed power. The stated two-arm equal-allocation framework does not turn the dose cohorts into randomized comparison groups.

The calculations' numerical outputs, the observed effect used, and any connection to a prespecified design are not reported in the registry record. A sample-size illustration cannot replace a missing primary endpoint result, denominator, or analysis plan. More generally, planning estimates depend on assumptions about the target effect and variability; if those assumptions differ from a future study's actual conditions, the planning result may not describe that study's performance.

What can be inferred from the safety summaries?

In general, adverse-event counts are descriptive unless the design and analysis support a defined comparison. Event counts across cohorts can help characterize what was recorded at different dose combinations, but the interpretation depends on exposure, observation time, event definitions, and complete denominators. The registry gives cohort-level numbers at risk and affected for serious and other adverse events. It does not report exposure-adjusted rates, time-to-event analyses, or a statistical comparison across cohorts. Serious-event term percentages are listed, but their denominator and calculation basis are not reported in the registry record.

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("S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib", "S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib", "S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib", "S1 C4: 40 mg Cobimetinib + 100 mg Pictilisib", "S1 C5: 40 mg Cobimetinib + 130 mg Pictilisib", "S1 C6: 60 mg Cobimetinib + 100 mg Pictilisib")
n      <- c(4, 3, 3, 9, 11, 10)
events <- c(0, 0, 0, 1, 1, 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  S1 C1: 20 mg Cobimetinib + 80 mg Pictilisib  4  0  0.0  0.0  60.2  0.0  49.0  0.5  52.2
ARM  S1 C2: 20 mg Cobimetinib + 100 mg Pictilisib  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  S1 C3: 40 mg Cobimetinib + 80 mg Pictilisib  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  S1 C4: 40 mg Cobimetinib + 100 mg Pictilisib  9  1  11.1  0.3  48.2  2.0  43.5  2.5  44.5
ARM  S1 C5: 40 mg Cobimetinib + 130 mg Pictilisib  11  1  9.1  0.2  41.3  1.6  37.7  2.1  38.5
ARM  S1 C6: 60 mg Cobimetinib + 100 mg Pictilisib  10  0  0.0  0.0  30.8  0.0  27.8  0.2  28.5

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 99 outcome measures, including the primary DLT endpoint and pharmacokinetic secondary outcomes. It reports no statistical analyses. A plan for handling multiplicity—such as whether any outcomes were considered confirmatory, whether tests were adjusted, or how outcomes were prioritized beyond the primary designation—is not reported in the registry record.

Multiplicity is a general concern when many outcomes or comparisons are examined: the chance of obtaining an apparently notable result can increase if many separate tests are performed. That concern is relevant to interpretation of a large outcome list, but no inferential findings are reported to evaluate. The registry does not say whether interim analyses occurred, how dose-escalation decisions were reviewed statistically, or whether any outcome analyses were prespecified beyond the endpoint descriptions.

The primary endpoint's evaluable population is defined as participants who received at least one dose and were evaluable for that outcome. The number in that population is not reported in the registry record. The record also does not report missing outcome data, reasons for non-evaluability, handling of participants with incomplete assessment windows, or imputation methods. These details matter because a count based only on evaluable participants can be difficult to interpret if the exclusions or missingness are not described.

The registry reports enrollment of 178, but does not give the primary endpoint denominator or a participant flow that links enrollment, treatment exposure, and endpoint assessment. Analysis populations for the pharmacokinetic outcomes are not reported in the registry record. Without those details, it is not possible to determine from the record how missing observations or differences in evaluability were handled.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: diarrhoea (40.0%), bile duct obstruction (33.3%), pneumonia (33.3%), sepsis (33.3%), blood bilirubin increased (33.3%).

The registry reports serious adverse event information separately by dose cohort, including the number at risk and the number affected. These cohort-specific counts describe recorded events in this dose-escalation and expansion study; they are not a randomized comparison. The listed cohorts have different dose combinations and schedules, so comparisons of their counts should not be read as estimates of the causal effect of a dose change.

The registry also lists serious adverse event terms and percentages: diarrhoea, 40.0%; bile duct obstruction, pneumonia, sepsis, blood bilirubin increased, and gastrooesophageal cancer, 33.3% each. The denominator, whether the percentages refer to participants or events, and the method used to calculate them are not reported in the registry record. They should therefore be treated as listed term summaries rather than interpreted as overall participant risks.

Serious adverse events are not interchangeable with dose-limiting toxicities. DLTs follow the specific severity, duration, attribution, and exception criteria defined for the primary endpoint; the registry does not state that every serious adverse event meets those criteria. Death counts are not reported in the registry record. The available safety summaries also do not establish comparative safety or provide a complete account of follow-up time.

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

The record describes an early-phase study designed to assess safety, tolerability, and pharmacokinetics when cobimetinib and pictilisib were administered in combination to people with locally advanced or metastatic solid tumors. Its primary endpoint was a defined count of DLTs during dose escalation. This endpoint is relevant to evaluation of dose combinations, but its result is not reported in the registry record.

The cohort-level serious and other adverse event counts provide some descriptive safety information. The registry also names serious adverse event terms with percentages. Because the term percentage denominator and calculation basis are not reported, those figures cannot be interpreted as overall risks for the enrolled population. The serious-event summaries also cannot be substituted for the DLT endpoint.

The design does not support a randomized treatment comparison: allocation was nonrandomized, masking was absent, and the study is recorded as single-group. Dose cohorts differed in regimen and were part of escalation and expansion stages. The data therefore do not establish that a specific dose caused a difference in adverse events relative to another dose, and they do not estimate the effect of the combination against a control treatment.

The record does not report the primary DLT count, the number evaluable for that outcome, pharmacokinetic results, or inferential analyses. It also does not report a reason for termination. No conclusion about efficacy, overall benefit, or comparative safety can be drawn from the information recorded. The appropriate interpretation is limited to the documented design, endpoint definition, and descriptive safety information, with substantial gaps in the reported outcome results.

In general, absence of a reported result is not evidence that an event did or did not occur. It means the registry record does not give the information needed to quantify that outcome. A fuller interpretation would require the endpoint results, participant denominators, analysis methods, and relevant missing-data information, none of which are reported for the primary endpoint in this registry record.

14. Why This Trial Matters Statistically

This study illustrates why early-phase design features matter when interpreting clinical safety data. Dose escalation asks questions about tolerability across regimens, while dose expansion adds experience at selected regimens. Those stages can produce useful descriptive evidence, but they do not create randomized comparisons. A reader must distinguish cohort-level observations from causal evidence about the effect of dose or treatment.

The endpoint definition is also central. A DLT count depends on a specific assessment window and a protocol definition that includes severity, duration, treatment attribution, and exceptions. An all-purpose adverse-event count cannot be used as a proxy for that endpoint. The registry's separate reporting of serious adverse events and the DLT primary outcome makes clear why endpoint labels and definitions should be read precisely.

Denominators are essential to interpreting event counts. Enrollment does not necessarily equal the number treated, the number evaluable for a particular outcome, or the number assessed in each cohort. The registry defines the safety-evaluable population but does not report the primary outcome denominator or result. This limits both interpretation of the event burden and assessment of precision.

Finally, a long list of secondary outcomes does not imply that results or statistical testing are available for each. The registry lists pharmacokinetic measures and many outcome measures but reports no analyses. The planning assumptions describe illustrations rather than the trial's own design justification, and cannot be read as observed power. Together, these features show how design, endpoint definitions, missing denominators, and analysis reporting shape what can responsibly be concluded from a clinical trial record.

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 trial-specific limitation for statistical interpretation is that the primary DLT result and its evaluable denominator are not reported in the registry record. Enrollment of 178 does not fill that gap. Without the count and denominator, the primary safety endpoint cannot be quantified or its precision assessed.

The study was nonrandomized, unmasked, and single-group. Its dose cohorts used different drug combinations and schedules, and cohort sizes varied. They therefore do not form like-for-like control groups. Observed differences between cohorts, if considered, could not be attributed to dose alone from the design described in the registry.

The registry lists serious and other adverse event counts by cohort, along with selected serious-event terms and percentages. It does not report the percentage denominator or calculation basis for those terms. Death counts, exposure-adjusted event rates, and time-to-event analyses are not reported in the registry record. The record also does not report participant flow, outcome-specific missingness, or the number contributing to pharmacokinetic measures.

The registry identifies 99 outcome measures but reports no statistical analyses. A formal statistical analysis plan, multiplicity approach, interim analysis information, sample-size justification, and explanation of termination are not reported in the registry record. The stated sample-size calculations are described as planning illustrations rather than the trial's design, and their numerical outputs and underlying observed effect are not reported. These gaps preclude a complete assessment of endpoint precision, missing-data effects, and the evidential strength of the study's results.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety, Tolerability and Pharmacokinetics of Cobimetinib in Combination With Pictilisib in Patients With Locally Advanced or Metastatic Solid Tumors — NCT00996892.
• Registry record last updated 2016-12-30; status last verified 2016-11.
• Results first posted 2016-12-30.
• 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

This Phase Ib study evaluated oral cobimetinib plus pictilisib in locally advanced or metastatic solid tumors. The registry describes a nonrandomized, open-label, single-group design with dose-escalation and dose-expansion stages and enrollment of 178. The study is listed as terminated; the reason is not reported in the registry record.

The primary endpoint was the number of participants with protocol-defined DLTs during dose escalation. The registry defines the endpoint and its assessment windows but does not report the DLT result or its evaluable denominator. Secondary outcomes included cobimetinib pharmacokinetic measures, but their results are not reported. Cohort-level serious and other adverse event counts are listed, along with serious-event terms and percentages whose denominator is not reported. No statistical analyses are reported, and the cohorts are not randomized comparative arms.