Japanese Study of Ipilimumab Administered in Combination With Paclitaxel/Carboplatin in Patients With Nonsmall-cell Lung Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Japanese Study of Ipilimumab Administered in Combination With Paclitaxel/Carboplatin in Patients With Nonsmall-cell Lung Cancer (NCT01165216), a non-randomized phase 1 study. The primary outcome is Number of Participants Experiencing a Dose-limiting Toxicity (DLT).

2. Clinical Question

This is a dose-finding question rather than a question about whether the combination is better than another treatment. In general, early-phase dose-finding studies examine whether toxicities that meet predefined criteria occur during a specified period of treatment. Such information can contribute to dose selection for further study, but the registry record does not report a recommended dose or the observed dose-limiting toxicity counts.

The listed secondary outcomes broaden the scope beyond the primary safety measure. They include participant counts for adverse events and best overall response, as well as serum concentration, exposure, peak timing, and half-life measures for ipilimumab. The record names these outcomes, but does not give their results in the information available for this analysis. The clinical question can therefore be described from the study’s stated aims, while conclusions about observed dose-limiting toxicities, response, or drug exposure cannot be drawn from the registry record.

3. Trial Design

This was a Phase 1 study sponsored by Bristol-Myers Squibb and marked completed in the registry. The study concerned Japanese patients with non-small-cell lung cancer and evaluated ipilimumab in combination with paclitaxel and carboplatin. The registry records enrollment of 15 participants, a start date of 2010-09, and primary completion in 2013-06.

The two described dose levels paired ipilimumab 3 mg/kg or 10 mg/kg with paclitaxel and carboplatin. The regimen descriptions specify paclitaxel at 175 mg/m², with administration every 3 weeks for up to 6 doses. They describe ipilimumab administration every 3 weeks. The carboplatin description gives an AUC of 6. The registry’s arm descriptions are truncated, so details beyond the text available in the record should not be inferred.

The allocation is listed as non-randomized, masking as none, and the model as single-group. The presence of two dose-level descriptions does not make this a randomized comparison. There is no randomized control arm, and differences between the dose-level groups could reflect how participants entered or were assigned to dose levels, as well as other differences. The record does not describe the dose-assignment procedure, so the basis for comparing the groups is not reported in the registry record.

The primary endpoint was the number of participants experiencing a dose-limiting toxicity. Its population was participants who received at least one dose of ipilimumab. The timeframe is stated as Day 1 of Cycles 1 and 2 and from Day 1 of Cycle 3 to Day 21 of Cycle 4. The study also listed outcomes concerning adverse events, response, and ipilimumab pharmacokinetics. The statistical plan, sample-size justification, and procedures for dose escalation 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: Participants were enrolled in successive cohorts of 3 to 6 patients, using a standard 3+3 design. Of 15 patients enrolled, all received some treatment (chemotherapy or ipilimumab); 12 received at least 1 dose of ipilimumab.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Participants who received at least 1 dose of ipilimumab

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 received at least 1 dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants Experiencing a Dose-limiting Toxicity (DLT), measured over Day 1 of Cycles 1 and 2 From Day 1 of Cycle 3 to Day 21 of Cycle 4.

The primary endpoint counts participants who experienced a dose-limiting toxicity, or DLT. It is a participant-count outcome, not a measure of the number of toxicity episodes. The population specified for this endpoint consists of participants who received at least one dose of ipilimumab. The registry defines the observation timeframe as Day 1 of Cycles 1 and 2 and from Day 1 of Cycle 3 to Day 21 of Cycle 4.

The DLT definition focuses on study drug-related adverse events during the first 2 cycles after ipilimumab administration in the induction phase. It includes specified severe blood-count changes, febrile neutropenia, selected gastrointestinal toxicities despite adequate or maximal medical intervention, certain liver enzyme elevations or rash that do not resolve to Grade 2 or lower within 2 weeks, and qualifying nonhematologic toxicities. Exceptions include Grade 3 fatigue, asthenia, transient arthralgia or myalgia, and transient abnormal electrolyte levels. The definition also specifies thresholds for neutrophil and platelet counts and the duration of some events.

In general, a DLT endpoint is used in dose-finding research because it focuses on toxicities judged important under the study’s stated rules and observation period. Counting participants with at least one qualifying event gives a direct summary of how often the endpoint occurred in the defined population. It does not capture every aspect of tolerability, the severity or duration of each event beyond the criteria, or whether an event occurred outside the specified timeframe.

The registry record states the endpoint definition but does not report the number of participants who experienced a DLT at either dose level. The endpoint’s stated purpose can therefore be explained, but its observed result cannot be interpreted from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant-count endpoint mean?

The primary outcome is a count of participants who experienced at least one event satisfying the DLT definition. In general, participant counts answer how many people met an outcome rule, rather than how many total episodes occurred. A person with multiple qualifying events can still be counted once in a participant-level endpoint. The registry names the endpoint and defines the event criteria, but does not report the observed count.

The endpoint definition matters because a broad label such as toxicity does not identify which events qualify. Here, the definition restricts the outcome to study drug-related adverse events and enumerates clinical and laboratory criteria. It also specifies a timeframe. In general, a prespecified definition improves consistency in classifying outcomes, but interpretation remains tied to the exact criteria and observation period. An event outside that period, or an event not meeting the stated criteria, would not necessarily count toward this endpoint.

Why distinguish the primary endpoint from adverse-event summaries?

The registry separately lists a DLT endpoint and adverse-event outcomes. They answer related but different questions. A DLT is defined by event attribution, criteria, and timing. Serious adverse events and other adverse events are broader safety summaries, and their labels do not by themselves establish that an event met the DLT rule. The serious adverse-event counts should therefore be read as safety descriptions, not as the missing primary endpoint result.

In general, safety reports may count participants, event occurrences, or both, depending on the outcome definition. Participant-level counts avoid treating repeated events in one person as separate people, but do not show how many total events occurred. The available registry information gives participant counts for the adverse-event categories and lists selected serious-event terms with percentages. The record does not provide enough detail to infer the relationship between those term percentages and each dose-level group.

What does non-randomized allocation imply?

Random allocation is a method for assigning participants to groups by chance. In general, it can help make groups comparable on measured and unmeasured characteristics. This study is listed as non-randomized, with no masking and a single-group model, while also describing two dose levels. The dose-level descriptions should not be interpreted as randomized control arms. Without a randomized assignment, a numerical contrast between the groups would not isolate dose as the only explanation for any difference.

A control comparison also differs from dose finding. The stated primary purpose was to establish a recommended dose of ipilimumab with the chemotherapy combination. A DLT count can inform that purpose when reported, but the registry does not give the counts or the dose-selection conclusion. The procedure used to assign participants to dose levels and any escalation rules are not reported in the registry record.

How should precision be understood?

In general, a confidence interval describes a range of values compatible with the data and the assumptions of the statistical method. A narrow interval indicates greater precision than a wide one, while neither interval width nor a point estimate alone establishes clinical importance. The registry record does not report a confidence interval or other inferential result for the primary endpoint. The small group counts available for adverse-event summaries should be understood as descriptive observations, not precise estimates of risk in a wider population.

When counts are sparse, estimates can be unstable: a change in the outcome of a participant may shift the observed count appreciably. This general issue is especially relevant to small dose-level groups. It does not justify calculating an unreported percentage or interval. The registry’s count data should be quoted as counts, and any uncertainty beyond those data should be acknowledged rather than filled in with a new calculation.

What is the status of the statistical analysis?

The registry record lists no analyses. It does not report a statistical analysis plan, the tests or models intended for the outcomes, an interim analysis approach, or a sample-size justification. These details are not reported in the registry record. In general, a prespecified analysis plan clarifies how outcomes are summarized, how missing observations are handled, and how multiple outcomes are interpreted. Without that information, the analysis choices cannot be reconstructed from outcome names alone.

The record describes planning assumptions for sample-size illustrations in general terms: a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect expressed as a fraction of the observed effect. Such illustrations are planning calculations, not observed power and not evidence that the trial was designed or analyzed according to those assumptions. The study itself is non-randomized and not a like-for-like control comparison, so those assumptions should not be mistaken for the trial’s design. No numerical sample-size illustration is available in the registry information addressed.

Finally, the study lists response and pharmacokinetic outcomes, including ipilimumab concentration and exposure measures. In general, pharmacokinetic summaries describe drug concentrations over time; their interpretation depends on how and when samples were collected and analyzed. The registry record names these measures but does not report their values or the associated statistical methods. Their presence in the outcome list is not evidence of a particular exposure or response result.

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("Dose Level 1: Ipilimumab, 3 mg/kg + Paclitaxel + C", "Dose Level 2: Ipilimumab, 10 mg/kg + Paclitaxel + ")
n      <- c(6, 6)
events <- c(2, 1)
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  Dose Level 1: Ipilimumab, 3 mg/kg + Paclitaxel + C  6  2  33.3  4.3  77.7  9.7  70.0  9.9  71.0
ARM  Dose Level 2: Ipilimumab, 10 mg/kg + Paclitaxel +   6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary DLT outcome and multiple secondary outcomes, spanning adverse events, best overall response, and ipilimumab pharmacokinetics. When a study examines multiple outcomes, general statistical practice distinguishes the primary question from secondary or exploratory questions. Testing many outcomes can increase the chance of observing an apparently notable result by chance if each is assessed separately. The registry record does not report a multiplicity strategy, such as an adjustment procedure, hierarchy, or a statement that secondary outcomes are descriptive.

The record lists no analyses and does not report inferential results for these outcomes. It therefore does not show whether statistical testing was performed, whether any multiplicity adjustment was used, or how outcome-specific uncertainty was assessed. Those details are not reported in the registry record and should not be inferred from the outcome list.

Missing-data handling is also not reported in the registry record. The endpoint population is described as participants who received at least one dose of ipilimumab, but the record does not state how participants with incomplete follow-up, unevaluable toxicity information, or missing measurements were treated. In general, missing observations can affect a participant-count endpoint if outcome status cannot be determined; the effect depends on the amount and reasons for missingness and on the analysis rules.

The registry names other outcomes that may require measurements at particular times, including pharmacokinetic measures and response. The record does not describe the handling of missing samples or unavailable assessments. The analysis populations for those outcomes are not reported in the registry record. The primary endpoint’s stated population should not automatically be assumed to apply to every secondary outcome.

These omissions limit reproducibility and prevent assessment of whether the reported analyses followed a prespecified plan. They do not establish that data were missing or that multiplicity adjustments were absent in the study itself; they mean those practices are not reported in the registry record.

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: pneumonitis (14.3%), hyponatraemia (12.5%), dyspnoea exertional (12.5%), hypoparathyroidism (12.5%), adrenal insufficiency (12.5%).

The registry reports serious adverse events for 3 of 8 participants in the 3 mg/kg dose-level group and 1 of 7 participants in the 10 mg/kg group. It reports other adverse events for 8 of 8 and 7 of 7 participants, respectively. These are participant counts within the group denominators recorded for those outcomes. They are descriptive and should not be read as a randomized comparison.

The record lists pneumonitis at 14.3%, and hyponatraemia, dyspnoea exertional, hypoparathyroidism, and adrenal insufficiency at 12.5% each among the serious adverse-event terms. The registry information does not specify how these listed percentages relate to dose-level groups. A person may also experience more than one event term, so the terms should not be added or interpreted as exclusive categories.

Serious adverse events are not interchangeable with DLTs. The primary DLT outcome applies specific criteria for study drug-related events and a defined timeframe. The safety counts do not show how many participants met that definition. Death counts are not reported in the registry record. These summaries describe recorded safety outcomes but do not, on their own, establish causation or support a controlled comparison.

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

The registry record establishes the study’s stated purpose and design: a Phase 1 evaluation of ipilimumab with paclitaxel and carboplatin, using two described ipilimumab dose levels in Japanese patients with non-small-cell lung cancer. Its primary question concerned dose-limiting toxicity and selection of a recommended dose. The record defines the primary endpoint, but does not report the DLT counts or a recommended dose.

The posted safety information gives participant counts for serious adverse events and other adverse events, along with selected serious-event terms and percentages. Those observations can be described as recorded. They cannot be treated as proof that an event was caused by a particular drug, nor do they show which dose level is preferable. The non-randomized design does not provide a randomized comparison, and the group counts are descriptive.

The absence of reported DLT results also means that the central dose-finding outcome cannot be assessed from this record. The listed secondary outcomes do not fill that gap because their results are not reported in the registry information. In particular, the outcome list alone does not establish a response result or a pharmacokinetic finding.

In general, an early-phase study can provide information about the conduct of a regimen and outcomes observed under its study conditions. It does not automatically establish comparative effectiveness or generalizability to people beyond the study population. The registry record does not describe enough detail to assess all aspects of eligibility, follow-up, analysis, or missing data. The appropriate interpretation is therefore limited: the study examined the stated combination and dose levels, and some adverse-event counts are recorded, but the key primary outcome result and several analytical details are not reported in the registry record.

14. Why This Trial Matters Statistically

Statistically, this study is a useful example of the distinction between a registered objective and a reported result. The primary purpose was dose selection, and the registry defines a DLT endpoint suited to a dose-finding question. Yet the DLT outcome counts and recommended dose are not reported in the record. A clear endpoint definition is valuable, but it cannot replace the observed endpoint data when assessing what happened.

The design also illustrates why dose-level groups should not automatically be treated as a controlled comparison. The registry describes non-randomized allocation, no masking, and a single-group model. It also names two dose levels. That combination of design labels and dose descriptions calls for care: the groups do not form a randomized comparison, and a difference between their observed counts would not by itself establish a dose effect.

Another statistical lesson is the importance of keeping distinct outcomes separate. The primary endpoint uses a study-specific definition of dose-limiting toxicity. Serious adverse-event counts, other adverse-event counts, response, and pharmacokinetic measures address different questions. The safety counts cannot stand in for the missing DLT result, and the names of secondary outcomes cannot be treated as their findings.

Finally, the record demonstrates how unavailable analysis details constrain interpretation. No analyses are listed, and multiplicity procedures, missing-data handling, and sample-size justification are not reported in the registry record. This prevents independent assessment of inferential methods and precision. The registry still provides useful design and outcome-definition information, but statistical conclusions must remain proportionate to the results and methods actually reported.

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 direct limitation is that the registry record does not report the primary DLT outcome counts or the recommended dose, despite defining the endpoint and stating dose selection as the primary purpose. This prevents assessment of the main study question from the posted registry information.

The study is listed as non-randomized, with no masking and a single-group model. The two dose-level descriptions do not amount to randomized control arms. The record does not explain how participants were assigned to dose levels, so any comparison between those groups would be vulnerable to differences unrelated to dose. A controlled estimate of a dose effect is not available from the design information.

The overall enrollment is 15, and the safety denominators are 8 and 7. These counts are limited for interpreting uncommon outcomes and provide only a descriptive view of the groups. The registry does not report confidence intervals or statistical tests for the safety summaries. The listed serious-event percentages are not mapped to the dose-level groups in the available record, which limits their interpretation.

Several design and analysis details are not reported in the registry record, including the dose-assignment or escalation procedure, sample-size justification, statistical analysis plan, multiplicity approach, missing-data handling, and analysis populations for secondary outcomes. The arm descriptions are truncated, so full regimen details cannot be reconstructed from the available text.

The record also lists response and pharmacokinetic outcomes without reporting their results. Death counts are not reported. Consequently, interpretation is restricted to the stated design, outcome definitions, and the adverse-event counts and terms that are explicitly recorded. These limitations describe what cannot be established from the registry record; they do not show that the study collected no further information.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Japanese Study of Ipilimumab Administered in Combination With Paclitaxel/Carboplatin in Patients With Nonsmall-cell Lung Cancer — NCT01165216.
• Registry record last updated 2014-07-22; status last verified 2014-06.
• Results first posted 2014-07-22.
• 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 completed Phase 1 study evaluated ipilimumab with paclitaxel and carboplatin in Japanese patients with non-small-cell lung cancer. Bristol-Myers Squibb is listed as sponsor. The registry records enrollment of 15, a start date of 2010-09, and primary completion in 2013-06.

The study described ipilimumab dose levels of 3 mg/kg and 10 mg/kg. Allocation is recorded as non-randomized, masking as none, and the model as single-group. The primary outcome was the number of participants experiencing a dose-limiting toxicity among those who received at least one dose of ipilimumab.

The registry record defines the primary endpoint but does not report its outcome counts or a recommended dose. It reports serious and other adverse-event participant counts and lists selected serious-event terms. It does not report analyses, and results for the listed response and pharmacokinetic outcomes are not included in the information available for interpretation.