ONO-4538 Phase I Study in Patients With Advanced Malignant Solid Tumors in Japan: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for ONO-4538 Phase I Study in Patients With Advanced Malignant Solid Tumors in Japan (NCT00836888), a na phase 1 study. The primary outcome is Cmax at Single Dose.

2. Clinical Question

3. Trial Design

This completed Phase I study was conducted at a single center and used an open-label, single-group design. Its official title describes dose escalation, a single dose followed by multiple doses, and evaluation of ONO-4538 in patients with advanced malignant solid tumors. The registry lists Japan as the setting and Ono Pharmaceutical Co., Ltd. as the sponsor.

Enrollment was 17. The study start is recorded as 2009-01 and primary completion as 2010-09. The registry marks the study completed. It does not report a randomized allocation scheme or a masking procedure; allocation is listed as not applicable and masking as none.

The safety record identifies cohorts receiving ONO-4538 at 1mg/kg, 3mg/kg, 10mg/kg, and 20mg/kg. The registry does not describe the dose-escalation rules, the order or timing of dose assignments, or how participants were distributed across the study’s single-dose and multiple-dose periods. Those procedural details are not reported in the registry record.

A single-group study can describe measurements and events observed among participants receiving the study intervention. Without a separate control group, it cannot make a like-for-like comparison with an untreated group or another treatment. The dose cohorts do not remove that limitation, because the registry does not identify them as randomized control groups. Details of the statistical plan, including any prespecified comparisons among dose cohorts, 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.

Overall Study

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Cmax at Single Dose, measured over day1(before administration, 1 hour after the start of administration, and 2 and 8 hours after the end of administration), day2(24 h), day3(48 h), day4(72 h), day8, day15, and day22 or at the discontinuation.

The named primary endpoint is “Cmax at Single Dose,” measured in μg/mL and specified as a mean with standard deviation. In general, Cmax is the highest measured concentration of a substance in blood or another sampled compartment over a defined observation period. For a pharmacokinetic study, it describes the observed peak concentration; it does not by itself describe the full concentration-time profile or establish a clinical effect.

The registry lists samples before administration, one hour after the start of administration, two and eight hours after the end of administration, at 24, 48, and 72 hours, on days 8, 15, and 22, or at discontinuation. These collection times define the scheduled observations relevant to the endpoint. A measured peak depends on the sampling schedule: a peak between scheduled samples may not be directly observed. This is a general consideration for concentration measurements, not a claim about what occurred in this study.

The registry does not provide the mean Cmax, its standard deviation, the number of participants contributing to the endpoint, or a confidence interval. It also does not specify the analysis population or explain how measurements after discontinuation were handled. Consequently, the endpoint’s definition and timing can be described, but its numerical result and precision cannot be evaluated from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry names a continuous primary endpoint and specifies that it is summarized using a mean and standard deviation. It does not report an endpoint estimate, a confidence interval, a hypothesis test, or a detailed statistical analysis. The concepts below explain how such methods are generally interpreted; they do not describe analyses confirmed to have been used in this study.

What do a mean and standard deviation describe?

In general, a mean gives a measure of the center of a set of numerical observations. A standard deviation describes how spread out those observations are around their mean. Together they provide a compact description of the observed values, but they do not show every value or explain why measurements vary. The standard deviation is not the same as the uncertainty in the mean. Estimating uncertainty in a mean requires information about the analysis sample and the statistical method used.

For Cmax, interpretation also depends on the sampling schedule and the participants whose measurements are included. The registry gives scheduled collection times but does not report the number of evaluable participants, the handling of missed samples, or whether the summary was calculated separately by dose cohort. Those details matter when judging how representative a mean is and how much information underlies it.

What would a confidence interval add?

In general, a confidence interval expresses uncertainty around an estimated quantity under a specified statistical procedure. It can show which values are reasonably compatible with the observed data and the assumptions of that procedure. A narrow interval indicates greater precision than a wide interval, but precision is not the same as clinical importance. No confidence interval for Cmax is reported in the registry record, so its precision cannot be judged from the posted results.

A confidence interval also would not resolve design limitations. In a single-group study, an interval around an observed mean would describe uncertainty about that group’s mean, not the difference between ONO-4538 and a control treatment. A comparison requires appropriate comparator data and a defined analysis. Neither a separate control group nor a comparative primary analysis is reported in the registry record.

What does the dose-cohort structure allow?

The safety listing distinguishes cohorts at 1mg/kg, 3mg/kg, 10mg/kg, and 20mg/kg. In general, dose cohorts can help describe observations at different dose levels. The meaning of a cross-cohort comparison depends on how participants were assigned, the timing and conduct of dose escalation, and whether differences in participant characteristics or follow-up are addressed. The registry does not report those details or a statistical method for comparing cohorts. The cohort counts should therefore be read as descriptive, not as estimates of causal differences between doses.

The record identifies no randomized comparator and lists a single-group model. A difference in counts across cohorts may reflect the small cohort sizes, the participants enrolled, the observation period, or other factors; the record does not provide information to separate those possibilities. No adjusted estimate or dose-response model is reported in the registry record.

How should planning calculations be understood?

In general, sample-size planning asks how many participants may be needed to detect a specified effect under stated assumptions. A planning illustration based on an observed effect is not an observed trial result and is not the study’s original design justification. The stated assumptions for planning illustrations are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect defined as a stated fraction of the observed effect. The illustrations are not the trial’s own design, and the study itself is a single-group trial rather than an equal-allocation comparison.

The registry does not report a sample-size justification or an effect-size target used when the study was designed. It also does not report the numerical Cmax result needed to assess an observed endpoint effect. Planning outputs, when interpreted generally, depend on their assumptions and should not be treated as observed power or as evidence that a result was significant. No sample-size calculation can substitute for the unreported endpoint estimate and analysis.

What can be concluded from the analysis record?

The registry lists five outcome measures and zero analyses. This describes the analysis information present in the record, not necessarily every analysis that may have occurred outside it. The statistical model, handling of repeated measurements, treatment of missing observations, and analysis populations are not reported in the registry record. Without those details, readers cannot reproduce an analysis or assess whether the reported endpoint and safety summaries followed a prespecified plan.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("ONO-4538 1mg/kg Cohorts", "ONO-4538 3mg/kg Cohorts", "ONO-4538 10mg/kg Cohorts", "ONO-4538 20mg/kg Cohorts")
n   <- c(3, 5, 6, 3)
m   <- c(24.4, 68.8, 192, 214)
sp  <- c(4.5, 10.9, 36, 68)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  ONO-4538 1mg/kg Cohorts  3  24.400  4.500  13.221  35.579
CARM  ONO-4538 3mg/kg Cohorts  5  68.800  10.900  55.266  82.334
CARM  ONO-4538 10mg/kg Cohorts  6  192.000  36.000  154.220  229.780
CARM  ONO-4538 20mg/kg Cohorts  3  214.000  68.000  45.079  382.921

11. Multiplicity, Missing Data and Analysis Populations

The registry lists five outcome measures and names Best Overall Response as a secondary outcome. The primary endpoint is Cmax at Single Dose. The registry record does not provide a full list of the outcome measures’ numerical results, their analysis time points beyond the primary endpoint’s stated schedule, or an analysis plan. It also records no analyses. A multiplicity adjustment, hierarchy among endpoints, or strategy for interpreting several outcomes is not reported in the registry record.

In general, when several outcomes or repeated tests are considered, the chance of a false-positive finding can rise if each is interpreted as an independent confirmatory test. Prespecified priorities or statistical adjustments can help address that issue. These are general statistical considerations; the registry does not establish that any particular approach was used in this study. Because numerical results for the secondary outcome are not reported, its findings and their uncertainty cannot be assessed.

Missing-data handling and analysis populations are also not reported in the registry record. For the Cmax endpoint, the record lists scheduled sampling from before administration through day 22 or discontinuation, but does not state how missed visits, incomplete concentration profiles, or discontinuations affected inclusion in the summary. It does not identify an intention-to-treat, safety, pharmacokinetic, or other analysis population.

These omissions limit reproducibility and interpretation. A reader cannot determine how many participants contributed to each outcome, whether all enrolled participants were analyzed, or whether missing observations were excluded or handled using a specified method. The registry information does not support assumptions about the planned analysis or the reasons for missing data.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pain in extremity (33.3%), malignant neoplasm progression (20.0%), dehydration (16.7%), alanine aminotransferase increased (16.7%), aspartate aminotransferase increased (16.7%).

The serious adverse event listing reports participants at risk and participants affected in each dose cohort. At 1mg/kg, 3 participants were at risk and 1 was affected; at 3mg/kg, 5 were at risk and 1 was affected; at 10mg/kg, 6 were at risk and 2 were affected; and at 20mg/kg, 3 were at risk and none were affected. The listed death count is 0 in every cohort. For other adverse events, the affected counts equal the at-risk counts in each cohort: 3, 5, 6, and 3, respectively.

The registry also lists serious-event terms with percentages: pain in extremity, 33.3%; malignant neoplasm progression, 20.0%; dehydration, alanine aminotransferase increased, aspartate aminotransferase increased, and blood bilirubin increased, 16.7% each. The registry does not report the denominator or calculation basis for these term percentages, so they should be read as listed rather than reconstructed.

These are descriptive counts, not comparative estimates. The registry does not provide event timing, duration, severity grades, or sufficient detail to determine relatedness to ONO-4538. The absence of recorded deaths in these cohort listings does not establish the absence of other harms or resolve uncertainty in a study with limited cohort sizes and no control group.

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

The registry record documents a completed Phase I, single-center, open-label study of ONO-4538 in Japanese patients with advanced malignant solid tumors. It identifies safety, tolerability, and pharmacokinetics as central aims and names Cmax at single dose as the primary endpoint. It also provides cohort-level adverse-event counts and lists Best Overall Response as a secondary outcome.

What the record does not provide is equally important for interpretation. Numerical Cmax results, response results, and detailed analyses are not reported in the registry record. The endpoint’s mean and standard deviation cannot be evaluated, and there is no reported confidence interval or comparative estimate. The serious adverse event counts describe the listed cohorts, but a single-group design cannot determine whether events were caused by the intervention or compare their frequency with a control group.

In general, early-phase studies can characterize measurements and safety observations in the participants enrolled, while uncertainty remains about how well those observations generalize. Here, the registry lists enrollment of 17 and small cohort-specific risk sets. Those counts do not establish the frequency of uncommon events or support a controlled comparison. The registry also does not describe the analysis populations, missing-data approach, or statistical plan needed to assess the completeness and conduct of the analyses.

The posted record therefore supports a narrow reading: it documents the study’s purpose, structure, endpoint definition, scheduled sampling, and recorded safety counts. It does not provide enough numerical outcome information to judge the primary pharmacokinetic result or the exploratory efficacy findings. These limits mean the record should not be treated as a complete report of all trial findings, nor as evidence for a treatment effect or lack of effect.

14. Why This Trial Matters Statistically

This study is statistically informative as an example of the distinction between a trial’s stated aims and the results available in a registry record. The record gives a specific continuous pharmacokinetic endpoint, its unit, summary measure, and sampling schedule. Those details clarify what was intended to be measured. Yet without a reported Cmax estimate, standard deviation, or analysis population, the numerical result and its precision cannot be assessed.

Its single-group structure also shapes what statistical conclusions are possible. Cohort-specific observations can describe what was recorded at the listed dose levels, but they do not create a randomized comparison. Differences between cohorts cannot automatically be attributed to dose, and there is no control group against which to estimate a treatment contrast. This distinction is important when interpreting dose-escalation studies and reading descriptive event counts.

The record further illustrates why completeness matters. A named secondary outcome and a count of outcome measures do not reveal the actual results, multiplicity strategy, or missing-data handling. The absence of numerical endpoint results prevents readers from judging variability or uncertainty, while the absence of a detailed analysis plan limits reproducibility.

For biostatistical interpretation, the study is therefore a reminder to separate design description, observed counts, and inferential results. The registry supports the first and offers some of the second, but does not report enough to evaluate the primary endpoint quantitatively. That boundary is central to a careful reading of this trial.

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.

Important trial-specific details are not reported in the registry record. The numerical Cmax result, its standard deviation, the number of participants contributing to the endpoint, and any confidence interval are absent. Numerical results for Best Overall Response and the other outcome measures are also not reported. Although five outcome measures are listed, the record does not provide their complete definitions or results.

The registry identifies a single-center, open-label, single-group study but does not describe eligibility criteria, participant characteristics, dose-escalation rules, or the distribution of enrollment across dose cohorts. The listed at-risk counts are available for safety summaries, but the record does not explain follow-up duration or the basis for those risk sets. No separate comparator group is reported, limiting comparative interpretation.

Analysis details are sparse. The statistical plan, analysis populations, missing-data methods, handling of measurements after discontinuation, and any multiplicity approach are not reported in the registry record. The record lists no analyses. These omissions prevent readers from reproducing the outcome summaries or determining how the planned analyses relate to the stated aims.

For safety, the registry gives cohort counts and selected serious-event terms but does not report event timing, duration, severity grades, or relatedness. The basis for the listed term percentages is not stated. These limitations constrain interpretation of both the event counts and the listed percentages.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: ONO-4538 Phase I Study in Patients With Advanced Malignant Solid Tumors in Japan — NCT00836888.
• Registry record last updated 2020-10-08; status last verified 2015-04.
• Results first posted 2020-10-08.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

The registry describes a completed Phase I, single-center, open-label, single-group study sponsored by Ono Pharmaceutical Co., Ltd. It enrolled 17 Japanese patients with advanced malignant solid tumors. The study start is recorded as 2009-01 and primary completion as 2010-09. ONO-4538 was evaluated as a single dose followed by multiple doses; the safety listing identifies cohorts at 1mg/kg, 3mg/kg, 10mg/kg, and 20mg/kg.

The primary endpoint is Cmax at single dose, in μg/mL, summarized as a mean with standard deviation. The registry gives sampling times but does not report the numerical endpoint result. Best Overall Response is listed as a secondary outcome; its results are not reported. Cohort-level serious and other adverse-event counts and death counts are recorded, but detailed event characteristics and a statistical analysis plan are not reported in the registry record.