A Study of EMD525797 in Solid Tumor Patients in Japan: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of EMD525797 in Solid Tumor Patients in Japan (NCT01327313), a non-randomized phase 1 study. The primary outcome is Number of Subjects With Dose-limiting Toxicities (DLTs).

2. Clinical Question

This is a dose-escalation question rather than a test of whether EMD525797 outperforms a control treatment. In a phase I study, early safety and tolerability observations help characterize what happened at the administered dose levels. Pharmacokinetic measurements address how drug concentrations change over time; the registry lists several such outcomes, including apparent terminal half-life and time to maximum observed serum concentration after single and multiple dosing.

The registry also names tumor response, clinical benefit and progression-free survival as secondary outcomes. Those outcomes address activity and disease course, but no numerical outcome results for them are reported in the registry record. Consequently, the available record does not establish how tumor outcomes varied by dose or how any such variation should be interpreted. The study question can be described from the objectives and endpoint definitions, but its primary numerical safety result cannot be recovered from this record.

3. Trial Design

The registry identifies NCT01327313 as a completed phase I trial of EMD525797 in patients in Japan with advanced or metastatic solid tumors. The trial was open-label, non-randomized and used a parallel model. It lists four EMD525797 dose groups: 250 mg, 500 mg, 1000 mg and 1500 mg. Enrollment was 27. The official title describes evaluation after single dosing and repeated dosing at different dose levels; specific schedules, escalation rules and assignment procedures are not reported in the registry record.

Because allocation was non-randomized, the dose groups should not be treated as equivalent groups created by random assignment. The registry lists no separate control treatment. Differences among groups, if observed, could reflect dose as well as other differences between the participants assigned to each group or their treatment experience. Open-label status also means the registry does not describe blinded assessment. The record does not report whether outcome assessors were otherwise kept unaware of dose.

The study began in 2011-01, reached primary completion in 2012-07 and is listed as completed. Its primary objectives were safety, tolerability and pharmacokinetics; secondary objectives included immunogenicity, progressive disease and anti-tumor activity. The record lists 29 outcome measures and no analyses. Arm descriptions contain no additional detail. The statistical plan, sample-size justification, interim-analysis arrangements and rules for moving between dose levels are not reported in the registry record.

The design is therefore best understood as an early clinical investigation describing outcomes across dose groups, not as a randomized efficacy comparison. The enrollment figure supplies the overall study size but does not by itself indicate how many participants contributed to each endpoint, or whether each participant completed the relevant observation period. Endpoint-specific analysis populations and missing-data details 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

Analysis population for the primary outcome, as defined in the registry: Dose escalation analysis set/DLT analysis set included all subjects who experienced a DLT or subjects who did not experience a DLT and had a relative dose intensity of \>= 75 percent (%) during the DLT observation period.

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: The all-subjects set included all the subjects who signed the informed consent and were treated.

6. Primary Endpoint

The registry lists the primary outcome as Number of Subjects With Dose-limiting Toxicities (DLTs), measured over Baseline up to Week 4.

The primary endpoint counts subjects with dose-limiting toxicities, or DLTs, from baseline up to Week 4. A count endpoint describes how many participants met the specified event definition; it is not a continuous measure of symptom severity or a rate per unit of follow-up. The registry defines a DLT as a Grade 3 or 4 haematological or non-haematological toxicity that occurred at any dose level by the end of Week 4 and was considered reasonably related to the investigational medicinal product by the Investigator and/or Sponsor.

The definition excludes allergic reactions or anaphylaxis. It also excludes certain Grade 3 or 4 out-of-range laboratory values without a clinical correlate if they were reversible within 7 days, unless the Investigator considered the event clinically significant. The record says those laboratory values were to be reassessed within 7 days. If the Investigator provided treatment because of the out-of-range laboratory values, the event was regarded as a DLT.

In early dose evaluation, this endpoint focuses attention on significant toxicities within a defined observation period. The trial's dose escalation analysis set/DLT analysis set included subjects who experienced a DLT, as well as subjects who did not experience a DLT and had relative dose intensity of at least 75% during the DLT observation period. The definition makes both event classification and evaluability relevant to interpreting a count. However, the number of DLTs in each dose group, and the number included in this analysis set, are not reported in the registry record. The endpoint's definition is available, but its numerical result is not.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

General statistical context: a count endpoint records the number of participants who meet an event definition. For this study, the event was a DLT within the stated observation period. Interpretation depends on both the event criteria and the participants included in the analysis. The registry defines the endpoint and describes a DLT analysis set, but it does not report the resulting count by dose or the analysis used to estimate or compare those counts.

What does non-randomized allocation mean?

General statistical context: random assignment is used to reduce systematic differences between treatment groups at the point of allocation. In a non-randomized study, observed group differences may reflect factors other than the treatment level. Here the registry explicitly identifies allocation as non-randomized and lists the four groups as different doses of the same intervention. A numerical difference between dose groups, if available, would therefore be descriptive and would not by itself establish that dose caused the difference. The record does not report allocation procedures or baseline characteristics by group that would help assess the comparability of participants.

How should a count be distinguished from a rate?

General statistical context: a count is the number of participants with an event, whereas a rate accounts for time at risk or observation. A proportion relates an event count to a defined denominator. The primary endpoint is described as a number of subjects, not a person-time rate. The registry does not report the DLT counts or endpoint-specific denominators, so a proportion or rate cannot be interpreted from the primary outcome information. The safety summary does give numbers at risk and numbers affected by serious adverse events within each dose group; these remain descriptive counts unless the observation and denominator rules are also clear.

The DLT observation window ran from baseline up to Week 4. A time window matters because an event occurring outside it would not meet the endpoint's timing criterion as described, even if it were clinically important. The event also had to meet the stated grade and relationship conditions, subject to the stated exclusions and laboratory-value rules. Since judgment by the Investigator and/or Sponsor is part of the definition, consistent classification is important. Adjudication procedures are not reported in the registry record.

What does the analysis population definition contribute?

The dose escalation analysis set/DLT analysis set included every subject who experienced a DLT and subjects who did not experience a DLT if their relative dose intensity was at least 75% during the DLT observation period. This definition recognizes that a participant who received less than the required level of planned exposure without a DLT may not provide the same evaluability for dose-limiting toxicity as a participant who received sufficient exposure. It also means that inclusion depends on both outcome status and relative dose intensity. The record does not report how many participants met each condition or whether other analysis populations were used.

General statistical context: a confidence interval describes the range of estimates compatible with the data and a specified statistical procedure. Its width reflects precision as well as the amount and variability of information. For a count or proportion based on small groups, uncertainty can be substantial. No confidence intervals for DLTs or serious adverse-event counts are reported in the registry record, so the precision of those event estimates cannot be quantified from the available results.

What can p-values and effect estimates tell a reader?

General statistical context: an effect estimate describes the magnitude and direction of a contrast or outcome, while a p-value measures how incompatible the observed data are with a specified null model, subject to the assumptions of that test. A p-value does not show the probability that a treatment is effective, and it does not measure clinical importance. In this study record, no primary-outcome estimate or p-value is reported. Further, the non-randomized allocation limits causal interpretation of unadjusted comparisons between dose groups. No adjusted analysis is described.

The registry lists a planning illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms and a normal approximation; it specifies that the effect to detect is a stated fraction of the observed effect. These are planning assumptions, not evidence that the study was designed with those settings. The trial's own sample-size justification is not reported in the registry record. Such illustrations are prospective planning exercises, not observed power, and they do not substitute for a reported effect estimate and its uncertainty.

Why do assumptions matter?

General statistical context: a normal approximation uses a simplified distribution to make calculations tractable. Its suitability depends on the data and setting; with limited event information, approximation quality may be a concern. Equal allocation is an assumption in the planning illustration, not a description of observed enrollment by dose. A two-sided significance level sets a threshold for a particular testing procedure, but the record does not state that threshold as the trial's analysis plan. The statistical plan, model choices, adjustment strategy and handling of repeated or multiple outcomes are not reported in the registry record.

Pharmacokinetic endpoints require a different statistical interpretation from event counts. The registry names apparent terminal half-life, time to maximum observed serum concentration and an elimination rate constant, including measurements after single or multiple dosing. These outcomes concern concentration-time behavior. No corresponding numerical results or analysis methods are reported in the registry record, so their estimates, variability and relationship to dose cannot be described. Overall, statistical interpretation must remain bounded by the design information and descriptive safety counts actually recorded.

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("EMD525797 250 mg", "EMD525797 500 mg", "EMD525797 1000 mg", "EMD525797 1500 mg")
n      <- c(8, 6, 6, 6)
events <- c(0, 0, 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  EMD525797 250 mg  8  0  0.0  0.0  36.9  0.0  32.4  0.3  33.6
ARM  EMD525797 500 mg  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  EMD525797 1000 mg  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  EMD525797 1500 mg  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0

11. Multiplicity, Missing Data and Analysis Populations

The registry names a broad set of secondary outcomes, including overall tumor response, clinical benefit, progression-free survival, pharmacokinetic measures, immunogenicity and progressive disease. Examining multiple outcomes can raise a multiplicity issue: when many hypotheses are tested, the chance of at least one apparently unusual result may increase. General statistical context: investigators can address multiplicity by specifying a hierarchy, adjusting testing thresholds or treating outcomes as exploratory. The registry record does not report a multiplicity strategy, a hierarchy among secondary outcomes or which outcomes were formally tested.

The record lists 29 outcome measures and no analyses. It does not report numerical results for the primary DLT endpoint or the named secondary outcomes. It also does not describe how missing endpoint observations were handled, whether participants discontinued, or whether there were exclusions from outcome-specific analyses. Those details are important because missing observations can affect both denominators and interpretation, especially when a participant's observation period or drug exposure is incomplete.

The DLT analysis set is defined using occurrence of DLT and relative dose intensity of at least 75% for participants without a DLT. However, the number meeting the definition, reasons for any lack of evaluability and treatment of other missing data are not reported in the registry record. The record does not give a statistical analysis plan, interim-analysis procedures or a sample-size justification. Consequently, it is not possible to assess whether the listed endpoints were all prespecified for formal inference, how multiplicity was handled, or whether missingness could have altered the reported findings.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: colitis (16.7%), decreased appetite (16.7%), cancer pain (16.7%), pneumonia (14.3%), atelectasis (12.5%).

The serious adverse-event summary reports participants at risk and participants affected by at least one serious adverse event in each dose group. For 250 mg, 8 were at risk and 1 was affected; for 500 mg, 6 were at risk and 1 was affected; for 1000 mg, 6 were at risk and 1 was affected; and for 1500 mg, 7 were at risk and 1 was affected. These are group-level descriptive counts. Since the trial was non-randomized and the groups are small, they should not be read as a controlled comparison of safety across doses.

The registry lists Colitis, Decreased Appetite and Cancer Pain at 16.7%, Pneumonia at 14.3% and Atelectasis at 12.5% among the top serious-event terms. The record does not report the denominators or dose-group attribution for these percentages. The number of deaths is not reported in the registry record; a missing death value should not be interpreted as a reported zero.

Serious adverse events are not identical to dose-limiting toxicities. DLT status depends on the endpoint's own toxicity grade, timing, relationship and exclusion criteria. The safety counts alone do not show which events met that definition, how long each participant was followed, or whether participants had more than one event.

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

The record establishes that a completed phase I study evaluated EMD525797 at four dose levels in Japanese patients with advanced or metastatic solid tumors. Its primary objective included assessment of safety and tolerability, and its primary endpoint was the number of subjects with DLTs during the period from baseline up to Week 4. The registry also records serious adverse-event counts by dose group and names additional tumor and pharmacokinetic outcomes.

What it does not establish is the number of participants with DLTs in any group. That primary numerical result is not reported in the registry record. The listed serious adverse-event counts do not fill that gap because seriousness and dose-limiting status are distinct classifications. The available record also does not provide numerical estimates for tumor response, clinical benefit, progression-free survival or pharmacokinetics. Therefore the registry objectives should not be mistaken for evidence of specific findings.

Nor do the safety summaries establish that one dose level is safer than another. Allocation was non-randomized, there was no separate control group listed, and the group counts are descriptive. A difference in counts between dose groups could not be attributed to dose alone from this design and record. No uncertainty intervals or adjusted analyses are reported to quantify the precision of comparisons.

The study's scope is early investigation, not a definitive assessment of clinical benefit. The registry record is useful for understanding the intended population, dose levels, endpoint definition and selected event summaries. It is insufficient for estimating the frequency of DLTs, judging the precision of a dose comparison, or drawing conclusions about anti-tumor activity. Any fuller interpretation would require numerical outcome results and analysis details that are not reported in the registry record.

14. Why This Trial Matters Statistically

This study illustrates a distinction central to reading clinical trial records: the endpoint definition and the endpoint result are different kinds of information. The registry gives a detailed DLT definition, including grade, timing, attribution and exceptions, but does not report the number of participants who met it. Without that count, readers cannot evaluate the primary safety endpoint numerically, even though its intended role in the study is clear.

The design also matters. Four dose groups can support descriptive learning about the experience at different doses, but non-randomized allocation does not ensure that groups are comparable. The group-level serious-event counts should therefore be read as observations within dose cohorts, not as causal evidence that dose level changed risk. This is especially important when a study has limited enrollment and the reported outcome is a count.

Finally, the record shows why the phrase phase I does not make every safety statistic interchangeable. The primary endpoint was DLT, whereas the safety summary separately reports serious adverse events. Different event definitions answer different questions. Knowing which participants experienced serious events cannot be used to reconstruct DLT counts, and the listed serious-event terms cannot be assigned to dose groups without the relevant detail.

Statistically, this trial matters as an example of the limits of interpretation when registry design details and outcome data are unevenly available. The study objectives identify what investigators intended to learn; the posted counts describe only selected safety information. The missing primary result, analysis details and uncertainty measures limit how far the evidence can be taken. Clear distinctions among design, endpoint definition, observed data and inference are essential for accurate interpretation.

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 primary limitation for statistical interpretation is that the registry record does not report the numerical DLT outcome, despite defining it as the primary endpoint. No DLT counts by dose group, endpoint-specific denominators, confidence intervals or tests are reported. As a result, the central safety endpoint cannot be assessed from this record. The record also lists no analyses and gives no statistical analysis plan.

The non-randomized, open-label design limits interpretation of any between-dose differences. Participants were not assigned by randomization, and the registry describes no separate control group. The record does not report baseline characteristics by dose, allocation procedures, detailed dose schedules, escalation rules or blinded outcome assessment. Arm descriptions contain no additional information. These omissions make it difficult to assess group comparability or fully reconstruct study conduct.

The safety summary is limited to counts of participants at risk and affected, plus a list of top serious-event terms and percentages. The record does not report death counts, denominators for the term percentages, event-level timing, recurrence, duration, outcome or dose-group attribution for those terms. The primary DLT classification cannot be inferred from serious-event counts.

Secondary outcomes are listed, but their numerical results and analysis populations are not reported in the registry record. Missing-data handling, withdrawals, protocol deviations and endpoint-specific evaluability are also not described. The DLT set definition is available, but the number of participants meeting it is not. Sample-size justification, interim-analysis procedures and multiplicity methods are not reported. These gaps constrain both reproducibility and assessment of the precision and robustness of any study findings.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study of EMD525797 in Solid Tumor Patients in Japan — NCT01327313.
• Registry record last updated 2016-05-13; status last verified 2016-04.
• Results first posted 2016-05-13.
• 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

NCT01327313 is a completed phase I, open-label, non-randomized, parallel trial of EMD525797 in Japanese patients with advanced or metastatic solid tumors and progressive disease following prior chemotherapy. Enrollment was 27. The four dose groups were 250 mg, 500 mg, 1000 mg and 1500 mg.

The primary endpoint was the number of subjects with DLTs from baseline up to Week 4. The registry defines DLT and the related analysis set, but does not report the numerical primary outcome. Serious adverse-event summaries list 1 affected participant in each dose group. Numerical results for the named secondary tumor and pharmacokinetic outcomes are not reported in the registry record.

Non-randomized allocation and the absence of a listed control group mean dose-group summaries are descriptive, not randomized comparisons. The statistical plan, sample-size justification, interim-analysis procedures and missing-data handling are not reported in the registry record.