Japanese Phase 1 Trial of Sym004 in Solid Tumors: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Japanese Phase 1 Trial of Sym004 in Solid Tumors (NCT01955473), a na phase 1 study. The primary outcome is Number of Subjects With Dose Limiting Toxicities (DLTs) Determined in Part-A.

2. Clinical Question

The study’s stated purpose was to assess the safety and tolerability of Sym004 in Japanese subjects with advanced solid tumors. Its structure included dose escalation in Part A and dose expansion in Part B. The registry summary describes weekly or biweekly monotherapy in Part A, while Part B used weekly monotherapy in Japanese subjects with advanced esophageal squamous cell carcinoma. The dose selected for Part B was to be determined after safety confirmation of weekly regimens in Part A, with the registry describing a dose at or below the maximum tolerated dose as a possibility.

The primary question is a safety and dose-limiting toxicity question, not a comparison of treatment effects against an untreated or active-control group. The posted primary endpoint is the number of subjects with dose-limiting toxicities in Part A during the stated observation period. Although the registry defines the qualifying toxicities, it does not report the numerical primary endpoint result. A count of dose-limiting toxicities therefore cannot be inferred from the description of the endpoint or from the adverse-event counts.

The registry lists secondary outcomes concerning Sym004 concentration over time, including area under the concentration-time curve for single and multiple doses under weekly and biweekly regimens. These are pharmacokinetic measures, distinct from the primary toxicity count. The registry record lists 43 outcome measures, but the posted information summarized for this trial does not provide the numerical findings for those secondary outcomes.

3. Trial Design

This was a Phase I, open-label, single-group trial of Sym004 as monotherapy in Japanese subjects. The registry reports that the study was completed, with a start date of 2013-10-31 and a primary completion date of 2015-10-31. Enrollment was 51. These registry-level descriptors do not by themselves indicate how many enrolled subjects contributed to any particular endpoint or analysis population.

The trial had two parts. Part A was a dose-escalation part and included weekly or biweekly regimens. Its primary endpoint was the number of subjects with dose-limiting toxicities during the observation period from Week 1 up to Week 4. Part B was a dose-expansion part in Japanese subjects with advanced esophageal squamous cell carcinoma, using weekly Sym004 monotherapy. The registry lists the Part B regimen as Sym004 12 mg/kg. It describes selection of the Part B dose as dependent on safety confirmation of weekly regimens in Part A.

The record lists allocation as not applicable, masking as none, and the model as single group. It does not describe a randomized assignment or a masked comparison. The dose cohorts are therefore descriptive groups within the study, not randomized treatment arms designed to estimate a causal difference between doses. Differences in event counts across those groups could reflect the distinct dose regimens, the different trial parts and populations, or other differences; the record does not establish that the groups are exchangeable.

The study was designed around dose escalation and expansion rather than a comparative efficacy question. The registry provides no statistical analysis plan, sample-size justification, or description of interim analyses. Those design details are not reported in the registry record. The listed enrollment is not a substitute for an endpoint-specific analysis count, and no number of subjects evaluated for the primary endpoint is reported in the posted primary result information. The absence of a comparator also means that the trial does not provide a direct estimate of how Sym004 compares with another treatment or with no treatment.

4. Participant Flow and Accounting

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

Before assignment: A total of 60 subjects were screened for eligibility, out of which and 51 subjects were randomized into the study.

Overall Study

Analysis population for the primary outcome, as defined in the registry: DLT Analysis Set consisted of all subjects who received at least 3 of 4 weekly administrations (for weekly dosing cohort) or who received 2 biweekly administrations (for biweekly dosing cohort) and experienced a DLT during 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: Safety analysis set consisted of all subjects (from Parts A and B) who received at least 1 administration of Sym004.

6. Primary Endpoint

The registry lists the primary outcome as Number of Subjects With Dose Limiting Toxicities (DLTs) Determined in Part-A, measured over Week 1 up to Week 4 (Part A).

The primary endpoint is the number of subjects with dose-limiting toxicities determined in Part A. The registry places its observation period from Week 1 up to Week 4. A dose-limiting toxicity was defined using selected NCI-CTCAE toxicity criteria, along with attribution and review requirements. The event had to be considered at least possibly related to study treatment by the investigator and confirmed by the Safety Monitoring Committee.

The listed criteria include specified severe hematologic toxicities, such as Grade 4 neutropenia and Grade 4 thrombocytopenia, and selected nonhematologic toxicities. The definition also includes exceptions and qualifications, including exclusions for some Grade 3 fatigue or skin toxicity and conditions relating to nausea, vomiting, diarrhea, and liver laboratory abnormalities. These details matter because the endpoint is not simply any adverse event or any serious adverse event. It is a defined subset of toxicities assessed within a specified observation period and subject to attribution and confirmation.

In general, a dose-limiting toxicity endpoint is used in dose-escalation research to characterize treatment tolerability and inform decisions about dose selection. It focuses attention on toxicities considered sufficiently important under the study’s definition and timeframe. It does not summarize every aspect of safety, nor does a count alone describe the severity, duration, reversibility, or clinical context of every event.

The registry record names the endpoint but does not report its numerical result. The DLT Analysis Set is described as subjects who met the specified treatment-exposure condition for their dosing cohort and experienced a DLT during the observation period. The record does not report the size of that analysis set or a primary endpoint count. Consequently, the endpoint definition can be interpreted, but the observed primary result cannot be quantified from the posted information.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What kind of outcome is the primary endpoint?

The primary outcome is a binary event summarized as a count of subjects with a qualifying dose-limiting toxicity. “Binary” means that, for the endpoint definition, each eligible subject is classified according to whether the specified event occurred during the specified period. The registry describes the endpoint as a number of subjects, rather than a continuous measurement such as a laboratory concentration. It does not report the observed count or the endpoint analysis denominator, so a rate or uncertainty interval for this outcome cannot be interpreted from the record.

In general, binary outcomes can be presented as event counts and denominators, or as proportions with uncertainty intervals. A confidence interval expresses the uncertainty around an estimated quantity under a statistical model; it is not a guarantee that the true value lies within the interval. No confidence interval for the primary endpoint is reported in the registry record. A denominator is essential to interpret a count, because the same count can have different meanings in groups of different sizes.

Why does the DLT definition matter?

The registry’s definition is more specific than “any toxicity.” It names qualifying hematologic and nonhematologic events, sets exceptions and conditions for some events, and requires investigator assessment of a possible relationship to treatment plus Safety Monitoring Committee confirmation. The endpoint also has a defined observation period, Week 1 up to Week 4. A toxicity outside that period, or an event that does not meet the stated criteria or review requirements, would not automatically qualify as a primary endpoint event under this definition.

In general, a prespecified event definition improves consistency in how investigators classify outcomes. It also limits what the outcome means: the count represents events that satisfy the stated rule, rather than the full burden of all adverse experiences. Interpretation depends on the rule, how it was applied, and which subjects were included in the analysis set. The registry describes the DLT Analysis Set as requiring a specified amount of treatment exposure for the relevant dosing cohort and experience of a DLT during the observation period. The number meeting this description is not reported.

How should the cohort structure be understood?

The study is described as a single-group, open-label Phase I trial, with dose escalation in Part A and dose expansion in Part B. In general, dose-escalation groups are investigated to characterize tolerability across regimens; they are not automatically equivalent to randomized comparison groups. Here, the registry specifies no randomized allocation, no masking, and no like-for-like control comparison. Part A and Part B also have different stated populations and roles in the study. A raw contrast between their counts would combine differences in regimen and trial part, and would not isolate a treatment effect.

For an event count, the number at risk and the number affected should be read together. The serious adverse-event entries give both values for each group. The record also lists counts for other adverse events. These summaries describe the posted groups; they do not show adjusted comparisons, account for differences in observation time, or provide a model-based estimate. Such methods are not reported in the registry record, so no adjusted effect should be inferred.

What do the analysis and planning methods establish?

The registry reports zero analyses for the posted outcome information and does not describe an inferential analysis plan for the primary endpoint. This means the record does not provide an analysis method, a hypothesis test, or a primary endpoint uncertainty interval to interpret. It does not establish that no analyses were conducted outside the information posted in the registry. The trial’s statistical plan, including any planned interim analyses, is not reported in the registry record.

The record describes sample-size calculations as planning 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 states that the effect to detect is a stated fraction of the observed effect. For time-to-event outcomes, the planning quantities refer to total events; for other outcomes, they refer to participants per arm. These calculations are illustrations, not evidence that the trial was planned using those assumptions, and they are not observed power. The registry does not report a sample-size justification for this single-group dose-escalation and dose-expansion design. A two-arm planning illustration should not be mistaken for the design actually used in this trial.

Why does over-dispersion matter in general?

Over-dispersion is a general issue for count data when variability exceeds what a simple statistical model assumes. If present, standard errors from an overly restrictive model can be too small, making uncertainty appear less than it is. This trial’s primary endpoint is a subject count of DLTs, and the posted information does not report a model or a dispersion estimate. There is therefore no basis in the registry record to claim that over-dispersion was assessed or to apply a correction. The concept is relevant as a general caution for count-data modeling, not as a reported feature of this trial’s analysis.

How should statistical significance be interpreted?

Statistical significance describes evidence against a specified statistical null hypothesis under an analysis plan; it does not by itself establish clinical importance or causality. This trial has no randomized control group listed, and no primary endpoint test or p-value is reported. There is consequently no registry-based significance result to interpret. Descriptive event counts remain useful for understanding what was recorded in the cohorts, but they should not be presented as a formal comparative test.

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("Part A: Sym004 6 mg/kg", "Part A: Sym004 9/6 mg/kg", "Part A: Sym004 12 mg/kg", "Part A: Sym004 18 mg/kg")
n      <- c(3, 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  Part A: Sym004 6 mg/kg  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Part A: Sym004 9/6 mg/kg  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Part A: Sym004 12 mg/kg  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Part A: Sym004 18 mg/kg  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 lists a primary endpoint and 43 outcome measures, including pharmacokinetic outcomes and safety outcomes. It reports zero analyses for the posted outcome information. A multiplicity strategy, such as an order for testing outcomes or a method to control the chance of false-positive findings across multiple tests, is not reported in the registry record. The number of listed outcomes alone does not show that they were all tested, nor does it establish how any testing was handled.

Missing-data methods are not reported in the registry record. The available descriptions do not state how subjects with incomplete follow-up, missed assessments, treatment discontinuation, or unavailable measurements were handled for the primary endpoint or secondary outcomes. They also do not report whether any outcome values were missing. No imputation method or sensitivity analysis is described, so none should be assumed.

The registry’s DLT Analysis Set description specifies that subjects had to meet a cohort-specific treatment-exposure condition and experience a DLT during the observation period. The record does not report the number meeting this definition or explain how subjects who did not meet its exposure criteria were represented in endpoint reporting. This means the listed enrollment of 51 cannot be treated as the primary endpoint denominator. The relationship between enrollment, the analysis set, and the reported safety groups is not fully described in the registry record.

In general, analysis populations determine which subjects contribute to a particular estimate. Different rules can produce different denominators and affect interpretation, especially when exposure or follow-up varies. Here, only the DLT Analysis Set description is available; the statistical analysis plan and additional analysis-population definitions are not reported in the registry record. The result is a limitation in assessing how completely and consistently outcomes were captured, rather than evidence that a particular missing-data problem occurred.

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: compression fracture (16.7%), venous thrombosis limb (16.7%), cardiac arrest (3.3%), dysphagia (3.3%), nausea (3.3%).

The registry separates serious adverse events from other adverse events and gives affected-subject counts alongside the number at risk for each listed group. For serious adverse events, the reported entries are 0 of 3 in Part A: Sym004 6 mg/kg, 0 of 6 in Part A: Sym004 9/6 mg/kg, 2 of 6 in Part A: Sym004 12 mg/kg, 0 of 6 in Part A: Sym004 18 mg/kg, and 9 of 30 in Part B: Sym004 12 mg/kg. For other adverse events, the affected count equals the number at risk in each group.

The registry also lists serious-event terms and frequencies: Compression fracture and Venous thrombosis limb at 16.7% each, and Cardiac arrest, Dysphagia, Nausea, and Lung infection at 3.3% each. These terms and percentages are registry summaries; they do not identify whether an event met the DLT definition. The record does not provide enough detail in these summaries to establish the timing, duration, recurrence, or causal relationship of each event.

In general, serious adverse events and dose-limiting toxicities answer different questions. Seriousness is an adverse-event classification, while the DLT endpoint applies the trial-specific toxicity criteria, observation period, attribution requirement, and committee confirmation. The two categories may overlap, but they should not be treated as equivalent. The counts are descriptive and should not be read as treatment-versus-control effects, since the trial had no like-for-like control group. Small group sizes also limit precision, and the registry does not report uncertainty intervals for these counts.

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

The registry record describes a completed Japanese Phase I study of Sym004 monotherapy in advanced solid tumors, with dose escalation in Part A and dose expansion in Part B. It documents the intended safety focus, the primary DLT endpoint definition, and adverse-event counts for the listed dose groups. The record also identifies pharmacokinetic outcomes as secondary measures. These details show what the study was organized to assess and how some safety events were summarized.

The primary endpoint’s numerical result is not reported in the registry record. Therefore, the posted information does not establish how many subjects experienced a qualifying DLT in Part A or how that count relates to the relevant analysis-set denominator. The serious adverse-event summaries offer some descriptive safety information, but they cannot fill that gap: serious adverse events are not identical to DLTs, and the registry does not report a conversion between those categories.

The study does not provide a randomized control comparison. Its dose groups differ by regimen and trial part, and Part B has a population description specific to advanced esophageal squamous cell carcinoma. As a result, counts across cohorts should not be interpreted as a causal comparison of doses or as evidence that one regimen is safer or less safe than another. The registry’s own note cautions that the arms are not a like-for-like control comparison.

In general, a safety-focused Phase I study can describe observed toxicities in the participants and cohorts studied. Such descriptions are not, by themselves, estimates of comparative benefit or evidence about outcomes in populations not represented by the trial. The record does not report a primary efficacy endpoint result, and no treatment-effect comparison is reported. The statistical precision of the primary endpoint cannot be assessed because its count and denominator are absent from the posted information.

The findings should therefore be understood narrowly: the record supplies the trial framework and certain adverse-event summaries, while leaving the primary DLT result and several analysis details unreported. This does not establish that the trial found no DLTs, that all safety outcomes were captured in the posted summaries, or that any treatment effect was present or absent. It describes the limits of what can be concluded from the registry record.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of the distinction between naming an endpoint and reporting an endpoint result. The registry defines a primary safety outcome in considerable detail, including its observation period, qualifying toxicity criteria, attribution, and confirmation. Yet the numerical result is not reported. Without the count and denominator, readers cannot estimate the observed frequency or assess its precision. A clear endpoint definition improves interpretability only when the corresponding result and analysis population are also available.

The study also illustrates why dose cohorts should not automatically be treated as comparative arms. The registry describes a single-group design with no randomized allocation and no masking. Part A is a dose-escalation component, while Part B is a dose-expansion component with a specified disease population and weekly regimen. In general, differences between such cohorts can reflect differences in population, regimen, and study purpose as well as chance. A direct numerical contrast would not isolate the effect of dose.

Another statistical lesson is that safety outcomes are not interchangeable. The serious adverse-event summaries and the DLT endpoint concern different classifications. DLTs use a study-specific definition and assessment process; serious adverse events are reported as a separate safety category. Reading them together can provide context, but one cannot substitute for the other. The registry’s separate reporting makes that distinction important.

Finally, the record demonstrates the value of reporting analysis populations, denominators, and uncertainty alongside event counts. Enrollment is reported as 51, but the primary endpoint analysis-set size is not. The posted event counts remain descriptive, and the record does not provide an inferential analysis plan or confidence intervals. For researchers, these gaps limit assessment of precision, completeness, and generalizability. They also show why planning illustrations should be distinguished from a trial’s actual design and from observed statistical power.

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 interpreting the main safety question is that the registry does not report a numerical DLT result or the number of subjects in the DLT Analysis Set. Although the record defines that analysis set and the DLT observation period, it does not provide the result needed to quantify the primary endpoint. The enrollment count of 51 cannot be used as a substitute for the endpoint denominator.

The trial is single-group, open-label, and without randomized allocation. There is no concurrent control group for estimating a comparative effect. The dose groups also span two study parts, with Part B focused on Japanese subjects with advanced esophageal squamous cell carcinoma. These features limit any interpretation of differences in event counts across groups as dose effects or as causal treatment comparisons.

The adverse-event summaries provide affected counts and group sizes, along with selected serious-event terms and percentages, but the registry does not report uncertainty intervals or adjusted analyses for these outcomes. The summaries also do not provide a complete account of event timing, duration, recurrence, or attribution. The serious adverse-event figures cannot be used to reconstruct the DLT result because the definitions differ.

Further limitations arise from unreported analysis details. The statistical analysis plan, sample-size justification, interim analyses, missing-data approach, multiplicity strategy, and endpoint-specific analysis populations beyond the stated DLT Analysis Set description are not reported in the registry record. The registry also lists secondary pharmacokinetic outcomes without numerical findings in the posted information. These omissions limit assessment of how outcomes were analyzed and how precisely they were estimated; they do not establish that any particular analysis or data-handling practice was or was not used outside the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Japanese Phase 1 Trial of Sym004 in Solid Tumors — NCT01955473.
• Registry record last updated 2017-08-23; status last verified 2017-07.
• Results first posted 2017-03-07.
• 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 record describes NCT01955473, a completed Japanese Phase I open-label trial of Sym004 monotherapy in subjects with advanced solid tumors. Enrollment was 51. The study included dose escalation in Part A, with weekly or biweekly regimens, and dose expansion in Part B, which enrolled subjects with advanced esophageal squamous cell carcinoma and used weekly Sym004 at 12 mg/kg. The listed primary endpoint was the number of subjects with dose-limiting toxicities in Part A from Week 1 up to Week 4.

The registry defines DLT criteria and describes the DLT Analysis Set, but does not report the primary endpoint count or analysis-set size. It reports serious and other adverse-event counts for the listed groups and selected serious-event terms. The design is single-group, with no randomized allocation, masking, or like-for-like control comparison. Statistical analysis, missing-data, and multiplicity details are not reported in the registry record.