Sym004 in Patients With Advanced Solid Tumors: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Sym004 in Patients With Advanced Solid Tumors (NCT01117428), a na phase 1, phase 2 study. The primary outcome is Number of Participants With Adverse Events (AEs).

2. Clinical Question

3. Trial Design

This was an open-label, multicenter study of Sym004 in people with advanced solid tumors. The registry lists both Phase I and Phase II. Its official title describes a Phase I dose-escalation study investigating safety and tolerability with multiple doses. The brief summary says the study consisted of five parts, while the posted adverse-event groups are labeled Part A through Part F. The record does not explain this difference.

The study is classified as single-group, with no masking and allocation listed as not applicable. Participants and investigators were therefore not described as blinded, and the study does not provide a randomized control arm for direct comparison. The intervention is listed as Sym004, but the registry information does not specify the individual doses, dose schedules, or how participants were assigned among the dose-expansion cohorts.

Enrollment was 111. The recorded start was 2010-03, primary completion was 2015-02, and the status is completed. The record lists metastatic colorectal cancer as a condition, although the title and official title refer more broadly to advanced solid tumors. Detailed eligibility criteria and the distribution of participants by tumor type are not reported in the registry record.

The safety results are organized across dose-escalation and dose-expansion groups. Because this is not a randomized comparison, differences among those groups should not be treated as treatment effects or as like-for-like comparisons. The groups may differ in ways not described in the registry record, and the posted counts do not establish why their results differ.

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

Reasons for not completing this 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: Part A: Dose escalation in patients with refractory or recurrent advanced solid tumors. Parts B, C, D, E and F: Dose expansion cohorts in patients wíth advanced anti-EGFR antibody refractory mCRC.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Adverse Events (AEs), measured over Visit 2 until first follow-up visit (up to 66 weeks).

The primary endpoint is the number of participants with adverse events. The registry specifies a timeframe beginning at Visit 2 and continuing until the first follow-up visit, up to 66 weeks. It describes summarizing adverse events using descriptive statistics, overall and by system organ class and preferred term, with counts and percentages of participants with events and total event counts.

Counting participants with events is a way to describe how widely adverse events occurred within the study group. A participant count is not the same as a count of all events: one person may experience more than one event, and the endpoint description distinguishes the number of affected participants from the total number of events. The registry record does not give the overall primary-endpoint result in the information. The posted group-level safety figures distinguish serious adverse events and other adverse events, but those figures should not be mistaken for a complete report of every element described for the primary endpoint.

Safety monitoring is central to a dose-escalation study because the study is intended to investigate safety and tolerability as doses are explored. This is a general explanation of the role of such an endpoint, not a claim about a particular dose decision or study procedure. A count of participants with events describes observed occurrence during the stated period; it does not, by itself, establish causation, severity beyond the categories reported, or comparative risk relative to another treatment.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The posted safety results are counts and percentages, so their interpretation is primarily descriptive. They report what was observed among the participants in the listed groups. A count identifies the number of participants with an event; the at-risk count supplies the group denominator for that reported category. A percentage can make frequencies easier to compare across groups of different sizes, but it needs a clear denominator and definition to be interpreted correctly. The denominator for the listed serious-event terms is not reported in the registry record.

What does a participant count measure?

A participant-level count answers whether a participant experienced at least one event in the category being summarized. It does not indicate the total number of episodes. If one participant experiences repeated events, the person can still contribute as one participant with an event while contributing more than one event to a total-event count. The registry description recognizes this distinction by referring to both participants with events and total events. The group-level figures listed in the record do not give the full event totals for every category.

The primary endpoint is described as the number of participants with adverse events over the stated follow-up period. The registry says adverse events were to be summarized descriptively, overall and by system organ class and preferred term. Descriptive summaries are useful for documenting event patterns, but they do not by themselves test a causal hypothesis. In a single-group study, an event observed after treatment can be reported as occurring during the study without establishing that treatment caused it.

Why is a control group important for comparison?

Randomized comparisons can help distinguish differences associated with treatment assignment from differences that arise because the groups started out unlike one another. This study is listed as single-group and has no randomized comparator. Its dose-escalation and expansion groups are not described as like-for-like controls. As a result, contrasts among their counts are not controlled estimates of a treatment effect. This is a general principle of comparative study design, not a claim about the reason for any particular group result.

Group size also affects how stable a count or percentage may be. With fewer observations, each participant represents a larger share of the group, so a small change in the count can noticeably alter the percentage. This general consideration makes it important not to overread apparent differences among groups, particularly when the record does not give uncertainty intervals or a planned between-group analysis.

What do confidence intervals add?

A confidence interval is a statistical range intended to express uncertainty around an estimate under a specified method. It is not a guarantee that the true value lies inside that particular interval. For safety summaries, intervals can help readers distinguish a relatively precise estimate from one that remains uncertain because of limited information. The registry record does not report confidence intervals for the group-level counts, so their precision cannot be fully assessed from these results alone.

The registry describes the primary endpoint as using descriptive statistics. It does not report a formal hypothesis test for the adverse-event counts in the information. Nor does it report a statistical model for comparing dose groups. Statistical significance should therefore not be inferred from visual or numerical differences in the descriptive counts.

How should planning estimates be understood?

Sample-size illustrations use assumptions to estimate how many participants per arm might be needed for a specified power under a particular hypothetical comparison. The assumptions described for these illustrations include a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the target effect is expressed as a fraction of the observed effect. Such estimates are planning illustrations, not observed power and not evidence that the original study was designed to detect that effect. The registry does not report the trial's sample-size justification, and it does not report a randomized two-arm design for this study.

General statistical concepts can clarify what these summaries do and do not support, but they cannot fill gaps in the registry record. Specific analysis populations, missing-data methods, prespecified dose comparisons, or interim analyses are not reported in the registry record. Without those details, interpretation should remain anchored to the event counts and descriptions that are 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("Part A: Dose Escalation", "Part B: Dose Expansion Cohort", "Part C: Dose Expansion Cohort", "Part D: Dose Expansion Cohort", "Part E: Dose Expansion Cohort", "Part F: Dose Expansion Cohort")
n      <- c(20, 29, 13, 12, 17, 20)
events <- c(20, 29, 13, 12, 17, 20)
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: Dose Escalation  20  20  100.0  83.2  100.0  83.9  100.0  83.9  99.9
ARM  Part B: Dose Expansion Cohort  29  29  100.0  88.1  100.0  88.3  100.0  88.4  99.9
ARM  Part C: Dose Expansion Cohort  13  13  100.0  75.3  100.0  77.2  100.0  76.8  99.8
ARM  Part D: Dose Expansion Cohort  12  12  100.0  73.5  100.0  75.8  100.0  75.3  99.8
ARM  Part E: Dose Expansion Cohort  17  17  100.0  80.5  100.0  81.6  100.0  81.5  99.9
ARM  Part F: Dose Expansion Cohort  20  20  100.0  83.2  100.0  83.9  100.0  83.9  99.9

11. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary endpoint and secondary outcomes that include antitumor activity, time-to-event endpoints for antitumor activity, and terminal half-life. The presence of multiple outcomes raises a general issue of multiplicity: when many outcomes or analyses are examined, the chance of finding an apparently notable result by chance can increase. The registry information does not report a multiplicity adjustment or a prespecified strategy for interpreting multiple tests. It also does not report inferential tests for the adverse-event counts.

Missing-data handling is not reported in the registry record. The record does not describe how participants with incomplete follow-up, missing adverse-event information, or early discontinuation were handled in the primary endpoint summary. The endpoint timeframe is stated as Visit 2 until the first follow-up visit, up to 66 weeks, but the rules for participants without observations throughout that period are not given.

The analysis population for the primary endpoint is also not reported in the registry record. The total enrollment is 111, while the safety groups have their own at-risk counts. The record does not explain the relationship between enrollment and those group-specific denominators or provide the criteria used to include participants in each analysis.

These omissions limit assessment of completeness and potential bias. They do not establish that data were missing or that a particular handling method was used; they mean the relevant procedures are not reported in the registry record. Interpretation should therefore avoid assuming a complete-case analysis, an imputation method, or a particular population definition.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: neoplasm malignant (46.2%), hypomagnesemia (20.0%), jaundice cholestatic (16.7%), gastric hemorrhage (8.3%), performance status decreased (8.3%).

The group summaries report serious adverse events and other adverse events separately. For each category, the at-risk count and affected-participant count are given. Read them as numbers of participants in that group who had an event in the category, rather than as the total number of event episodes. The registry’s general endpoint description distinguishes participant counts from total event counts, but the group figures do not provide all event-level detail.

The serious adverse-event terms are listed with percentages: Neoplasm malignant, 46.2%; Hypomagnesemia, 20.0%; Jaundice cholestatic, 16.7%; Gastric hemorrhage, 8.3%; Performance status decreased, 8.3%; and Jaundice, 8.3%. The registry information does not state the denominator used for these percentages, nor does it establish that the listed terms are attributable to Sym004. They should be treated as recorded categories, not as comparative rates.

Deaths are also listed by group, but their causes, timing, and relationship to treatment are not reported in the registry record. Neither those counts nor the adverse-event counts alone establish causation. Since the study has no randomized control group, the figures describe observed safety events in the study and do not provide a controlled estimate of excess risk.

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

The results describe adverse events recorded during a study of Sym004 in participants with advanced solid tumors. They show that serious and other adverse events were reported across the listed dose-escalation and dose-expansion groups. The registry also identifies several serious adverse-event terms and records deaths by group. These are relevant observations for understanding what was reported during the study, but the record does not give the detail needed to establish the cause of individual events.

The results do not establish that Sym004 caused the reported events. Events occurring during a study may have multiple explanations, and a single-group design does not provide a randomized untreated or active-treatment comparison to help distinguish them. The results also do not establish that one dose group had a higher or lower treatment-related risk than another. The groups are not identified as randomized, comparable controls, and the registry does not describe factors that could account for differences in their counts.

The endpoint is a participant count, not a complete characterization of event severity, duration, recurrence, or clinical course. The record describes a plan to report total event counts as well, but those details are not included in the group summaries. The percentages listed for serious-event terms lack a stated denominator in the registry information, which limits interpretation of their scale.

Nor do the results answer the study's secondary questions about antitumor activity or time-to-event outcomes in the information. The trial title and listed outcomes indicate those topics were part of the study record, but their results are not included among the registry entries. The record also does not report an overall primary-endpoint result with uncertainty intervals.

The appropriate reading is consequently descriptive and bounded: the record documents adverse-event and death counts in the study groups, but it does not support a comparative causal conclusion, a precise estimate of risk, or a conclusion about treatment benefit. Missing details about the analysis population, follow-up completeness, and event attribution further constrain interpretation.

14. Why This Trial Matters Statistically

This study illustrates why safety reporting requires attention to both the endpoint definition and the design used to collect the data. A participant count with an adverse event is not interchangeable with a count of all event episodes, and the registry’s endpoint description refers to both. Separating serious events from other adverse events adds useful context, while still leaving open questions about event-level detail and attribution.

The study is also an example of the limits of interpreting dose-group summaries without a randomized comparison. A dose-escalation and expansion structure can produce descriptive information across groups, but counts across those groups do not automatically function as controlled comparisons. Differences may reflect factors other than dose, and the registry record does not describe enough about group comparability to resolve that concern.

Numerators and denominators matter when reading safety frequencies. The group summaries identify participants at risk and affected participants, while the serious-event terms are reported as percentages without a denominator in the information. A percentage is only fully interpretable when its population and event definition are clear.

Finally, registry reporting and statistical interpretation are distinct tasks. The record gives a primary endpoint and describes descriptive summaries, but it does not report a sample-size justification, missing-data rules, or an inferential comparison plan in the information. Recognizing what is documented—and what is not—helps prevent descriptive safety counts from being mistaken for a precise causal estimate.

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.

Several limitations specific to this study affect interpretation. First, the trial is listed as single-group, open-label, and without a randomized comparator. This prevents a like-for-like controlled comparison of adverse-event frequencies. The dose-escalation and dose-expansion groups are descriptive groups, not randomized control arms.

Second, the registry’s brief summary says the study consisted of five parts, whereas the adverse-event group labels extend from Part A through Part F. The record does not explain this discrepancy. The specific dose levels and schedules assigned to the groups are not reported in the registry information, which also limits interpretation of group patterns.

Third, enrollment is recorded as 111, but the at-risk denominators differ across the safety groups. The record does not explain the inclusion criteria for each group or how the group denominators relate to total enrollment. The analysis population and handling of incomplete follow-up are not reported in the registry record.

Fourth, the serious adverse-event term percentages are listed without a denominator in the information. The record does not provide event-level context, causal attribution, or the timing and causes of the recorded deaths. It also does not report confidence intervals for the group-level safety counts in the details.

Finally, although the primary endpoint description refers to both affected participants and total events, the group-level figures do not include all those event totals. The results therefore do not provide a complete quantitative account of adverse-event frequency, precision, or attribution.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Sym004 in Patients With Advanced Solid Tumors — NCT01117428.
• Registry record last updated 2018-10-15; status last verified 2018-09.
• Results first posted 2017-07-12.
• 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

NCT01117428 is a completed, open-label, multicenter study of Sym004 in advanced solid tumors, listed as Phase I and Phase II. The official title describes a Phase I dose-escalation study, and the registry lists enrollment of 111. The recorded study start was 2010-03 and primary completion was 2015-02.

The primary endpoint was the number of participants with adverse events from Visit 2 until the first follow-up visit, up to 66 weeks. The safety results are organized into groups labeled Part A through Part F and report serious and other adverse-event counts, along with serious-event terms and death counts. The registry’s brief summary refers to five parts, a difference the record does not explain.

The study is single-group, with no randomized comparator. Its safety results are descriptive and do not establish causal attribution or controlled differences among groups. The registry record does not report the analysis population, missing-data methods, sample-size justification, or confidence intervals for the group-level safety counts.