Phase 3 Study of Futuximab/Modotuximab in Combination With Trifluridine/Tipiracil Versus Trifluridine/Tipiracil Single Agent in Participants With Previously Treated Metastatic Colorectal Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase 3 Study of Futuximab/Modotuximab in Combination With Trifluridine/Tipiracil Versus Trifluridine/Tipiracil Single Agent in Participants With Previously Treated Metastatic Colorectal Cancer (NCT05223673), a randomized phase 3 study. The primary outcome is Incidence of Dose-limiting Toxicities (DLTs) (Safety Lead-In Part).

2. Clinical Question

3. Trial Design

NCT05223673 is described as a randomized, open-label, multi-centre, parallel Phase 3 study with two arms and a safety lead-in part. Its intended comparison was futuximab/modotuximab combined with trifluridine/tipiracil versus trifluridine/tipiracil alone for previously treated metastatic colorectal cancer with KRAS/NRAS and BRAF wild-type tumours. Masking is recorded as none. The sponsor is Institut de Recherches Internationales Servier.

The study record distinguishes two purposes. In the safety lead-in, the main objective was to assess safety and tolerability of the combination. In the Phase III part, the stated primary objective was to compare overall survival. The registered primary outcome, however, is incidence of dose-limiting toxicities during the safety lead-in, measured through the end of cycle 1, with each cycle described as up to 28 days. The registry also lists secondary outcomes covering overall survival in the safety lead-in, overall survival in triple-negative participants, progression-free survival, and adverse events.

The record lists enrollment as 7, gives a start date of 2022-04-21 and a primary completion date of 2023-06-21, and marks the study terminated. It does not report the reason for termination, participant flow, or how enrollment was distributed across study parts and arms. The adverse-event record lists a combination group with 7 at risk; that record does not establish the allocation or outcome status of every enrolled participant. No comparative analysis is posted, so the intended randomized design should not be mistaken for evidence that a treatment contrast was estimated.

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: Sponsor decided to discontinue the study during the Lead-In part and the Phase III (randomized) part was not started due to strategic reasons.

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.

6. Primary Endpoint

The registry lists the primary outcome as Incidence of Dose-limiting Toxicities (DLTs) (Safety Lead-In Part), measured over End of cycle 1 (Each cycle is up to 28 days).

The registry's primary outcome is the incidence of dose-limiting toxicities during the safety lead-in, expressed as a number of dose-limiting toxicities. The assessment timeframe is through the end of cycle 1, with each cycle lasting up to 28 days. The record defines a dose-limiting toxicity as a clinically significant adverse event graded according to NCI-CTCAE version 5.0 during the initial 28-day treatment period following the first IMP administration. It must be assessed as unrelated to underlying disease, disease progression, intercurrent illness, or concomitant medications; judged by the investigator to be at least possibly related to the IMPs; and meet criteria described in the protocol.

A count of dose-limiting toxicities is used in a safety lead-in to characterize clinically important toxicities under the stated definition and observation window. This is a different question from whether the combination changes survival relative to the comparator. The registry record identifies overall survival as the Phase III primary objective in its brief summary, but records dose-limiting toxicities as the primary outcome measure. No dose-limiting-toxicity count or comparative survival estimate is reported in the registry record. The endpoint definition alone therefore describes what was to be assessed, not what was observed.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes random allocation, no masking, and a parallel model. In general, random allocation aims to make assigned groups comparable with respect to both measured and unmeasured characteristics, on average, so that a difference in outcomes can be interpreted as a treatment contrast. That benefit depends on the conduct of the trial, adequate outcome data, and an analysis that follows the design. The record does not report the randomization procedure, allocation concealment, stratification factors, or deviations from assigned treatment.

What does open-label mean for interpretation?

Open-label means that masking is recorded as none. In general, knowledge of assigned treatment can influence care, decisions about continuing treatment, or how outcomes are assessed and reported. The extent to which such influences matter depends on the outcome and the safeguards used. The registry record does not describe outcome adjudication, blinded review, or other procedures to limit assessment bias. Overall survival is a relatively direct outcome, while judgments about adverse events and their relationship to treatment involve assessment. The record does not provide details that would allow those processes to be evaluated.

What does the endpoint definition contribute?

The primary outcome is a count of dose-limiting toxicities in the safety lead-in, with a specified treatment period and clinical definition. A tightly described endpoint can make it clearer which events qualify and when they are counted. The definition includes clinical significance, grading under NCI-CTCAE version 5.0, investigator assessment of relatedness, and protocol criteria. In general, these requirements help distinguish the endpoint from an unfiltered count of every event. They do not reveal the observed count, how many participants were evaluable, or whether any participants lacked assessment; those details are not reported in the registry record.

Why is a comparison not available?

The record contains no analyses and identifies fewer than two arms in the primary outcome. The primary outcome is tied to the safety lead-in, whereas the planned Phase III objective is an overall-survival comparison. These are distinct estimands: one describes the specified toxicity count in the lead-in, and the other would compare time-to-event outcomes between randomized strategies. A result for one cannot be substituted for the other. The registry record does not report a treatment effect, standard error, confidence interval, or statistical test for either question.

How should planning illustrations be read?

In general, a sample-size calculation is a planning exercise based on assumptions about the effect to detect, the significance level, allocation, and statistical method. The record's stated illustration assumptions include a two-sided significance level of 0.05, equal allocation, and a normal approximation; it describes the effect to detect as a stated fraction of the observed effect. For time-to-event tables, the stated convention is total events, while other calculations use participants per arm. These are planning assumptions, not findings from the trial. The registry record does not supply a usable comparative primary-outcome estimate in the posted analyses, and its skip note identifies the lack of a two-arm primary-outcome comparison. Any planning illustration must not be read as observed power or as evidence that a treatment effect was demonstrated.

What can a confidence interval say?

In general, a confidence interval expresses the range of effect estimates compatible with the observed data under the analysis model, with its width reflecting statistical precision. A narrow interval indicates greater precision than a wide interval, but neither guarantees that the model is appropriate or that the result is free from bias. No comparative confidence interval is reported in the registry record, so the precision of the intended Phase III treatment contrast cannot be assessed from the posted analyses.

Why might over-dispersion matter?

In general, count outcomes can vary more than a simple model assumes; this is called over-dispersion. If it is present and ignored, standard errors and uncertainty estimates may be too small. Whether over-dispersion is relevant depends on the endpoint distribution and analysis model. The registry record does not report a statistical model for the dose-limiting-toxicity count or enough outcome detail to assess its distribution. No claim about over-dispersion or an adjustment for it can therefore be made.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary outcome for the safety lead-in and several secondary outcomes, including overall survival, progression-free survival, and adverse events. When a study evaluates multiple outcomes or makes repeated statistical comparisons, multiplicity can raise the chance of a misleading positive finding if the analysis does not account for that structure. The registry record does not report a multiplicity strategy, hierarchy for testing outcomes, or adjustment procedure. It also reports no analyses, so there are no posted inferential results to interpret in light of multiplicity.

Missing-data handling is not reported in the registry record. The record does not describe participant disposition by arm, treatment discontinuation, loss to follow-up, censoring rules, or how missing endpoint assessments would be handled. These details matter because missingness can affect both the analysis population and the interpretation of estimates. For time-to-event outcomes, censoring and follow-up rules are especially relevant to understanding how observed survival information contributes to an estimate; the registry record does not provide those methods or a survival estimate.

Analysis populations are also not reported in the registry record. It does not specify whether analyses were intended to follow assignment, include only participants who received treatment, or use another defined population. The posted data therefore do not establish which participants would contribute to a primary or secondary analysis. These omissions limit assessment of the prespecified analysis strategy, but they do not prove that no such plans existed outside the registry entry.

11. 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: vertigo (14.3%), cholecystitis acute (14.3%), jaundice (14.3%), pneumonia bacterial (14.3%), sepsis (14.3%).

The posted safety entry describes the combination group as having 7 at risk. It records 3 affected by serious adverse events, 7 affected by other adverse events, and 1 death. These are counts in the registry entry, not comparative estimates. The record does not provide corresponding comparator-group figures, event timing, participant-level detail, or attribution of the death. Counts alone do not show whether events were considered related to treatment.

The serious-event terms listed are Vertigo, Cholecystitis acute, Jaundice, Pneumonia bacterial, Sepsis, and Blood creatinine increased; each is accompanied by 14.3%. The registry record does not specify the denominator for each listed term or clarify whether a participant could contribute more than one event term. The percentages should therefore be read as reported, not recalculated or treated as direct comparative risks. A serious adverse event is not interchangeable with a dose-limiting toxicity: the latter has a specific timing, relatedness assessment, and protocol-based definition in this study. The safety entry does not report the primary dose-limiting-toxicity count.

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

The record establishes that a randomized, open-label Phase 3 study was planned to compare futuximab/modotuximab plus trifluridine/tipiracil with trifluridine/tipiracil alone in a specified previously treated metastatic colorectal cancer population. It also establishes that the study was terminated, that enrollment was recorded as 7, and that the registry includes safety observations for the combination group. These registry entries describe study conduct and posted records; they do not establish a comparative treatment effect.

The primary outcome field concerns dose-limiting toxicities in the safety lead-in. The brief summary separately identifies overall survival as the primary objective of the Phase III part. Neither a dose-limiting-toxicity result nor a comparative overall-survival result is reported in the registry record. The absence of a posted analysis means the relative effect, uncertainty, and compatibility of the results with different treatment effects cannot be assessed from this record.

The adverse-event counts and terms are useful as a description of what the registry records for the combination group, but they do not by themselves establish causation, comparative safety, or the frequency of events under the comparator. The record does not report enough detail to resolve attribution, denominators for the listed terms, participant flow, or the circumstances of the recorded death.

These limits do not show that the planned study questions are unimportant, nor do they substitute for findings that are not posted. They mean only that the registry record does not provide the comparative outcome evidence needed to answer those questions. No conclusion about benefit or lack of benefit should be drawn from the design description or the available group-level safety counts alone.

13. Why This Trial Matters Statistically

This trial is statistically notable because its registry record brings together two different research aims: a safety lead-in focused on dose-limiting toxicities and a planned Phase III comparison focused on overall survival. Keeping those aims distinct is essential. A toxicity count in a lead-in does not answer a survival comparison, and the statement of an intended survival objective is not itself an observed survival result.

The record also illustrates why design labels should be separated from evidence. Randomization and a parallel comparison describe how a study was designed, while an estimate and its uncertainty describe what the data support. Here, the registry reports no analyses and notes that the primary outcome lacks a two-arm comparison. The intended randomized contrast therefore cannot be reconstructed from the posted primary-outcome record.

Finally, a terminated study with enrollment recorded as 7 and selected safety counts can be informative about what was documented while remaining insufficient for the planned comparative question. Statistical interpretation requires attention to what endpoint was measured, in which study part, among which analysis population, and with what uncertainty. The registry record leaves several of those elements unreported. Recognizing those gaps prevents descriptive counts, trial intentions, and comparative conclusions from being treated as if they were the same kind of evidence.

14. 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 registry record does not report why the study was terminated, how participants were distributed between the safety lead-in and Phase III parts, or the number assigned to each arm. Although enrollment is recorded as 7 and the combination safety group lists 7 at risk, these entries do not establish participant flow or analysis populations. The record also does not report whether participants completed follow-up or how many were evaluable for each endpoint.

There is no posted analysis for the registered primary outcome, and no comparative overall-survival result is reported. The record does not include treatment-effect estimates, uncertainty intervals, statistical tests, or the analysis methods used for the planned comparison. Protocol-level criteria for dose-limiting toxicities are referenced but not reproduced in detail. The statistical analysis plan, missing-data procedures, censoring rules, multiplicity approach, and handling of protocol deviations are not reported in the registry record.

The safety entry is limited to the combination group. It lacks comparator-group event counts, event-level details, and the stated denominators for each serious-event term percentage. Attribution and the circumstances of the recorded death are not given. As a result, the listed safety observations cannot establish comparative safety or treatment causation. These limitations are specific to what the registry record reports; they do not establish what information may exist outside that record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Phase 3 Study of Futuximab/Modotuximab in Combination With Trifluridine/Tipiracil Versus Trifluridine/Tipiracil Single Agent in Participants With Previously Treated Metastatic Colorectal Cancer — NCT05223673.
• Registry record last updated 2024-08-20; status last verified 2024-07.
• Results first posted 2024-03-05.
• 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.

18. Record Summary

NCT05223673 is a randomized, open-label, parallel Phase 3 study sponsored by Institut de Recherches Internationales Servier. It planned to compare futuximab/modotuximab with trifluridine/tipiracil against trifluridine/tipiracil alone in previously treated metastatic colorectal cancer with KRAS/NRAS and BRAF wild-type tumours. The study included a safety lead-in and a planned overall-survival comparison. The registered primary outcome is dose-limiting toxicities during the safety lead-in, through the end of cycle 1.

The record lists enrollment as 7, gives dates of 2022-04-21 and 2023-06-21 for study start and primary completion, and marks the study terminated. It reports no analyses. Safety data are recorded for the combination group, including serious and other adverse-event counts and 1 death, but no comparative safety result. The registry record does not report a primary-outcome result, comparative survival estimate, or reason for termination.