Safety, Tolerability and Efficacy of Regorafenib in Combination With FOLFIRINOX in Patients With Colorectal Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety, Tolerability and Efficacy of Regorafenib in Combination With FOLFIRINOX in Patients With Colorectal Cancer (NCT03828799), a na phase 1, phase 2 study. The primary outcome is Number of Participants With Pre-specified Treatment-related Adverse Events.

2. Clinical Question

3. Trial Design

The registry describes a dose-escalation phase I/II trial of regorafenib combined with FOLFIRINOX in patients with RAS-mutated metastatic colorectal cancer. Its model is sequential, and allocation is listed as not applicable. Masking is listed as none. These features mean the record does not describe a blinded randomized comparison; the dose groups are not equivalent to randomized treatment and control arms.

The intervention is recorded as FOLFIRINOX plus regorafenib. The serious adverse event record separates three groups by the irinotecan and regorafenib doses: irinotecan 150 mg/m² with regorafenib 120 mg, irinotecan 180 mg/m² with regorafenib 120 mg, and irinotecan 180 mg/m² with regorafenib 160 mg. The registry does not give a separate control intervention. The sequential, dose-escalation context is relevant when reading the group counts: the record does not establish that the groups were assembled to support direct comparisons.

The trial is listed as phase 1 and phase 2, with enrollment of 13. The registry reports a start date of 2019-05-14, primary completion on 2021-12-02, and completed status. These record details describe the study timeline and scale, but do not establish when each participant entered or completed treatment.

The primary endpoint concerns prespecified treatment-related toxicities during the first three cycles. Each cycle is 14 days, and the assessment timeframe is at the end of cycle 1 to 3. The registry names secondary outcomes including progression-free survival, disease control, objective response, overall survival, tumor-size regression, and maintenance treatment with regorafenib alone. It also lists circulating free DNA concentration and resection rates as not available. Although the record reports 9 outcome measures, it reports 0 analyses. Numerical results for efficacy outcomes and a statistical analysis plan 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.

Before assignment: Screening based on Uridine diphosphate-GlucuronosylTransferase (UGT1A1) status and DiHydroPyrimidine Dehydrogenase (DHPD) status with serum uracile \< 16 ng/ml.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Evaluable population for Dose-limiting toxicity (DLT). The list of DLTs is pre-specified in the protocol.

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 Number of Participants With Pre-specified Treatment-related Adverse Events, measured over At the end of cycle 1 to 3 (each cycle is 14 days).

The primary endpoint counts participants with prespecified treatment-related adverse events. It is framed as a participant count, rather than a measure of the severity of every event or the total number of events. The registry says physicians determine which toxicities meet the protocol’s prespecified dose-limiting toxicity list and grade them using Common Terminology Criteria for Adverse Events, NCI-CTC Version 5. The listed grades range from mild to death.

The assessment timeframe is at the end of cycle 1 to 3, with each cycle lasting 14 days. The stated population is the evaluable population for dose-limiting toxicity. This endpoint is used in a dose-escalation setting to describe treatment-related toxicity during early treatment and to inform tolerability assessment. In general, prespecifying the toxicities and assessment window helps make the safety question explicit; it does not by itself show how the endpoint was analyzed or what decision followed from it.

The registry record does not report the primary endpoint count, grade distribution, or an estimate of uncertainty. The serious adverse event figures listed elsewhere are not a substitute for the primary endpoint: the record does not establish that they represent the same event definition, assessment window, or population.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Interpreting this study requires separating the design, the endpoint definition, and the results that the registry actually reports. The registry labels the study phase 1 and phase 2, describes it as dose-escalation, and gives a sequential model. Allocation is not applicable and masking is none. These terms describe a study that is not recorded as a randomized, blinded comparison. The dose groups can be described, but the record does not support treating them as exchangeable arms for causal comparisons.

What does a sequential dose-escalation design imply?

In general, a sequential dose-escalation design evaluates treatment combinations in an ordered process rather than assigning participants randomly among fixed groups. This context matters because group membership may depend on the sequence of study conduct and decisions made during the trial. The registry does not describe the actual escalation rules, decision thresholds, or the procedure used to choose doses. Those details are not reported in the registry record and should not be inferred from the design label alone.

The safety groups specify irinotecan 150 mg/m² with regorafenib 120 mg, irinotecan 180 mg/m² with regorafenib 120 mg, and irinotecan 180 mg/m² with regorafenib 160 mg. Their counts can be read as descriptive summaries of the recorded groups. General statistical reasoning cautions against comparing such groups as though treatment dose were their only difference: without random allocation and information on participant characteristics and exposure, observed differences cannot be attributed solely to dose.

What does the primary endpoint count?

The primary endpoint is the number of participants with prespecified treatment-related adverse events. The physician determines relevant toxicities using a list of dose-limiting toxicities prespecified in the protocol and grades them with NCI-CTC Version 5. The registry describes grades from mild through death. The endpoint is assessed at the end of cycle 1 to 3, with each cycle lasting 14 days, in the evaluable population for dose-limiting toxicity.

In general, a participant-based count answers how many people meet the endpoint definition; it is not necessarily the same as a count of all events. A participant may experience more than one event, but the primary endpoint wording alone does not tell how recurrent events were handled. The registry record does not provide the primary endpoint result, the number assessed, or the grading details of any observed events. It also does not report the operational definition of evaluability beyond naming the evaluable population.

How should the safety counts be read?

The adverse event record gives, for each dose group, the number at risk and the number affected by serious adverse events, other adverse events, and deaths. Those are descriptive counts. In general, counts depend on the group size and the event definitions, while interpretation also depends on the observation period and completeness of follow-up. The registry does not report the exposure duration or clarify in this record whether the different adverse event categories overlap. The death counts are reported separately, but a relationship to treatment is not stated.

Some listed serious adverse event terms carry a reported percentage of 16.7%. The denominator and calculation details for those term percentages are not reported in the registry record. Without that context, the percentages should not be used to infer a rate in the full enrolled population or to compare groups. Similarly, a zero recorded serious adverse event count in a group does not establish absence of risk; it describes only the events reported for that group in the registry.

What statistical analysis is available?

The registry reports 0 analyses. It does not provide a treatment effect estimate, confidence interval, p-value, or a stated model for the primary endpoint. In general, a confidence interval expresses the range of values compatible with an estimate under a specified statistical procedure; it can communicate precision, but cannot remedy limitations in the design or event ascertainment. No such interval is reported for the primary endpoint.

The record also does not report a statistical analysis plan, a sample-size justification, interim analyses, adjustment for baseline factors, or a method for handling repeated or missing observations. Those omissions do not establish that a method was or was not used outside the registry record; they mean that it cannot be evaluated from the posted information. No efficacy estimate should be reconstructed from outcome names alone.

Planning illustrations, when used for future study design, are distinct from observed results. The stated illustration assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect expressed as a fraction of an observed effect. For time-to-event outcomes, the stated illustration uses a total event count; other illustrations use participants per arm. These are planning assumptions, not features that establish the design or analysis of this trial. The registry does not report an observed effect on which to base a trial-specific interpretation of such illustrations.

In general, over-dispersion occurs when variability in count data exceeds what a chosen model assumes. Accounting for it can affect uncertainty estimates and inference. The registry does not report a count model or an assessment of over-dispersion, so this is a general methodological consideration rather than a claim about the analysis used in this study. Given the absent analyses and limited record, the appropriate statistical reading is descriptive and explicitly bounded by the information reported.

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("Experimental: Irinotecan 150 mg/m² and Regorafenib", "Experimental : Irinotecan 180 mg/m² and Regorafeni", "Experimental : Irinotecan 180 mg/m² and Regorafeni")
n      <- c(3, 6, 4)
events <- c(3, 5, 3)
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  Experimental: Irinotecan 150 mg/m² and Regorafenib  3  3  100.0  29.2  100.0  43.9  100.0  39.8  99.4
ARM  Experimental : Irinotecan 180 mg/m² and Regorafeni  6  5  83.3  35.9  99.6  43.6  97.0  42.1  96.3
ARM  Experimental : Irinotecan 180 mg/m² and Regorafeni  4  3  75.0  19.4  99.4  30.1  95.4  28.4  94.7

11. Multiplicity, Missing Data and Analysis Populations

The registry names several secondary outcomes: progression-free survival, number of patients with disease control, number of participants with objective response, overall survival, median regression of tumor size, and maintenance treatment with regorafenib alone. It also names circulating free DNA concentration and resection rates, each marked not available. The record reports 9 outcome measures and 0 analyses, but does not provide results or explain how the secondary outcomes were analyzed.

When a study examines multiple outcomes, general statistical practice considers whether and how to address multiplicity, since repeated testing can affect the interpretation of chance findings. No multiplicity strategy, testing hierarchy, or primary-versus-secondary testing procedure is reported in the registry record. It is therefore not possible to determine whether any adjustment was planned or used.

The primary endpoint specifies an evaluable population for dose-limiting toxicity. The registry record does not report the number included in that population, how evaluability was determined, or whether all enrolled participants contributed to the endpoint. Analysis populations for the secondary outcomes are not reported. Missing-data methods, censoring rules for time-to-event outcomes, and procedures for incomplete follow-up are also not reported in the registry record.

These gaps limit interpretation but do not show that analyses or procedures were absent in the full study documentation. They mean that the posted record does not allow readers to assess how missing observations, multiple outcomes, or population definitions may have affected the reported findings. Because no outcome analyses are posted, there are no reported estimates to qualify for these issues.

12. Safety Results

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

Deaths

Other (non-serious) adverse events

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

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: hyperparathyroidism primary (16.7%), neutropenia (16.7%), intestinal subocclusive syndrom (16.7%), atrial fibrillation (16.7%), device related sepsis (16.7%).

For serious adverse events, the registry lists 3 participants at risk and 0 affected in the irinotecan 150 mg/m² with regorafenib 120 mg group; 6 at risk and 4 affected in the irinotecan 180 mg/m² with regorafenib 120 mg group; and 4 at risk and 0 affected in the irinotecan 180 mg/m² with regorafenib 160 mg group. These are group-level counts as recorded, not randomized comparisons or adjusted estimates.

The record separately lists other adverse events affecting 3, 6, and 4 participants in those groups, and deaths of 3, 2, and 0. It does not specify in this record whether these categories overlap, how long participants were followed for adverse events, or whether deaths were considered treatment-related. A death count should therefore not be interpreted as a count of treatment-caused deaths.

The listed serious adverse event terms each carry a registry percentage of 16.7%. The record does not state the denominator or calculation method for those percentages. In general, a count or percentage needs its event definition, observation window, and denominator to support a clear rate interpretation. These details are not reported in the registry record. The counts describe the posted safety information but do not establish comparative safety or exclude events that were not captured or reported.

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

The record establishes that this was a completed, sequential phase I/II dose-escalation trial of FOLFIRINOX combined with regorafenib in patients with RAS-mutated metastatic colorectal cancer. It specifies a primary safety endpoint based on prespecified treatment-related toxicities, assessed through cycle 1 to 3, and provides adverse event counts for three dose groups. Those details make the study question and some reported safety information identifiable.

The record does not provide the primary endpoint result or analyses for the listed outcomes. It therefore does not show how many participants met the primary endpoint, how precisely an event rate was estimated, or what the efficacy outcomes were. The listed secondary outcomes are not numerical findings. Outcomes marked not available cannot be interpreted as evidence of either an event or no event.

The serious adverse event counts are not evidence of a causal dose effect. The study is not recorded as randomized, and the groups should not be treated as like-for-like controls. The registry does not provide information needed to assess comparability, exposure, timing, or follow-up across the groups. Counts of zero in some groups are observations in the record, not proof that serious events cannot occur at those doses.

More generally, an observed result and a treatment effect are different claims. An observed count describes events recorded under a particular study design and endpoint definition. A treatment effect requires an appropriate comparison and analysis, along with assumptions that are not established by these registry entries. No confidence intervals or inferential statistics are posted to characterize uncertainty.

The study record can support a cautious description of the protocol framework and the posted safety counts. It cannot, by itself, establish that the combination is effective, ineffective, safer, or more harmful than another treatment. It also cannot resolve whether the outcomes reflect treatment, disease course, or other factors. These limits follow from the information reported and should remain explicit when interpreting the trial.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of why design labels and outcome definitions matter when reading early-phase clinical research. It is described as a sequential dose-escalation study, not a randomized comparison. The three dose groups provide context for the recorded safety data, but do not by themselves support an unbiased estimate of the effect of changing either drug dose.

The primary endpoint is framed around participants with prespecified treatment-related toxicities during the first three cycles. That focus reflects a distinct statistical question from long-term efficacy outcomes such as progression-free survival or overall survival. Keeping these endpoints separate prevents early safety counts from being mistaken for evidence about tumor response or survival. The registry names efficacy outcomes but does not post their analyses.

The record also illustrates the difference between a well-defined endpoint and an available result. It specifies the grading system, the assessment period, and the evaluable population for dose-limiting toxicity. Yet it does not report a primary endpoint count, estimate, or uncertainty measure. A methodologically clear outcome description cannot substitute for observed results and analysis.

Finally, small descriptive group counts require careful language. They may be useful for conveying what the registry recorded, but they offer limited precision and cannot resolve whether differences across sequential groups are due to dose or other factors. The distinction between recorded safety information and a comparative statistical conclusion is central to responsible interpretation of this trial.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

Several trial-specific limitations follow directly from the registry record. Allocation is listed as not applicable, the model is sequential, and masking is none. The record therefore does not describe a randomized or blinded comparison. The dose groups should not be read as control and treatment arms with established comparability, and the safety counts do not isolate dose effects.

The registry reports enrollment of 13, but does not state how many participants were evaluable for the primary dose-limiting toxicity endpoint. The definition of that evaluable population is not described beyond its name. The primary endpoint result itself is not reported, and the record lists 0 analyses. No confidence intervals, p-values, or statistical model are available for assessment.

The serious adverse event information lacks context on event timing, observation duration, exposure, and the relationship of deaths to treatment. The record does not clarify whether serious and other adverse event categories overlap. For the listed serious adverse event terms, the denominator behind the reported 16.7% figures is not stated.

The registry names secondary outcomes but does not report numerical findings for them. Circulating free DNA concentration and resection rates are explicitly marked not available. Eligibility details, baseline characteristics, adherence, and follow-up completeness are not reported in the registry record. Nor does it describe multiplicity handling, missing-data procedures, interim analyses, or a statistical analysis plan. These limitations restrict interpretation of the posted information; they do not establish what may be available in other study materials.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety, Tolerability and Efficacy of Regorafenib in Combination With FOLFIRINOX in Patients With Colorectal Cancer — NCT03828799.
• Registry record last updated 2026-02-27; status last verified 2026-02.
• Results first posted 2025-01-15.
• 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 a completed phase I/II, sequential dose-escalation trial of FOLFIRINOX plus regorafenib in RAS-mutated metastatic colorectal cancer. Enrollment is listed as 13. The primary endpoint counts participants with prespecified treatment-related adverse events in the dose-limiting toxicity evaluable population, assessed at the end of cycle 1 to 3, with each cycle lasting 14 days.

Three dose groups are described in the safety record. It reports group counts for serious adverse events, other adverse events, and deaths, but these are descriptive and not a randomized comparison. The registry lists secondary outcomes including progression-free survival, disease control, objective response, overall survival, tumor-size regression, and maintenance treatment. Circulating free DNA concentration and resection rates are marked not available.

The registry reports 0 analyses and does not provide the primary endpoint result, efficacy estimates, or measures of statistical uncertainty. The record therefore supports a description of the study design and the safety counts, but not conclusions about comparative effects.