M3541 in Combination With Radiotherapy in Solid Tumors: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for M3541 in Combination With Radiotherapy in Solid Tumors (NCT03225105), a non-randomized phase 1 study. The primary outcome is M3541 50 mg + 100 mg + 200 mg + RT: Number of Participants With Dose Limiting Toxicities (DLTs).

2. Clinical Question

The broader study aim was to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory antitumor activity when M3541 was combined with palliative radiotherapy. The listed secondary outcomes include adverse events and laboratory abnormalities, best overall response under RECIST 1.1, investigator-assessed progression-free survival, and maximum observed plasma concentration of M3541. The registry record lists these outcomes but does not report their results. It also does not report the reason the study was terminated.

3. Trial Design

The registry record identifies this as a Phase I, open-label, uncontrolled, multicenter, sequential dose-escalation study. Allocation was non-randomized and masking was absent. Participants received one of four listed M3541 dose levels—50 mg, 100 mg, 200 mg, or 300 mg—in combination with palliative radiotherapy. Because dose assignment was not randomized and there was no control group, differences between dose groups cannot be interpreted as controlled estimates of dose effects.

The described radiotherapy regimen was 30 Gray in 10 fractions of 3 Gray per fraction day, over 2 consecutive calendar weeks. M3541 was taken orally once per fraction day. The arm descriptions indicate treatment breaks over intervening weekend days, though some of those descriptions are cut off in the registry text. Further detail about the dosing schedule is not reported in the registry record.

The registry reports enrollment of 15 participants, a start date of 2017-09-06, primary completion on 2019-09-02, and a status of terminated. These dates describe the record’s study timeline; they do not explain the reason for termination. The reason is not reported in the registry record. The number of participating centers is also not reported in the registry record.

The primary outcome was a count of participants with dose-limiting toxicities (DLTs), assessed from baseline up to 5 weeks, including 2 weeks of treatment and 3 weeks of follow-up. The primary outcome title names the 50 mg, 100 mg, and 200 mg groups. The registry’s DLT analysis population required at least one M3541 dose and at least one of two criteria: a DLT during the evaluation period, regardless of the number of doses received, or receipt of at least 80% of the planned dose of each treatment. The actual number meeting these criteria is 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: This dose-escalation study was planned to be conducted as per 3 dosing schedules for M3541 including M3541 once per Fraction Day daily, M3541 twice and thrice weekly in combination with fractionated RT given in 10 fractions. However, due to early termination of the study, 2 intermittent schedules (thrice weekly and twice weekly) were never opened and did not enroll any participants.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: DLT analysis set included participants who received at least 1 dose of M3541and met at least one of the following criteria: Experienced at least 1 DLT during the DLT evaluation period, regardless of the number of doses of M3541 administered or received at least 80% of planned dose of each treatment, that is, 8 fractions of RT and 8 of 10 M3541 administrations during the treatment 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 included all participants who received at least 1 dose of M3541.

6. Primary Endpoint

The registry lists the primary outcome as M3541 50 mg + 100 mg + 200 mg + RT: Number of Participants With Dose Limiting Toxicities (DLTs), measured over Baseline up to 5 weeks (including 2 weeks of treatment and 3 weeks of follow-up period).

The primary endpoint is the number of participants with a dose-limiting toxicity during the DLT evaluation period. A DLT is a prespecified toxicity category, rather than a measure of all adverse events. The registry defines DLTs using CTCAE version 4.03 and lists qualifying events that include certain grade 3 or higher non-hematologic toxicities, selected severe blood-count abnormalities, treatment-related liver injury, and toxicity that interrupts or delays study treatment. Some specified exceptions and duration conditions also apply.

Counting participants with a DLT is useful in an early-phase dose-escalation study because it gives a direct summary of how many participants met the protocol’s toxicity definition at each relevant dose level. Such counts can inform evaluation of tolerability within the study’s defined treatment and follow-up period. They do not, by themselves, describe the full range, timing, duration, or severity of all adverse events.

The outcome title names the 50 mg, 100 mg, and 200 mg groups, while the record also describes a 300 mg group. A DLT result for the primary endpoint is not reported in the registry record. Therefore, the frequency of DLTs cannot be described from the posted primary outcome information. The registry definition and analysis-population criteria clarify what was intended to count, but they do not substitute for the missing observed counts.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The study’s primary endpoint is a participant count, not a continuous measurement or a time-to-event estimate. Each participant in the DLT analysis population would be classified according to whether a DLT occurred during the defined evaluation period. A count is straightforward to interpret, but its meaning depends on the precise event definition, observation window, and analysis population. The registry gives these definitions, while the observed DLT count is not reported in the registry record.

What does a DLT count capture?

The registry uses CTCAE version 4.03 to define DLTs and names several qualifying toxicity categories and conditions. Some toxicities are qualified by grade or duration, and some are excluded under stated conditions. This specificity matters because a count based on a protocol-defined DLT is not interchangeable with a count of all adverse events, all serious adverse events, or all events judged related to treatment. General statistical point: a binary event definition makes an outcome easier to tabulate, but can conceal differences in the type, duration, and clinical course of events grouped together.

The DLT analysis population also has explicit eligibility criteria. Participants had to receive at least one dose of M3541 and then meet one of two conditions: experience at least one DLT during the evaluation period, regardless of the number of M3541 doses, or receive at least 80% of the planned dose of each treatment. This definition affects the denominator used to interpret the endpoint. The record does not report how many participants met the analysis-population criteria, how many were excluded, or the DLT counts by group.

How should the dose groups be understood?

The study is described as sequential and non-randomized. In general, sequential dose escalation examines dose levels in an ordered process rather than assigning participants randomly to all dose levels. The registry does not report the detailed escalation rules, cohort decision process, or dose-selection criteria. Without those details, the dose groups should not be treated as independent randomized arms or as a controlled dose-response experiment. Any differences between them could reflect factors other than dose, including the sequential assignment process and the small group sizes.

The record lists 3 participants at risk for serious adverse events in the 50 mg group, 4 in the 100 mg group, 5 in the 200 mg group, and 3 in the 300 mg group. These small denominators make individual participant outcomes influential in the group counts. General statistical point: when denominators are small, a count can be described exactly, but it gives limited precision about the underlying event frequency in a broader population. The registry record does not report confidence intervals for these safety summaries.

What do inferential analyses add?

Inferential methods use observed data to estimate an effect or event frequency while representing uncertainty. A confidence interval, in general, gives a range of values compatible with the data under a specified method and assumptions; it does not guarantee that the true value lies within the interval. No confidence interval or inferential analysis for the primary outcome is reported in the registry record. The record lists zero analyses, so there is no posted inferential result to interpret for the outcomes described.

General statistical point: over-dispersion arises when variation in count data is greater than expected under a simple count model. It can make standard errors too small if a model assumes less variability than the data contain. The primary endpoint is a count of participants with an event, and no count-model analysis or dispersion assessment is reported in the registry record. There is therefore no basis to describe a model-based estimate or its assumptions for this study.

How do planning illustrations differ from trial results?

Planning sample sizes are not observed outcomes and are not “observed power.” The stated planning approach uses a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect defined as a stated fraction of the observed effect. For time-to-event illustrations, the stated method concerns the total number of events using Schoenfeld; other illustrations are expressed as participants per arm. These are general planning assumptions, not a description of the study’s actual non-randomized sequential design. The registry record does not report the observed effect used for these illustrations or the resulting sample-size values, and does not report that these assumptions formed the trial’s own design justification.

Because allocation was not randomized and there was no control group, equal allocation between two arms is not a description of the trial design. Any planning illustration based on two-arm comparisons should therefore be read as a hypothetical planning exercise rather than as an analysis of this study. The trial’s observed enrollment was 15; that number does not establish whether the study met a formal sample-size target, since a justification or target is not reported in the registry record.

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("M3541 50 mg + RT", "M3541 100 mg + RT", "M3541 200 mg + RT")
n      <- c(3, 4, 5)
events <- c(0, 0, 1)
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  M3541 50 mg + RT  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  M3541 100 mg + RT  4  0  0.0  0.0  60.2  0.0  49.0  0.5  52.2
ARM  M3541 200 mg + RT  5  1  20.0  0.5  71.6  3.6  62.4  4.3  64.1

11. Multiplicity, Missing Data and Analysis Populations

The registry lists multiple outcomes: DLTs, several categories of adverse events and abnormalities, tumor response, progression-free survival, and M3541 maximum observed plasma concentration. It does not report an adjustment for multiple testing, a hierarchy for testing secondary outcomes, or a statistical analysis plan. Multiplicity handling is therefore not reported in the registry record. General statistical point: when many outcomes are examined, the chance of at least one apparently notable result can increase, so prespecified priorities and multiplicity procedures can help readers interpret collections of tests. No collection of inferential results is reported.

Missing-data procedures are not reported in the registry record. The record does not describe how participants with incomplete follow-up, missing outcome assessments, or early treatment discontinuation were handled for the primary or secondary outcomes. The DLT population definition addresses who could enter that endpoint analysis, but it does not specify how missing observations were handled.

The DLT analysis population is described as participants who received at least one dose of M3541 and met at least one of the stated DLT-or-dose-received criteria. The record does not report the number in that analysis population or the outcome counts within it. Analysis populations for the secondary endpoints are not reported in the registry record. The numbers at risk in the safety summary are reported by dose group, but the record does not explain whether these are the same populations used for other outcomes.

No inferential analyses are recorded. The reason for study termination, any interim review procedures, and any prespecified statistical decision rules are not reported in the registry record. Without these details and the observed primary outcome, the available information cannot establish how missingness, multiple outcomes, or analysis-population choices affected the study’s conclusions.

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: urinary tract infection (25.0%), blood creatinine increased (20.0%), dehydration (20.0%), hyponatraemia (20.0%).

The registry’s safety summary reports participants at risk and participants affected by serious adverse events, other adverse events, and deaths for each dose group. Serious adverse events were reported for 0 of 3 participants in the 50 mg group, 1 of 4 in the 100 mg group, 1 of 5 in the 200 mg group, and 0 of 3 in the 300 mg group. Other adverse events were reported for 3 of 3, 4 of 4, 5 of 5, and 3 of 3 participants, respectively. Death counts were 0, 4, 2, and 0, respectively.

These are descriptive counts from groups with small denominators. They do not by themselves show whether events were caused by M3541, radiotherapy, underlying disease, or another factor. The registry record does not report treatment relationship for the deaths or provide additional context to reconcile these counts with the other safety categories. Serious adverse events and deaths are distinct summaries and should not be assumed to refer to the same events or participants without further detail.

The listed serious adverse-event terms are urinary tract infection at 25.0%, and blood creatinine increased, dehydration, and hyponatraemia at 20.0% each. The registry record does not provide accompanying event counts, timing, or treatment attribution for these terms. The safety summary is not a substitute for the missing primary DLT results, since DLTs follow a separate protocol definition.

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

The registry record establishes that M3541 was studied with palliative radiotherapy in a Phase I, open-label, uncontrolled, sequential dose-escalation study. It records 15 participants enrolled and describes four dose groups. It also sets out a primary DLT endpoint and a set of secondary safety, response, progression-free survival, and pharmacokinetic outcomes.

What the posted information does not establish is the observed primary DLT count, the results of the secondary outcomes, or an estimate of uncertainty around those outcomes. The registry record does not report inferential analyses. The available safety summary reports adverse-event and death counts, but does not establish causation, comparative risk, or a dose-response relationship. Because the study was non-randomized and uncontrolled, the dose groups do not provide a like-for-like comparison, and there is no control group against which to estimate a treatment effect.

General statistical point: an event count describes what was observed in the recorded participants, while an estimate intended to generalize beyond those participants requires attention to uncertainty, selection, follow-up, and the study design. Small group counts can be informative as descriptive observations but are not, by themselves, precise evidence about event frequencies in a wider population. In this record, confidence intervals and other inferential results are not reported.

The registry’s stated aims include exploratory antitumor activity, but results for best overall response and progression-free survival are not reported in the registry record. No conclusion about antitumor activity can be drawn from the outcome titles alone. Likewise, the listed pharmacokinetic outcome does not establish a measured concentration result when no result is recorded.

The most defensible reading is therefore descriptive and limited: the record documents the design, eligibility concept for the DLT analysis population, planned outcomes, and some group-level safety counts. It does not provide the primary endpoint result or enough analysis detail to support causal or comparative conclusions. The reason for termination is not reported in the registry record.

14. Why This Trial Matters Statistically

This study illustrates a common statistical challenge in early-phase research: the principal question is often whether a prespecified toxicity threshold is met at dose levels, while the design is sequential and group sizes are small. A DLT endpoint can provide a structured way to summarize selected toxicities during a defined period, but its interpretation depends on the event definition, observation window, and analysis population. The registry describes those elements, yet does not report the observed DLT counts.

The study also illustrates why design details matter when comparing groups. Non-randomized sequential dose groups are not equivalent to randomized treatment arms. Differences in counts between groups, if available, would need to be interpreted in light of how dose levels were assigned, the small denominators, and the lack of a control group. The registry record does not report detailed escalation rules or statistical decision criteria.

Safety outcomes are not interchangeable. A DLT is a protocol-defined endpoint, whereas serious adverse events, other adverse events, and deaths are separate summaries. Reporting several categories can help describe different aspects of safety, but readers need clear definitions, denominators, attribution, and follow-up context. Some group-level counts are recorded, while the primary DLT result and further context for the deaths are not reported.

Finally, the record lists a broad range of outcomes, including response, progression-free survival, and pharmacokinetics, but does not report their results or inferential analyses. This highlights the distinction between registering an outcome and reporting its findings. For statistical interpretation, the outcome definitions and design are useful, but they cannot replace observed estimates and information about uncertainty.

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 most important limitation of the posted record for statistical interpretation is that the primary DLT count is not reported, despite DLTs being the primary endpoint. The registry also does not report results for the listed secondary outcomes, including tumor response, progression-free survival, laboratory abnormalities, and M3541 maximum observed plasma concentration. Without these results, the study’s stated safety, pharmacokinetic, pharmacodynamic, and exploratory antitumor aims cannot be assessed from the record.

Enrollment was 15, and the safety groups at risk contain small numbers. As a general statistical matter, small group counts can be highly sensitive to individual outcomes and yield imprecise estimates. The registry does not report confidence intervals or other uncertainty measures. The non-randomized, uncontrolled, sequential design also precludes a randomized comparison and leaves dose-group contrasts vulnerable to differences associated with the assignment process.

The record does not report the detailed dose-escalation rules, a sample-size justification, an interim analysis plan, or statistical decision criteria. It does not report methods for missing data, multiplicity, or analysis populations for secondary endpoints. The reason for study termination is not reported in the registry record. Although the safety summary includes death counts, the registry does not report whether deaths were considered related to study intervention or provide context for their timing.

Some arm descriptions are incomplete in the registry text. The radiotherapy schedule and the M3541 dose levels are described, but fuller dosing details for all groups are not available in the record. These omissions limit how fully the treatment regimen and analysis conduct can be reconstructed.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: M3541 in Combination With Radiotherapy in Solid Tumors — NCT03225105.
• Registry record last updated 2023-11-22; status last verified 2023-01.
• Results first posted 2023-11-22.
• 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

NCT03225105 is a Phase I, open-label, uncontrolled, multicenter, sequential, non-randomized dose-escalation study of M3541 with palliative radiotherapy in participants with solid tumors. The record lists 15 participants enrolled and four M3541 dose groups: 50 mg, 100 mg, 200 mg, and 300 mg. The primary endpoint is the number of participants with DLTs in the 50 mg, 100 mg, and 200 mg groups, assessed from baseline up to 5 weeks.

The registry lists secondary safety, response, progression-free survival, and pharmacokinetic outcomes. It reports group-level counts for serious adverse events, other adverse events, and deaths, but the primary DLT count and secondary outcome results are not reported in the registry record. No inferential analyses are recorded. The study status is terminated; the reason for termination is not reported in the registry record.