First in Human Dose Escalation of M3258 as a Single Agent and Expansion Study of M3258 in Combination With Dexamethasone: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for First in Human Dose Escalation of M3258 as a Single Agent and Expansion Study of M3258 in Combination With Dexamethasone (NCT04075721), a non-randomized phase 1 study. The primary outcome is Part A: Number of Participants With Dose-Limiting Toxicities (DLTs) as Per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0.

2. Clinical Question

The registry describes a first-in-human dose-escalation study with an expansion component. Its stated aims included evaluating safety, tolerability, pharmacokinetics, pharmacodynamics, and early signs of efficacy for M3258 alone and in combination with dexamethasone. These aims describe the scope of the investigation, not findings. The registry record does not report a primary endpoint result, an efficacy result, or a comparison between regimens. It also does not give the allocation of participants across the listed regimens beyond the adverse-event counts. Consequently, the record can frame the safety question and describe some recorded safety counts, but it cannot establish a treatment effect or support a reliable comparison of the schedules.

3. Trial Design

This was a phase I, open-label, non-randomized study with a parallel-group model. It enrolled 10 participants with multiple myeloma. The record lists the study start as 2019-09-26, primary completion as 2021-04-01, and status as terminated. The reason for termination is not reported in the registry record.

The study title and description identify two components: first-in-human dose escalation of M3258 as a single agent, and an expansion study involving M3258 with dexamethasone. The listed arm names, however, specify M3258 10 mg once daily, M3258 10 mg twice per week, and M3258 20 mg twice per week. The arm descriptions are blank, and the listed interventions identify M3258 and M3258 20 mg. The precise relationship between the stated combination component and the listed regimens is not reported in the registry record. It would therefore be inappropriate to infer which participants received dexamethasone or how combination treatment was administered.

Open-label means that treatment assignment was not masked, while non-randomized means participants were not allocated to the listed regimens by random assignment, according to the design fields. These features matter when interpreting group differences: dose schedules may have been studied in different participants or under different study circumstances, and the record does not establish that groups were comparable at baseline. The listed regimens should not be treated as randomized comparison arms.

The registry lists 22 outcome measures and zero analyses. It reports no study-specific statistical analysis plan, detailed dose-escalation rules, interim analysis procedures, or sample-size justification. Such details are not reported in the registry record. The listed design and enrollment alone do not show whether the planned study objectives were completed or whether all intended study components contributed results.

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 study was planned to be conducted in 2 parts; Part A: Dose escalation part and Part B: Dose expansion part. However, because of early discontinuation, only Part A was conducted; due to lack of participant enrollment before Part A reached its primary objective and before Part B was started.

Overall Study

Analysis population for the primary outcome, as defined in the registry: DLT analysis set: all participants who received at least 1 dose of study intervention and meet at least 1 of criteria specified in statistical analysis plan.

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 were administered any dose of the study medication.

6. Primary Endpoint

The registry lists the primary outcome as Part A: Number of Participants With Dose-Limiting Toxicities (DLTs) as Per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0, measured over Day 1 up to Day 28.

The primary endpoint is the number of participants with dose-limiting toxicities, or DLTs, from Day 1 up to Day 28. It is a count of participants who meet the defined toxicity criteria, rather than a measure of the total number of events or the severity of every adverse event. The registry states that DLTs were assessed under National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 and confirmed by the Safety Monitoring Committee.

The definition focuses on adverse events considered not related to underlying disease, previous or concomitant medication, or concurrent conditions during the first treatment cycle. It includes specified severe nonhematologic events and specified hematologic events, with exceptions for some events or laboratory findings. The complete criteria in the record include grade thresholds and duration conditions. Those rules are intended to distinguish events that qualify as dose-limiting from events that may be important but do not meet the study’s DLT definition.

In general, early-phase dose-escalation studies use a DLT endpoint to characterize short-term tolerability and inform decisions about the doses or schedules worth studying further. A DLT count is not a complete account of safety: it is restricted by its definition, observation window, and analysis population. The registry record does not report the number of participants who met this primary endpoint, so the observed DLT frequency cannot be described from this record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count represent?

The primary endpoint is a binary participant-level outcome: each person either meets the study definition of a DLT within the stated window or does not. A count of participants with an event is different from a count of all event episodes. One participant could experience more than one event, but the primary endpoint counts participants meeting the DLT definition. The record names the outcome as a count and identifies the intended analysis population, but does not report the observed count or an estimate of the proportion affected.

In general, a binary outcome is often described with both the number affected and the number assessed. The denominator matters because the same count can convey different information in groups of different sizes. For this study, the total enrollment is 10, and the adverse-event record provides group-specific numbers at risk for its safety summaries. The DLT analysis set is defined separately. Its size and the number of participants included in the primary analysis are not reported in the registry record, so the adverse-event denominators should not be substituted for a DLT denominator.

What would uncertainty measures add?

In general, a confidence interval describes a range of values compatible with the observed data under a specified statistical method. For a participant-level event outcome, it can show how imprecise an estimated event frequency is, especially when few people are observed. A point estimate alone can conceal considerable uncertainty. No confidence interval, primary endpoint estimate, or inferential analysis is reported in the registry record. Therefore, precision for the DLT outcome cannot be assessed from the posted results.

In general, a hypothesis test addresses a specified statistical question under defined assumptions; a p-value does not measure the probability that a treatment works, nor does it describe the size or clinical importance of an effect. The registry lists zero analyses and does not report a primary endpoint test or a between-group comparison. No test method, significance threshold for the trial’s own endpoint analysis, or inferential result is reported in the registry record. The sample-size illustration’s stated significance level is an assumption for a planning calculation, not evidence that the trial conducted or reported a test using that level.

Why does the design affect interpretation?

In general, random allocation helps balance measured and unmeasured participant characteristics across treatment groups, on average. This study is explicitly non-randomized, and the record warns that its arms are not a like-for-like control comparison. Differences in outcomes between its schedules could reflect differences in who entered each group, treatment exposure, timing, or other factors, as well as any treatment effect. The registry does not provide an adjusted comparative analysis that could address such concerns. Even a descriptive difference would not, by itself, establish a causal effect.

Open-label treatment means participants and study personnel were not masked to treatment assignment. In general, knowledge of treatment can affect reporting, assessment, or management of events. The endpoint description does state that the Safety Monitoring Committee confirmed DLTs, but details of its procedures and any blinding of that review are not reported in the registry record. The record also does not describe whether endpoint assessment was independent of other study personnel.

How should planning calculations be read?

In general, a sample-size calculation asks how many observations a future study might need under assumptions about an outcome, a target effect, a statistical method, and the desired operating characteristics. A planning illustration based on an observed effect is not a property of the original trial design and does not show that the trial had a particular probability of detecting an effect. The stated illustration uses a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; its target effect is a stated fraction of the observed effect. For time-to-event outcomes, the stated convention is a total number of events, while other outcomes use participants per arm. These are planning assumptions, not reported design decisions for this study. The trial’s own sample-size justification is not reported in the registry record. Any planning values should not be described as observed power.

More generally, observed effects from small studies can be unstable. A planning calculation anchored to an observed effect inherits uncertainty in that estimate and does not guarantee that a later study will reproduce it. The registry record does not report an observed primary DLT effect to use for such an interpretation. Accordingly, no conclusion about a suitable future sample size can be drawn from the DLT endpoint information in this record.

Why can over-dispersion matter?

In general, over-dispersion arises when variation in observed counts is greater than a statistical model expects. If a count model assumes less variation than the data contain, uncertainty can be understated and inferential results can appear more precise than warranted. This is a general consideration for count outcomes; the primary endpoint is a count of participants meeting a binary event definition. The registry record does not report an over-dispersion assessment or a count-model analysis, and no such method should be attributed to the study.

Across these concepts, the central distinction is between a study objective, a reported observation, and an inferential conclusion. The registry specifies the DLT objective and some safety counts, but does not report the primary endpoint result or analyses that would quantify its uncertainty. General statistical methods can explain what such results would mean, but cannot fill in the missing study findings.

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("M3258 10 mg QD", "M3258 10 mg Twice Per Week", "M3258 20 mg Twice Per Week")
n      <- c(2, 4, 3)
events <- c(1, 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  M3258 10 mg QD  2  1  50.0  1.3  98.7  9.5  90.5  9.4  90.6
ARM  M3258 10 mg Twice Per Week  4  0  0.0  0.0  60.2  0.0  49.0  0.5  52.2
ARM  M3258 20 mg Twice Per Week  3  1  33.3  0.8  90.6  6.1  79.2  6.8  80.6

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 22 outcome measures, spanning safety and pharmacokinetic outcomes, but reports zero analyses. It does not identify a multiplicity strategy, such as a prespecified hierarchy, adjustment, or allocation of a statistical error rate across endpoints. A plan for handling multiple comparisons is therefore not reported in the registry record. Without such information, the presence of several outcomes should not be read as evidence that any particular endpoint was designated for formal confirmatory inference beyond the primary endpoint title.

The primary outcome description identifies a DLT analysis set: participants who received at least one dose and met at least one criterion specified in the statistical analysis plan. The criteria for membership in that set and the plan itself are not reported in the registry record. The primary endpoint’s result, analysis denominator, and any exclusions are also not reported. This limits the ability to determine how many enrolled participants contributed to the endpoint or how the outcome was handled for participants with incomplete observation.

Missing-data procedures are not reported in the registry record. It does not describe how a participant who stopped treatment, missed assessments, or lacked a complete observation window would be handled in the DLT analysis. The endpoint window is stated as Day 1 up to Day 28, but an observation window alone does not specify how incomplete follow-up is treated. No imputation method, sensitivity analysis, or missingness summary is reported.

These are distinct issues: multiplicity concerns interpretation across multiple outcomes or tests, while missing-data methods concern incomplete observations and analysis inclusion. The available record does not resolve either issue. In a small, early-phase study, both can materially affect how much confidence readers place in any apparent pattern, but no unreported procedure can be assumed.

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: thrombocytopenia (50.0%), respiratory tract infection (25.0%), cardiac failure (25.0%), neutropenia (25.0%), pathological fracture (25.0%).

The serious adverse-event summary reports, by regimen, participants at risk and participants affected. In the M3258 10 mg once-daily group, 2 participants were at risk and 0 were affected. In the M3258 10 mg twice-per-week group, 4 were at risk and 3 were affected. In the M3258 20 mg twice-per-week group, 4 were at risk and 3 were affected. These are descriptive counts from the registry record, not a randomized comparison and not the primary DLT endpoint.

The record lists thrombocytopenia at 50.0% among the top serious-event terms. Respiratory tract infection, cardiac failure, neutropenia, pathological fracture, and abdominal pain are each listed at 25.0%. The denominator and detailed event counts for these term percentages are not reported in the registry record. The listed terms may not constitute a complete inventory of serious events.

One death is listed for the M3258 20 mg twice-per-week group, with none listed for the other groups. The registry does not report a causal attribution for that death. Serious adverse events, deaths, and DLTs are not interchangeable measures. These figures describe recorded safety information; they do not by themselves establish whether a regimen caused an event or allow a precise comparison of risk across schedules.

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

The available record establishes that the study was designed to investigate M3258 in a first-in-human phase I setting, including dose escalation and an expansion component. It specifies a short-term DLT endpoint, its general assessment framework, and several regimen groups. It also reports adverse-event counts and selected serious-event terms. These details describe what the study sought to examine and some of the safety information registered for its participants.

The record does not report the primary DLT count, a primary endpoint analysis, or efficacy results. It therefore cannot answer how many participants experienced a DLT, characterize the estimated frequency of DLTs, or establish a difference between M3258 schedules. Nor does the stated interest in early efficacy signs demonstrate that an efficacy signal was observed. An absence of a reported result should not be interpreted as a finding of no events or no effect.

The safety counts also have limits. The groups are not randomized comparators, the numbers at risk are small, and the record does not provide the detail needed to assess the listed serious-event percentages fully. One death is recorded in one group, but the record does not attribute it to treatment. These data cannot establish causation or provide a reliable ranking of regimens by safety.

In general, early-phase studies can generate information to guide further investigation, but their role and evidentiary strength depend on the results and methods reported. Here, the registry record does not provide enough outcome or analysis information to estimate the primary endpoint’s precision or draw comparative conclusions. The defensible interpretation is limited to the study design, endpoint definition, and descriptive safety information that the record actually reports.

14. Why This Trial Matters Statistically

Statistically, this study illustrates why an endpoint definition is not a result. The registry describes DLT criteria, an assessment window, and the intended analysis population. Those details help readers understand what would count as the primary safety outcome. But without the number of participants meeting that definition, the denominator analyzed, or an uncertainty estimate, the central endpoint remains unquantified in the registry record.

The study also highlights the distinction between dose-regimen exploration and comparative evidence. Its non-randomized design and listed schedules can support descriptive reporting, but they do not create a like-for-like control comparison. Any apparent differences across groups would need cautious interpretation, particularly when group sizes are limited and participant allocation is not randomized. A design label alone cannot substitute for information about baseline comparability, exposure, follow-up, and analysis.

Finally, the record makes clear that safety summaries and DLT outcomes answer different questions. Serious adverse-event counts provide relevant descriptive context, but they do not replace the prespecified DLT definition. The listed terms, percentages, and death count need their denominators, event details, and attribution context for a fuller interpretation; several of those details are not reported in the registry record. This separation between endpoint, supporting safety outcomes, and causal inference is important when readers assess early-phase clinical evidence.

The statistical value of a registry record depends not only on its planned questions but also on transparent reporting of results and methods. Here, the design and endpoint are identifiable, while the primary analysis and several methodological details are absent. That boundary is itself consequential: it prevents readers from mistaking a stated objective or a descriptive safety summary for a precise answer to the study’s central statistical question.

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 for interpretation is that the registry record does not report the primary DLT outcome or any analyses. It gives the endpoint definition and window but not the number of participants meeting the definition, the analysis denominator, or an estimate of uncertainty. As a result, the principal safety question cannot be answered from the posted results.

The study is listed as non-randomized and explicitly not a like-for-like control comparison. Differences across the M3258 schedules cannot be interpreted as treatment effects without assumptions that the registry record does not establish. Enrollment was 10 participants, with the adverse-event summary listing small group counts. Such limited group information provides little basis for precise comparisons.

The registry’s account of treatment is also incomplete. The study description includes a combination component with dexamethasone, while the listed regimen names specify M3258 schedules; the arm descriptions are blank. The record does not report which participants received dexamethasone or provide enough detail to resolve this apparent mismatch. Detailed dosing, exposure, follow-up, and reasons for termination are not reported in the registry record.

Other limitations include the absence of the statistical analysis plan, sample-size justification, multiplicity strategy, missing-data procedures, and detailed analysis-population criteria. The registry does not report an efficacy result. For serious-event term percentages, underlying denominators and detailed counts are not reported. The one death listed in a regimen group has no reported causal attribution. These gaps prevent stronger claims about event frequency, comparative safety, efficacy, or the reasons the study ended.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: First in Human Dose Escalation of M3258 as a Single Agent and Expansion Study of M3258 in Combination With Dexamethasone — NCT04075721.
• Registry record last updated 2023-03-24; status last verified 2022-06.
• Results first posted 2023-03-24.
• 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

This phase I study of M3258 in relapsed refractory multiple myeloma is listed as open-label, non-randomized, and parallel-group, with enrollment of 10 participants. The registry describes first-in-human dose escalation of M3258 as a single agent and an expansion component involving dexamethasone. Listed regimen groups are M3258 10 mg once daily, M3258 10 mg twice per week, and M3258 20 mg twice per week. The record lists a start date of 2019-09-26, primary completion date of 2021-04-01, and terminated status.

The primary endpoint is the number of participants with DLTs from Day 1 up to Day 28. The registry record does not report a primary endpoint result or any analyses. It reports descriptive serious and other adverse-event counts, including one death in the M3258 20 mg twice-per-week group, without reporting causal attribution for that death. The reason for termination, detailed analysis methods, and efficacy results are not reported in the registry record.