Study to Assess Safety and Efficacy of the Second Mitochondrial-derived Activator of Caspases (SMAC) Mimetic Debio 1143: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Assess Safety and Efficacy of the Second Mitochondrial-derived Activator of Caspases (SMAC) Mimetic Debio 1143 (NCT04122625), a non-randomized phase 1, phase 2 study. The primary outcome is Part A: Number of Participants With Dose-limiting Toxicities (DLTs).

2. Clinical Question

The registry record reports enrollment of 46 participants overall, but does not report the primary endpoint result or numerical antitumor activity results. Accordingly, the record supports describing the study’s questions and design, but not judging the observed frequency of dose-limiting toxicities or the magnitude of tumor response.

3. Trial Design

This was a Phase Ib/II, nonrandomized, unmasked, sequential study. It enrolled 46 participants and is recorded as completed. Part A was a dose-optimization stage. It evaluated Debio 1143 150 mg and 200 mg in combination with nivolumab, with the aim of identifying a recommended phase 2 dose. The stated considerations included dose-limiting toxicities in Cycle 1, overall safety and tolerability, pharmacokinetics, and treatment compliance.

Part B was a basket study intended to examine preliminary antitumor activity at the recommended phase 2 dose. Its tumor cohorts included small cell lung cancer; squamous cell carcinoma of the head and neck; gastrointestinal cancers with specified MSI-H/MMRd or DNA damage repair abnormalities; and selected gynecologic cancers with specified molecular features or platinum resistance. The registry describes the 200 mg Debio 1143 dose with nivolumab for these cohorts.

Schedules were not identical across the study. In Part A, Debio 1143 was scheduled on Days 1 to 10 and Days 15 to 24 of each 28-day cycle. In Part B, it was scheduled on Days 1 to 28. Nivolumab was scheduled on Days 1 and 15 of each 28-day cycle. The listed schedules allowed treatment for a maximum of 26 cycles.

Because assignment was not randomized and there was no like-for-like control group, differences between doses or cohorts cannot be interpreted as controlled treatment effects. Sequential dose optimization and the basket structure address different questions: the former focuses on dose selection and early-cycle toxicity, while the latter explores activity across distinct tumor groups. Further details about allocation procedures or protocol-defined analysis plans 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: A total of 46 participants were enrolled in this study, 11 participants with advanced solid malignancies who failed prior systemic standard treatments into Part A and 35 participants into Part B of the study. Part B of the study was started after recommended phase 2 dose (RP2D) was determined in Part A and did not include any participants from Part A.

Part A (up to 2.92 Years)

Reasons for not completing this period:

Part B (up to 2.33 Years)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Recommended phase 2 dose (RP2D) population included participants who received at least 70% of Debio 1143 (i.e., a maximum of 6 missed Debio 1143 doses) and at least one nivolumab dose as planned in Cycle 1.

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 enrolled and received at least one dose of any study drug.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Part A: Number of Participants With Dose-limiting Toxicities (DLTs), measured over Part A: Cycle 1 (28 days).

The primary endpoint counted participants with dose-limiting toxicities in Part A during Cycle 1, defined as 28 days. The registry specifies that qualifying events were treatment-emergent adverse events assessed under NCI CTCAE Grade V5.0 criteria and considered possibly, probably, or definitely related to the combination treatment. The listed criteria include specified severe hematologic or nonhematologic toxicities, febrile neutropenia, certain thrombocytopenia, prolonged treatment-related toxicity, a treatment-related delay in starting Cycle 2, insufficient completion of scheduled Debio 1143 dosing because of toxicity, and dose reduction or withdrawal for treatment-related toxicity.

This endpoint is used in dose optimization because the frequency and nature of early toxicities can inform whether a dose is suitable for further study. It is a count of affected participants, not a measure of tumor response. The defined analysis population included participants who received at least 70% of Debio 1143, described as a maximum of 6 missed doses, and at least one planned nivolumab dose in Cycle 1.

The registry record does not report how many participants in that population had a dose-limiting toxicity. It also does not report an estimate of uncertainty around the endpoint. The endpoint definition and its purpose can therefore be described, but its observed frequency cannot be interpreted from the record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Design and comparison. The study is nonrandomized, unmasked, and sequential. In a randomized comparison, random assignment is intended to make treatment groups comparable on average at baseline. That protection is not present. Participants were studied in dose groups and tumor cohorts that were part of the study’s sequential structure, not assigned to a comparable control condition. Any differences in event counts across groups may reflect differences in cohort size, tumor type, participant characteristics, treatment exposure, or other factors. The registry record does not report enough information to separate these possibilities.

The design has two distinct aims. Part A was dose optimization, with attention to early-cycle toxicity, safety, tolerability, pharmacokinetics, and treatment compliance. Part B was a basket evaluation of preliminary activity across cohorts defined by tumor type and, for some cohorts, molecular characteristics. These aims should not be conflated: a dose-limiting toxicity count addresses early tolerability, while antitumor outcomes address activity. The registry record does not report numerical results for the primary endpoint or antitumor activity.

Counting an endpoint. The primary endpoint is a count of participants with at least one qualifying dose-limiting toxicity during Cycle 1. Such participant counts are binary at the individual level: a participant either meets the endpoint definition or does not. The count summarizes how many participants met the definition, while the number at risk supplies the context needed to interpret that count. The registry describes an analysis population based on treatment exposure in Cycle 1. It does not report the observed count, the denominator used in an endpoint result, or a confidence interval for the count or an associated proportion.

The definition uses event grade, timing, and relationship to combination treatment, as well as consequences for treatment delivery. These criteria make the endpoint more specific than a count of any adverse event. The registry describes the toxicity criteria in detail, including severe events, certain blood-related toxicities, treatment delays, missed doses due to toxicity, dose reduction, and withdrawal. Applying such a definition requires consistent event assessment and attribution. Additional operational details about adjudication or how ambiguous events were handled are not reported in the registry record.

Uncertainty and confidence intervals. General statistical explanation: a confidence interval expresses the range of values reasonably compatible with the observed data under the method used. It conveys precision in addition to the point estimate. Small groups generally yield less precise estimates than larger groups, although actual precision depends on the estimate and analysis. No confidence interval for the primary endpoint or the listed serious adverse event counts is reported in the registry record. Without an endpoint estimate and its uncertainty, the strength of statistical evidence cannot be assessed.

Over-dispersion and count data. General statistical explanation: counts can vary more across participants or groups than a simple model assumes. This is called over-dispersion and can arise when observations are heterogeneous. If a model assumes less variability than is present, its standard errors may be too small and confidence intervals too narrow. The primary endpoint is a participant count, but the registry record does not report a model, variance estimate, or analysis of over-dispersion. No model-based inference about this endpoint can therefore be reconstructed from the record.

Planning illustrations. The sample-size assumptions describe a planning illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The target effect is expressed as a stated fraction of the observed effect. For time-to-event outcomes, the illustration is based on a total number of events; for other outcomes, it is expressed as participants per arm. Such calculations are planning illustrations, not observed power and not evidence that a future study will achieve a particular result. The registry record does not report a trial-specific sample-size justification, and no numerical planning results are included in the registry record described for this analysis.

Multiplicity. General statistical explanation: when many outcomes, cohorts, or comparisons are examined, the chance of at least one apparently unusual result can increase. A prespecified approach may control or otherwise address that issue, depending on the scientific aims. This study lists 27 outcome measures and 0 analyses in the registry record. Whether an adjustment for multiple testing was planned, which outcomes were prioritized beyond the stated primary endpoint, and how cohort-specific findings were to be interpreted are not reported in the registry record. Accordingly, isolated findings should not be treated as confirmatory without the relevant analysis plan and estimates.

Missing data and analysis populations. General statistical explanation: missing outcome information can affect both the number analyzed and the interpretation of an estimate. Different assumptions about missingness can lead to different results, so a transparent report typically describes missingness, exclusions, and the analysis population. The registry identifies the RP2D population for the primary endpoint using Cycle 1 treatment exposure, but does not report a missing-data method, a participant flow for that endpoint, or sensitivity analyses. It is therefore not possible to assess whether missing outcome information affected the primary result.

These methods considerations place limits on what can be concluded. The record provides design details, endpoint definitions, and group-level safety counts, but does not provide the primary endpoint result, efficacy estimates, uncertainty intervals, or detailed analysis methods. Those absences prevent independent assessment of statistical precision and prevent causal comparisons across the nonrandomized groups.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Part A - Debio 1143 150 mg + Nivolumab", "Part A - Debio 1143 200 mg + Nivolumab")
n      <- c(3, 6)
events <- c(0, 0)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Part A - Debio 1143 150 mg + Nivolumab  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Part A - Debio 1143 200 mg + Nivolumab  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 27 outcome measures and 0 analyses. It does not report whether multiplicity was addressed, whether a testing hierarchy was specified, or whether any cohort-specific or secondary analyses were intended to be confirmatory. General statistical context: testing or examining multiple outcomes can increase the opportunity for chance findings, so the prespecified analysis strategy matters when interpreting multiple results. In the absence of a reported strategy and numerical estimates, no multiplicity-adjusted interpretation can be made.

The record defines the primary endpoint population as participants who received at least 70% of Debio 1143, with a maximum of 6 missed Debio 1143 doses, and at least one nivolumab dose as planned in Cycle 1. It does not report the number included in that population or how missing endpoint information was handled. Whether participants with incomplete assessments were excluded, counted in another way, or included through an imputation method is not reported in the registry record.

General statistical context: missing outcomes can alter both the denominator and the estimate, and the impact depends on why data are missing. Reporting the analysis population, the amount of missing information, and sensitivity analyses helps readers assess robustness. Those details are not reported in the registry record. The primary endpoint result itself is also not reported, so its analysis population and precision cannot be evaluated from posted results.

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: fatigue (25.0%), respiratory failure (25.0%), abdominal pain (12.5%), dysphagia (12.5%), pancreatitis acute (12.5%).

The serious adverse event figures are participant counts by treatment group. They are 0 of 3 for Part A Debio 1143 150 mg plus nivolumab; 8 of 8 for Part A Debio 1143 200 mg plus nivolumab; 0 of 8 for the Part B small cell lung cancer cohort; 6 of 8 for the Part B head and neck cohort; 5 of 8 for the Part B gastrointestinal cohort; and 5 of 11 for the Part B gynecologic cohort. The group sizes and counts should be read together. Because the study was nonrandomized, the groups are not like-for-like controls, and differences between counts do not establish comparative treatment risks.

The registry also lists deaths by group, in the same order: 2, 4, 5, 7, 6, and 7. These counts do not establish whether a death was caused by treatment, the underlying cancer, or another circumstance. The registry record does not report causal attribution for these figures in the information.

Among the listed serious adverse event terms, the registry gives Fatigue and Respiratory failure at 25.0% each, and Abdominal pain, Dysphagia, Pancreatitis acute, and Disease progression at 12.5% each. These percentages are reported terms; the registry information does not establish that each event was treatment-related. Seriousness, severity, and causal relationship are distinct concepts and should not be treated as interchangeable.

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

The study addresses an early development question: dose optimization for Debio 1143 with nivolumab in Part A, followed by an exploratory evaluation of preliminary antitumor activity across tumor-specific cohorts in Part B. Its sequential, nonrandomized design is suited to describing experience within the study groups, but it does not create a randomized comparison against a control group.

The registry record does not report the number of participants with dose-limiting toxicities, even though this is the primary endpoint. It also does not report numerical objective response results or other antitumor activity estimates. The purpose of an endpoint is not a result; without the observed estimate, the record cannot establish how often the endpoint occurred or what degree of activity was observed. No uncertainty interval for these outcomes is reported.

The posted safety information gives counts of participants with serious adverse events and deaths in each group, together with selected serious adverse event terms and percentages. Those data describe reported events in the registry. They do not, by themselves, determine cause, establish that an event resulted from a particular study drug, or support a controlled comparison between cohorts.

General statistical context: an estimate is most informative when interpreted with its design, denominator, uncertainty, and analysis population. In a nonrandomized study with small and clinically distinct cohorts, descriptive counts can be useful for documenting observed experience, but they are not a substitute for a controlled estimate of treatment effect. The registry record does not report the numerical efficacy findings, endpoint precision, or detailed analysis methods needed for stronger statistical conclusions.

Thus, the record supports a careful description of the study design, endpoint definitions, and listed safety counts. It does not support a conclusion about whether the combination improved outcomes, whether one dose or cohort had a better outcome, or whether observed adverse events were caused by treatment. Those questions require results and analysis details that are not reported in the registry record.

14. Why This Trial Matters Statistically

This study is statistically notable for bringing together dose optimization and a multi-cohort exploratory evaluation within a sequential design. Part A’s primary endpoint focuses on dose-limiting toxicities during Cycle 1, while Part B’s stated purpose is to examine preliminary activity across several tumor cohorts. These are distinct estimands and should be interpreted separately: early toxicity counts inform dose-selection questions, whereas tumor response outcomes address activity.

The design also illustrates why a basket study’s cohort definitions matter. The Part B groups were organized by cancer type and, in some cohorts, molecular characteristics. Participants across these groups are not automatically exchangeable. Pooling their outcomes or comparing their counts without accounting for those differences could obscure clinically relevant heterogeneity. The registry record does not report a pooled efficacy estimate or cohort-specific numerical results.

The safety listings show why denominators and study structure are essential. Group sizes differ, and serious adverse event counts vary across the listed groups. In a nonrandomized study, these descriptive differences cannot be interpreted as treatment contrasts. Counts should be considered in context, and causal conclusions require more than event totals.

The record also makes the distinction between a protocol objective and evidence especially important. The stated objectives identify what investigators intended to assess; the posted registry information does not include the primary endpoint result or numerical efficacy estimates. Statistical interpretation therefore depends on recognizing both the information that is available and the central results that are not reported.

Finally, planning calculations based on an observed effect are not equivalent to observed evidence or observed power. The stated planning assumptions can describe a hypothetical future study framework, but do not fill gaps in the trial’s reported results or establish the precision of this study’s estimates.

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 principal limitation for statistical interpretation is that the registry record does not report the primary endpoint result. The number of participants with dose-limiting toxicities in the specified Part A population is not given, and no confidence interval or other measure of uncertainty is reported. Numerical antitumor activity results are also not reported, despite Part B’s exploratory activity objective.

The study was nonrandomized and unmasked, with sequential dose groups and distinct tumor cohorts. There is no like-for-like control comparison. Group-level differences in safety counts cannot be interpreted as causal effects of dose or treatment, especially because the cohorts differ in tumor type and size. The registry does not report adjustment methods or other analysis details that would support a cross-cohort comparison.

The record describes the primary endpoint population by treatment exposure in Cycle 1, but does not state how many participants met that definition, how many had evaluable endpoint data, or how missing data were handled. It also does not report sensitivity analyses, a detailed participant flow, or the statistical methods used for endpoint estimation. The protocol’s sample-size justification and any interim analysis plans are not reported in the registry record.

Safety listings include serious adverse event counts, death counts, and selected event terms. The listed counts do not establish treatment causality, and the registry information does not provide enough detail to interpret duration, recurrence, or exposure-adjusted risk. The absence of numerical efficacy and primary endpoint results limits conclusions about the study’s main questions, while the nonrandomized structure further restricts comparative interpretation.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study to Assess Safety and Efficacy of the Second Mitochondrial-derived Activator of Caspases (SMAC) Mimetic Debio 1143 — NCT04122625.
• Registry record last updated 2023-06-12; status last verified 2023-05.
• Results first posted 2023-06-12.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

NCT04122625 is a completed, nonrandomized, unmasked, sequential Phase Ib/II study of Debio 1143 with nivolumab in participants with advanced solid tumors. Enrollment was 46. Part A evaluated dose optimization, including 150 mg and 200 mg Debio 1143 combinations; Part B was an exploratory basket study using the 200 mg dose across four tumor cohorts.

The primary endpoint was the number of Part A participants with dose-limiting toxicities in Cycle 1, defined as 28 days, among a specified treatment-exposure population. The registry record does not report the endpoint count or numerical antitumor activity results. It does list serious adverse event and death counts by treatment group. Because there was no randomized control group, those counts are descriptive and do not establish comparative or causal effects.