Berzosertib + Topotecan in Relapsed Platinum-Resistant Small-Cell Lung Cancer (DDRiver SCLC 250): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Berzosertib + Topotecan in Relapsed Platinum-Resistant Small-Cell Lung Cancer (DDRiver SCLC 250) (NCT04768296), a non-randomized phase 2 study. The primary outcome is Safety Run-in Part: Number of Participants With Dose Limiting Toxicities (DLTs).

2. Clinical Question

The study’s stated purpose was to assess efficacy, safety, tolerability and pharmacokinetics of berzosertib in combination with topotecan in participants with relapsed, platinum-resistant small-cell lung cancer. Its structure had two parts: a safety run-in and a main part. The safety run-in was conducted in Japan, while the 210 mg/m^2 berzosertib regimen is described for both the dose-level-two run-in and the main part.

The question for the safety run-in is principally about short-term tolerability at the studied doses: whether participants experienced drug-related events meeting the protocol’s dose-limiting toxicity definition during the assessment window. This is distinct from asking whether the combination improves outcomes compared with another treatment. The registry record describes several later outcomes for the main part, including response duration, progression-free survival, overall survival, quality-of-life measures, treatment-emergent adverse events and changes in vital signs. The numerical results for those outcomes are not reported in the registry record.

Because treatment was not randomized and no control group is described, the study can characterize outcomes among treated participants, but it cannot isolate the combination’s effect from other explanations for those outcomes. The posted safety counts also do not by themselves answer the primary question: the dose-limiting toxicity result is not reported in the registry record.

3. Trial Design

This was a phase II, open-label, non-randomized, single-arm study. The registry reports enrollment of 76 participants and a completed study, with a start date of 2021-03-29 and primary completion on 2023-07-21. The stated overall purpose was to assess efficacy, safety, tolerability and pharmacokinetics of berzosertib combined with topotecan in relapsed, platinum-resistant small-cell lung cancer.

The study had a safety run-in part and a main part. The safety run-in was conducted in Japan. At dose level one, participants received berzosertib 105 mg/m^2 intravenously on Day 2 and Day 5 of each 21-day cycle, with topotecan 1.25 mg/m^2 intravenously on Days 1 through 5 of each cycle. The other described regimen used berzosertib 210 mg/m^2 on Day 2 and Day 5 with topotecan 1.25 mg/m^2 on Days 1 through 5. The registry describes this regimen for dose level two of the safety run-in and for the main part. Treatment continued until disease progression, according to the arm descriptions.

There was no masking. In an open-label study, participants and study personnel know the treatment being given. This is relevant to outcomes involving clinical judgment or participant reporting, including response assessment and quality-of-life questionnaires. The registry lists independent review committee assessment for the main-part response duration and progression-free survival outcomes, but other details of assessment and analysis are not reported in the registry record.

The non-randomized, single-arm structure is central to interpretation. The dose levels are sequential parts of the study, not randomized treatment groups. Their outcomes should not be read as estimates from a controlled comparison. The registry record does not report a sample-size justification, randomization procedure, or masking procedure beyond stating that masking was none. Nor does it report enough information to reconstruct how enrollment was distributed across every study part.

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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full Analysis Set (FAS) included all participants who were administered at least 1 dose of berzosertib.

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 Safety Run-in Part: Number of Participants With Dose Limiting Toxicities (DLTs), measured over Up to Cycle 1 Day 21 (each cycle is of 21 days).

The primary endpoint is the number of participants with dose-limiting toxicities in the safety run-in. The assessment period extends up to Cycle 1 Day 21, with each cycle lasting 21 days. A dose-limiting toxicity is a drug-related event meeting one of the stated severity or duration criteria. These include Grade 4 neutropenia lasting more than 7 days; febrile neutropenia with an absolute neutrophil count below 1000 per mm^3 and a specified fever; infection with Grade 3 or 4 neutropenia; thrombocytopenia of Grade 3 or higher; or a non-hematological adverse event of Grade 3 or higher.

This endpoint is used in a safety run-in to identify serious toxicities within an early treatment period and inform evaluation of the regimen’s dose. It is a count, not a measure of tumor response or comparative benefit. The definition also makes the endpoint narrower than “any adverse event”: an event must be drug-related and meet the specified criteria to qualify as a dose-limiting toxicity.

The registry record describes a DLT analysis set involving participants who received any study intervention in the safety run-in in Japan, with additional eligibility criteria. However, the population description is incomplete in the registry record. The number of participants meeting the endpoint is also not reported in the registry record, so the primary endpoint’s observed frequency and precision cannot be assessed from the posted information.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies a count of participants with dose-limiting toxicities as the primary endpoint. A count is a direct way to describe how many participants met a defined event criterion during the assessment window. For interpretation, the count needs to be considered alongside the number of participants evaluated and the rules defining the analysis population. The registry’s description of that population is incomplete, and the primary count is not reported in the registry record. A frequency estimate or its uncertainty therefore cannot be reconstructed from the information available.

What does a confidence interval communicate?

In general, a confidence interval describes statistical uncertainty around an estimated quantity under the assumptions of the method used. For an event frequency, a wider interval indicates less precision, while a narrower interval indicates more precision. The interval does not remove design limitations, establish causation, or account automatically for sources of bias. No confidence interval for the primary endpoint is reported in the registry record.

For a small safety run-in, uncertainty can be substantial even when an event count is clearly stated. Each participant represents an appreciable part of the observed group, so the estimate can change meaningfully with a small change in the count. This general point is especially important when the aim is to characterize uncommon or serious events: absence of an observed event does not establish that the event cannot occur. The posted information does not give a DLT count, so this principle cannot be applied to a numerical primary estimate for this study.

Why do the groups not form a treatment comparison?

In general, randomized allocation helps make treatment groups comparable in expectation, while a single-arm study observes outcomes after treatment without a concurrent randomized control. This study is described as non-randomized, open-label and single-arm. The safety run-in’s dose levels are sequential components, and the higher dose is also described for the main part. Their group counts should not be interpreted as a randomized comparison of dose levels. Differences in observed event counts may reflect differences in the groups or study context as well as any dose-related difference.

Open-label conduct can matter when outcome ascertainment involves judgment or participant report. The registry identifies independent review committee assessment for main-part response duration and progression-free survival, which is a specific safeguard described for those outcomes. The record does not report further details about adjudication, blinding of reviewers, or assessment procedures for the other outcomes. It is therefore not appropriate to assume that the same review process applied to every measure.

How should the adverse-event counts be read?

The posted safety information distinguishes serious adverse events from other adverse events and gives counts by reported group. These categories are not the same as the primary endpoint. The primary endpoint requires a drug-related event that meets defined toxicity criteria during its assessment window; the broader adverse-event counts include events under separate registry categories. A participant may have more than one event, and event counts are not necessarily participant counts unless the record explicitly reports participants. The posted group counts are described as participants affected, but the registry does not provide detailed event-level timing, duration or attribution for every event.

In general, an adverse event occurring after treatment is not automatically caused by treatment. Attribution requires clinical assessment, and an observed group count alone cannot distinguish treatment effects from underlying illness, other care or chance. The record also gives death counts but does not establish, in the information available, that those deaths were treatment-related. The serious-event terms and percentages need denominators and grouping context for a fuller interpretation; that context is not reported in the registry record.

What do the sample-size illustrations mean?

General sample-size calculations estimate the amount of information needed for a specified design, effect and statistical criterion. They are not evidence that a completed study had a particular probability of detecting an effect. The planning illustration described for the posted results uses a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation and effects defined as fractions of an observed effect. Time-to-event illustrations are described as total event counts; other illustrations are described as participants per arm. Those are planning conventions, not the design used in this non-randomized single-arm study. The registry record does not report that these assumptions formed the trial’s own sample-size justification.

A recalculation from summary statistics, when one is presented, is generally an unadjusted calculation and may not match a sponsor’s prespecified analysis. No such recalculated efficacy result or sponsor analysis is reported in the registry record. The record also does not report analysis methods for the outcome measures, including model choices, adjustment variables, confidence-interval methods or inferential testing. These details matter because different reasonable methods can yield different estimates or uncertainty assessments, especially when data are sparse or incomplete.

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("Safety run-in Part (DL 1): Berzosertib 105 mg/m^2 ", "Safety run-in Part (DL2) + Main Part: Berzosertib ")
n      <- c(3, 3)
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  Safety run-in Part (DL 1): Berzosertib 105 mg/m^2   3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Safety run-in Part (DL2) + Main Part: Berzosertib   3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 41 outcome measures, including multiple measures of response, survival, quality of life, adverse events and vital signs. When many outcomes are assessed, the chance of at least one apparently notable result can increase if each is tested separately. General statistical approaches can address multiplicity by defining a hierarchy, adjusting significance thresholds, or treating analyses as descriptive. The registry record does not report a multiplicity strategy, a hierarchy among secondary outcomes, or which analyses were considered confirmatory.

Missing data can affect both the estimate and its precision. For example, missing quality-of-life responses may differ systematically from observed responses, and incomplete follow-up can affect time-to-event outcomes. General methods include describing the amount and pattern of missingness, stating the analysis population, and explaining assumptions or sensitivity analyses. These details are not reported in the registry record. The record names an analysis population for the primary endpoint, but its description is incomplete; analysis populations for the other outcomes are not specified in the information available.

The registry record contains no analysis entries, and numerical results for the primary endpoint and listed secondary outcomes are not reported in the registry record. It is therefore not possible to assess whether missing observations were excluded, imputed, censored or handled in another way, or whether analyses accounted for repeated assessments. The posted adverse-event counts remain descriptive group summaries; they do not reveal the completeness of follow-up or event collection.

These gaps are important for interpretation, not merely formal reporting details. Without a reported analysis plan, multiplicity approach, missing-data methods and outcome-specific populations, readers cannot determine whether estimates were prespecified, how robust they are to analytic choices, or how much information was available for each outcome.

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: dyspnoea (8.2%), anaemia (5.5%), febrile neutropenia (5.5%), covid-19 (5.5%), thrombocytopenia (4.1%).

The registry reports serious adverse events in 0 of 3 participants in the 105 mg/m^2 berzosertib group and 31 of 73 participants in the 210 mg/m^2 berzosertib group. For other adverse events, the counts are 3 of 3 and 70 of 73, respectively. The reported death counts are 1 and 63, respectively. These are descriptive counts for the named groups; they are not randomized comparisons and should not be read as proof that treatment caused or prevented an event.

Serious adverse events are not interchangeable with dose-limiting toxicities. The primary endpoint applies a drug-relatedness requirement, specific severity or duration criteria, and a defined safety run-in period. The posted serious-event counts do not show which participants met the primary DLT definition. The numerical DLT result is not reported in the registry record.

The record also lists dyspnoea at 8.2%, anaemia at 5.5%, febrile neutropenia at 5.5%, COVID-19 at 5.5%, thrombocytopenia at 4.1%, and COVID-19 pneumonia at 4.1% among the leading serious-event terms. The denominator, group assignment and attribution basis for these percentages are not reported in the registry record. The death counts are not identified as treatment-related in the information available. These limitations prevent a causal interpretation or a complete assessment of event timing and severity.

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

The record establishes that this was a completed phase II study of berzosertib with topotecan in relapsed, platinum-resistant small-cell lung cancer, with a safety run-in and a main part. It describes the study’s doses, the primary safety endpoint and several secondary outcomes. It also reports group-level counts for serious adverse events, other adverse events and deaths. Those details give readers a basic account of the design and the types of safety data collected.

The record does not report the primary dose-limiting toxicity count or the numerical results for the listed efficacy and other secondary outcomes. It therefore does not support a conclusion about the observed DLT frequency, response, progression-free survival, overall survival or quality-of-life change. An endpoint’s presence in a registry is not itself evidence of a particular result.

The study’s single-arm, non-randomized design also limits causal interpretation. The outcomes among treated participants do not show what would have happened to comparable participants under another treatment or no study treatment. The sequential dose groups are not randomized controls, and their counts cannot be treated as a fair estimate of the effect of one dose versus the other. The open-label design is relevant to assessments that depend on judgment or participant report, although the registry identifies independent review committee assessment for certain main-part outcomes.

The adverse-event figures describe what was recorded in the reported groups. They do not establish that the treatment caused each event or death, and the listed serious-event percentages lack reported denominator and grouping context. Nor do the available counts provide a complete picture of event timing, duration, recurrence or attribution.

Accordingly, the registry record is informative about the trial’s structure and some descriptive safety counts, but it does not provide enough outcome results or analysis detail to quantify treatment effects or their precision. This distinction is important: a study can collect many outcomes while the available registry record still leaves the main statistical findings unreported.

14. Why This Trial Matters Statistically

This trial is statistically notable because it combines a safety run-in with a main study in a single-arm design. The safety run-in’s primary endpoint is a defined count of dose-limiting toxicities over an early treatment period. That endpoint is suited to describing whether specified toxicities occurred during the dose-evaluation stage, but its interpretation depends on the endpoint result, analysis population and follow-up being clearly reported. The primary count and a complete population definition are not reported in the registry record.

The design also illustrates why descriptive safety findings and comparative treatment effects should be kept separate. Counts of participants with adverse events can be clinically important descriptions of observed experience, but without random allocation and a concurrent control group they do not estimate a causal difference between treatment strategies. Sequential dose levels do not resolve that limitation because dose and study part are not randomized independently of other differences.

Another statistical issue is the breadth of outcomes. The record lists 41 outcome measures, spanning response, survival, quality of life and safety. Multiple outcomes require clear reporting of which questions were primary, how analyses were prioritized and how multiplicity was handled. Those analysis details are not reported in the registry record. Similarly, missing-data methods and outcome-specific analysis populations are not described, limiting evaluation of the reliability of any estimates that might otherwise be available.

The record’s serious-event counts demonstrate why denominators and event definitions matter. The safety summaries use participant counts, while serious-event term percentages require a clear denominator and group assignment to be interpreted. For this record, that context is not reported. The example reinforces a broader statistical principle: accurate interpretation depends not only on a value, but also on its population, endpoint definition, timeframe and method of analysis.

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 limitations are specific to the information available for this trial. The registry describes the primary endpoint as the number of participants with dose-limiting toxicities during the safety run-in but does not report its numerical result. The DLT analysis-population description is incomplete, so eligibility for that endpoint cannot be fully reconstructed from the registry record.

The study was non-randomized, open-label and single-arm. There is no like-for-like control comparison, and the sequential dose groups should not be treated as randomized arms. The results therefore cannot isolate treatment effects from other differences between participants or study parts. Open-label conduct may also matter for outcomes involving judgment or self-report; only certain main-part outcomes are specifically described as independently reviewed.

The registry lists 41 outcomes, but the numerical results for the primary endpoint and secondary outcomes are not reported in the registry record. No analysis entries are present in the record. Statistical methods for effect estimation, uncertainty intervals, missing observations, multiplicity and outcome-specific analysis populations are not described. The stated sample-size illustration assumptions do not amount to a reported sample-size justification for the actual single-arm design.

For safety, the registry provides serious-event, other-event and death counts, but does not establish treatment attribution for the deaths in the available information. The serious adverse-event term percentages are reported without denominator and group context in the information available. These gaps mean the counts cannot provide a complete assessment of the frequency, timing, severity or cause of events. They should be interpreted as descriptive registry summaries rather than adjusted comparative estimates.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Berzosertib + Topotecan in Relapsed Platinum-Resistant Small-Cell Lung Cancer (DDRiver SCLC 250) — NCT04768296.
• Registry record last updated 2024-09-26; status last verified 2024-08.
• Results first posted 2024-09-26.
• 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

NCT04768296 is a completed phase II, open-label, non-randomized, single-arm study of berzosertib with topotecan in relapsed, platinum-resistant small-cell lung cancer. The study included a safety run-in conducted in Japan and a main part. Its primary endpoint was the number of participants with dose-limiting toxicities in the safety run-in up to Cycle 1 Day 21.

The registry reports enrollment of 76 participants and describes berzosertib dose levels of 105 mg/m^2 and 210 mg/m^2 with topotecan 1.25 mg/m^2. It lists 41 outcome measures and provides adverse-event group counts, but the primary endpoint result and numerical secondary outcome results are not reported in the registry record. The available safety counts are descriptive and do not constitute randomized comparisons or establish treatment causation.