Study of Peposertib in Combination With Capecitabine and RT in Rectal Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Peposertib in Combination With Capecitabine and RT in Rectal Cancer (NCT03770689), a non-randomized phase 1, phase 2 study. The primary outcome is Number of Participants Who Experienced Dose Limiting Toxicity (DLT) Confirmed by Safety Monitoring Committee (SMC).

2. Clinical Question

3. Trial Design

The registry record identifies NCT03770689 as a completed study of peposertib combined with capecitabine and radiotherapy for locally advanced rectal cancer. It lists Phase I and Phase II, an enrollment of 19, a start date of 2019-03-20, and a primary completion date of 2021-06-21. The registry’s stated main purpose was to define the maximum tolerated dose and recommended Phase II dose, as well as safety and tolerability of the combination.

The listed treatment arms use peposertib doses of 50 mg, 100 mg, 150 mg, and 250 mg. Each arm also includes capecitabine and radiotherapy. Capecitabine is described as 825 mg/m^2 twice daily, 5 days per week. Radiotherapy is described as 50 to 50.4 Gy to the tumor area and 45 Gy to electively irradiated tissues, delivered in 25 to 28 fractions. The described treatment period is up to 5.5 weeks.

There is a design-description tension in the record. The official title describes an open-label Phase Ib part followed by a randomized, placebo-controlled, double-blind Phase II part. However, the record’s overall design fields identify non-randomized allocation, no masking, and a single-group model, and the listed arms are dose cohorts rather than a placebo-controlled comparison. The registry record does not clarify this discrepancy or establish which design features applied to each part. The listed design fields are the appropriate basis for interpreting the posted arm-level information, while the title alone is not evidence of a randomized comparison.

The primary endpoint is a safety and dose-escalation measure: the number of participants with a dose-limiting toxicity confirmed by the Safety Monitoring Committee. The record lists 18 outcome measures, including safety outcomes and response and survival outcomes. It does not report the primary endpoint count or a comparative estimate for the secondary outcomes in the registry record for this analysis.

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: The study was planned to be conducted in two phases: Phase Ib and Phase II. Phase II of the study was never initiated due to early discontinuation as per sponsor's decision.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Dose escalation (DE) analysis set included all participants treated in dose escalation cohorts, who received at least 80% of peposertib, 50% of capecitabine, and 80% of RT planned dose and complete DLT period (5 or 5.5 weeks after start of treatment or for the entire duration of treatment). DE set also included participants treated in dose escalation cohorts who experience a DLT during DLT period regardless of the amount of each study intervention received/completion of the DLT 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: The safety (SAF) analysis set included all participants who received at least 1 dose of study intervention.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants Who Experienced Dose Limiting Toxicity (DLT) Confirmed by Safety Monitoring Committee (SMC), measured over Time from first study intervention up to 19 weeks (including 5.5 weeks of treatment and 13.5 weeks of short term safety follow-up period).

The primary endpoint counts participants who experienced a dose-limiting toxicity confirmed by the Safety Monitoring Committee. The registry defines dose-limiting toxicity through treatment-emergent adverse events considered possibly related to study treatment by the investigator and/or sponsor, subject to committee confirmation. Examples include an adverse drug reaction considered clinically significant for dose escalation, drug-induced liver injury meeting Hy’s law criteria, specified severe toxicities, and toxicity leading to receipt of more than 80% of a planned peposertib, capecitabine, or radiotherapy dose. The definition also includes stated exclusions for certain toxicities.

The endpoint timeframe runs from first study intervention up to 19 weeks, including 5.5 weeks of treatment and 13.5 weeks of short-term safety follow-up. The registry’s dose-escalation analysis population also refers to completion of a DLT period, described as 5 or 5.5 weeks after treatment start or the full treatment duration. These descriptions define the observation and eligibility rules; they do not supply the number of participants who met the endpoint.

As a general statistical concept, dose-limiting toxicity counts are used in dose escalation because they summarize whether clinically important toxicity occurred during a defined observation period. They can inform dose selection alongside other safety and tolerability information. A count does not, by itself, quantify comparative benefit or establish how often toxicity would occur in a different population or treatment setting. The primary endpoint result is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry’s primary endpoint is a count of participants with a qualifying event, rather than a continuous measurement such as a laboratory value. The count is defined over a specified observation period and depends on clinical assessment and Safety Monitoring Committee confirmation. This makes the endpoint a combination of event occurrence and a decision rule about whether an event meets the protocol definition. A reported count would therefore need to be interpreted alongside the eligibility rules for the analysis population and the completeness of follow-up.

What does the endpoint definition contribute?

The registry describes multiple qualifying toxicity categories and exclusions. This matters because a count based on a composite definition can combine events of different types and clinical significance. The committee-confirmation requirement adds a review step rather than treating every adverse event as a DLT automatically. The endpoint description specifies that events were considered possibly related to study treatment by the investigator and/or sponsor, with the Safety Monitoring Committee making the confirmation. The registry record does not report the committee’s individual decisions, the number of events considered but not confirmed, or the primary count.

The observation window is part of the endpoint: the primary measure covers time from first study intervention up to 19 weeks, including treatment and short-term safety follow-up. The dose-escalation population description separately requires completion of a DLT period, described as 5 or 5.5 weeks after treatment starts or the full treatment duration. If participants differ in how much of the observation period they complete, a simple count can be difficult to interpret without information about missing follow-up and the analysis rules. Those details are not reported in the registry record.

How should the arm counts be read?

For a binary event, an arm-level count identifies how many participants had the event and how many were at risk in the posted safety summary. The reported counts should be read as descriptive summaries of the listed cohorts, not as estimates adjusted for differences among participants or their time on treatment. A formal comparison would require a defined contrast, an appropriate analysis model, and an account of uncertainty. No such primary-endpoint analysis is reported in the registry record. The record also labels the study non-randomized and single-group, so the arm counts do not constitute randomized evidence of a dose-related effect.

Small cohorts produce imprecise estimates: a change in the status of one participant can noticeably alter an arm’s observed proportion. This general point does not require calculating an unreported percentage or confidence interval. For this study, the arm sizes shown in the safety record are limited, and the primary DLT counts are absent. It is therefore not possible to quantify the uncertainty around the primary endpoint from the registry entries.

What does a confidence interval usually add?

In general, a confidence interval expresses the range of values compatible with the observed data under a statistical model and its assumptions. It communicates precision, not the probability that a particular treatment effect is true. For event counts, intervals can help show how uncertain an estimated event frequency is, especially when the number at risk is limited. No confidence interval for the primary DLT endpoint is reported in the registry record, and no interval should be inferred from the arm counts alone.

How should planning illustrations be understood?

Any sample-size planning illustrations associated with the posted results are not the trial’s observed power and are not evidence that the study was designed with those assumptions. The stated illustration approach uses a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect to detect set as a stated fraction of the observed effect. For time-to-event outcomes, the illustration is based on a total number of events using the Schoenfeld approach; other outcomes are expressed as participants per arm. These are planning assumptions, not reported trial outcomes. In particular, the posted design is identified as non-randomized, and the registry entries do not provide a primary DLT effect estimate from which to interpret a planning illustration.

Over-dispersion is a general concern when event counts vary more than a simple statistical model expects. If present, it can make standard errors too small and confidence intervals too narrow unless the model accounts for it. The registry entries do not report a count-model analysis or an assessment of over-dispersion. More broadly, the registry record reports no analyses for the listed outcomes, so there is no basis to attribute a particular statistical model, adjustment, or inferential procedure to the investigators.

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("Peposertib 50 mg + RT + Capecitabine:", "Peposertib 100 mg + RT + Capecitabine:", "Peposertib 150 mg + RT + Capecitabine:", "Peposertib 250 mg + RT + Capecitabine:")
n      <- c(1, 5, 6, 6)
events <- c(0, 1, 1, 3)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Peposertib 50 mg + RT + Capecitabine:  1  0  0.0  0.0  97.5  0.0  79.3  1.3  84.2
ARM  Peposertib 100 mg + RT + Capecitabine:  5  1  20.0  0.5  71.6  3.6  62.4  4.3  64.1
ARM  Peposertib 150 mg + RT + Capecitabine:  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  Peposertib 250 mg + RT + Capecitabine:  6  3  50.0  11.8  88.2  18.8  81.2  18.4  81.6

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 18 outcome measures, including safety outcomes, composite pathological or clinical complete response, disease-free survival, pathological complete response, and clinical complete response. It does not report a multiplicity strategy for interpreting results across these measures. As a general statistical matter, examining multiple outcomes can increase the chance of at least one apparently notable result if each is tested separately. Methods such as a prespecified hierarchy or adjustment can address that issue, but the record does not identify such a method. No outcome-specific significance claims can be assessed in the registry record because outcome analyses are not reported in the registry record.

Missing-data handling is also not reported in the registry record. The primary endpoint’s observation period and the dose-escalation analysis-set requirements are described, including a requirement to complete the DLT period. However, the available population description is incomplete, and the record does not state how participants with incomplete follow-up, treatment discontinuation, or unevaluable endpoint data were handled. It also does not report imputation, censoring rules for the listed outcomes, or sensitivity analyses.

The registry describes the dose-escalation analysis set as including treated participants who received at least 80% of planned peposertib, 50% of planned capecitabine, and 80% of planned radiotherapy, and who completed the DLT period. The population description ends before the full criteria are available in the registry record. This matters because analysis-set definitions can affect who contributes to an endpoint count. The record does not report how many participants met this full analysis-set definition or provide the primary DLT result within it.

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: enterocolitis (33.3%), diarrhoea (16.7%), proctitis (16.7%), small intestinal obstruction (16.7%), pneumonia (16.7%).

The serious adverse-event summary gives an at-risk count and an affected-participant count for each dose cohort. The 50 mg arm reports 0 affected among 1 at risk; the 100 mg arm reports 3 among 6; the 150 mg arm reports 0 among 6; and the 250 mg arm reports 4 among 6. These counts describe the posted cohorts. They should not be interpreted as a randomized comparison or as evidence that a particular dose caused more or fewer serious events.

The record also lists other adverse-event counts of 1 among 1, 5 among 6, 6 among 6, and 6 among 6 across the dose arms in ascending dose order. The definitions and ascertainment details for this other category are not reported in the registry record in the registry record for this analysis. Deaths are listed as 0 in the 50 mg arm and 1 in each of the other arms. Their causes and treatment relationship are not reported in the registry record.

The listed top serious terms are Enterocolitis at 33.3%, and Diarrhoea, Proctitis, Small intestinal obstruction, Pneumonia, and Sepsis at 16.7% each. The denominator and the way these term percentages were calculated are not reported in the registry record. These term percentages should not be treated as participant-level risks or as a complete description of serious events without that context. Small cohort counts are descriptive and do not establish comparative safety.

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

The registry record documents a completed dose-escalation study of peposertib combined with capecitabine and radiotherapy in locally advanced rectal cancer. It identifies the study’s intended safety and dose-selection purpose, gives the dose levels and treatment regimen, defines the primary DLT endpoint, and reports selected arm-level safety counts. These details establish what the study set out to assess and offer a limited description of the adverse-event information posted for the dose cohorts.

The primary endpoint result is not reported in the registry record. That absence prevents interpretation of the most direct measure for the stated dose-escalation question: how many participants experienced a committee-confirmed DLT during the defined period. The record therefore does not establish the maximum tolerated dose or recommended Phase II dose. The adverse-event counts cannot substitute for the DLT result because the endpoint has specific attribution, severity, exclusion, timeframe, and committee-confirmation rules.

The posted information also does not establish a causal comparison among doses. The record’s design fields describe non-randomized allocation, no masking, and a single-group model. The cohorts may differ in ways that cannot be separated from dose using the posted counts. The discrepancy between those fields and the official title’s description of a randomized, placebo-controlled, double-blind Phase II part is not resolved in the registry record.

Response and survival measures appear in the outcome list, but their results are not reported in the registry record. The record therefore does not support conclusions about tumor response, disease-free survival, comparative efficacy, or the balance of benefit and harm. The safety summaries are small-cohort descriptions, not precise estimates for a broader population. As a general principle, absence of a reported event in a small cohort is not proof that the event cannot occur.

The appropriate reading is narrow: the record describes a study intended to assess dose-limiting toxicity and other safety outcomes, but the main endpoint count and outcome analyses are not available in the registry entries. No treatment recommendation or conclusion about treatment effectiveness follows from these data.

14. Why This Trial Matters Statistically

This trial is statistically notable because its central question is a dose-selection question rather than a straightforward comparison of a treatment against a control. In dose escalation, toxicity is used to inform whether a dose can be considered for further study. The endpoint therefore relies on an operational definition, a fixed assessment period, and committee confirmation. Each element affects what the reported count would mean.

The registry’s design metadata are particularly important to interpretation. The official title describes a randomized, placebo-controlled, double-blind Phase II part, but the overall registry fields identify non-randomized allocation, no masking, and a single-group model. The listed treatment arms are dose cohorts. Statistical interpretation depends on the actual allocation structure: dose-cohort counts cannot be treated as if they came from a randomized, like-for-like control comparison. The discrepancy itself limits how confidently the full study design can be reconstructed from the record.

The safety summaries also illustrate why counts and uncertainty matter. Arm sizes are small, so a single participant’s event status can materially affect a cohort’s summary. Comparing raw counts across cohorts without an inferential analysis risks over-reading random variation or differences in participant characteristics. The registry record does not report a primary-endpoint analysis or uncertainty estimates, so precision cannot be assessed for the key dose-limiting toxicity question.

Finally, the record lists multiple safety and clinical outcome measures, but does not report their analyses or a multiplicity approach. A list of outcomes is not equivalent to evidence for those outcomes. For statistical readers, the key distinction is between a study’s planned questions, the outcomes actually reported, and the strength of inference supported by the design and analysis. Here, the registry gives useful design and safety context, while leaving the principal endpoint result and broader outcome interpretation unresolved.

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 is that the primary DLT count is not reported in the registry record. The endpoint is described in detail, but without the result the central dose-escalation question cannot be evaluated from the registry entries. The registry also does not report the analysis or uncertainty for that endpoint.

The design information is internally difficult to reconcile. The official title describes a randomized, placebo-controlled, double-blind Phase II part, while the overall fields specify non-randomized allocation, no masking, and a single-group model. The listed arms are dose cohorts. The registry record does not clarify whether the Phase II design was implemented, how the study parts relate, or whether any placebo group contributed to the posted results. This prevents treating the listed cohorts as a randomized comparison.

The safety counts are based on small arm-level groups and lack reported confidence intervals or adjusted analyses. The record does not give event timing, duration, exposure-adjusted rates, or causes and treatment relationships for deaths. It also does not state the denominator used for the listed serious-event term percentages. These gaps limit interpretation of both the magnitude and pattern of reported safety events.

The analysis-population description is incomplete in the registry record. Although dose and treatment-completion thresholds are described, the full criteria and the number meeting them are not reported. Missing-data handling, multiplicity procedures, and outcome-specific analyses are also not reported in the registry record. The listed response and survival measures therefore cannot be interpreted as results, and the findings should not be generalized beyond the descriptive information that is actually posted.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study of Peposertib in Combination With Capecitabine and RT in Rectal Cancer — NCT03770689.
• Registry record last updated 2023-03-21; status last verified 2023-03.
• Results first posted 2022-07-07.
• 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

NCT03770689 is listed as a completed Phase I and Phase II study in locally advanced rectal cancer, with an enrollment of 19. It assessed peposertib at 50 mg, 100 mg, 150 mg, or 250 mg in combination with capecitabine and radiotherapy. The stated main purpose was to define the maximum tolerated dose and recommended Phase II dose and assess safety and tolerability.

The primary endpoint was the number of participants with a Safety Monitoring Committee-confirmed dose-limiting toxicity during the specified period. The primary endpoint result is not reported in the registry record. Arm-level serious and other adverse-event counts are reported, but the registry fields identify the study as non-randomized, unmasked, and single-group, despite the official title’s description of a randomized, placebo-controlled, double-blind Phase II part. The record does not resolve this difference or report analyses for the listed secondary outcomes.