NUC-3373 in Combination With Other Agents in Patients With Advanced Solid Tumours: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for NUC-3373 in Combination With Other Agents in Patients With Advanced Solid Tumours (NCT05714553), a non-randomized phase 1, phase 2 study. The primary outcome is Number of Participants With DLTs in Each Module.

2. Clinical Question

3. Trial Design

This is a Phase Ib/II, open-label, non-randomized, parallel-cohort study sponsored by NuCana plc. Its stated purpose is to assess safety, pharmacokinetics, and efficacy of NUC-3373 in combinations with other agents in patients with advanced solid tumours. The modular design allows different combinations and tumour settings to be examined separately. Each module is described as having a dose-validation phase followed by a dose-expansion phase.

Module 1 evaluates NUC-3373 plus leucovorin with pembrolizumab. The arm description specifies NUC-3373 at 1875 mg/m2, leucovorin at 400 mg/m2, and pembrolizumab at 200 mg. Module 2 evaluates NUC-3373 plus leucovorin with docetaxel; the arm description specifies 750 mg/m2, 400 mg/m2, and 55 mg/m2, respectively. These are descriptions of the study regimens, not evidence that every enrolled participant received every planned dose or completed treatment.

The registry describes Phase Ib as assessing safety and tolerability to inform further clinical evaluation, with preliminary efficacy also assessed. Phase II is described as a further assessment of safety and efficacy. The brief description gives approximate intended enrolment ranges for these stages, but does not establish that those targets were reached. Overall enrollment is 19. The safety population consists of participants who received at least one dose: 13 in Module 1 and 4 in Module 2.

The study started on 2023-03-08, has a primary completion date of 2025-05-30 in the record, and is listed as terminated. The registry record does not report the reason for termination. No randomized allocation or masking is reported; masking is listed as none. The distinct cohort populations and combinations mean that one module does not serve as a control for the other.

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 a modular Phase Ib/II study, with each module consisting of a Phase Ib dose-validation phase and a potential Phase II dose-expansion phase. However, the Phase II dose-expansion phase was not initiated in either module. All participants reported in the Participant Flow were enrolled in the Phase Ib part. Arms/groups were combined within each module because no participants were assigned to or treated in any Phase II expansion arm.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The safety population was used and consisted of all patients who received at least one dose of study treatment (n=13 in Module 1 and n=4 in Module 2).

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 Number of Participants With DLTs in Each Module, measured over Assessed during Cycle 1 (first 28 days) in Module 1 and during Cycles 1 and 2 (first 56 days) in Module 2.

The primary endpoint is described as the number of participants with dose-limiting toxicities in each module. A DLT count is used in early-phase dose assessment because it records toxicities that meet a protocol-defined threshold during a specified assessment period. In general, this kind of endpoint helps characterize whether a regimen can be considered for further evaluation. The registry record does not state the criteria used to define a DLT, so the threshold and the clinical events that qualified cannot be assessed from the posted information.

The assessment periods differ: Cycle 1, the first 28 days, in Module 1 and Cycles 1 and 2, the first 56 days, in Module 2. Counts from these windows therefore do not represent identical observation periods. The outcome description says the measure presented is the number of DLTs per module, whereas the outcome title refers to participants with DLTs. These formulations may describe related but distinct counts: events and affected participants need not be the same when a person can experience more than one event. The record does not clarify this discrepancy or provide either count.

Safety results are relevant to dose validation, but the listed serious adverse-event summaries are not a substitute for the primary DLT result. The registry record does not report module-level DLT counts, nor does it report the prespecified analysis procedure for this endpoint. Therefore, the primary endpoint's observed result and its precision cannot be evaluated from the posted record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The study uses a parallel-cohort structure. In a parallel design, participants are assigned to a cohort and assessed within that cohort rather than crossing through multiple treatments. Here, the registry identifies the allocation as non-randomized and the masking as none. This matters for interpretation: treatment groups are not formed through random allocation, and participants and study staff are not masked to treatment according to the registry. Differences among cohorts can therefore reflect cohort composition and other factors as well as treatment. In this study, the modules also involve different combinations and tumour settings, so they are not direct control groups for one another.

What does a count endpoint represent?

The primary endpoint is a count-based safety measure, described as participants with DLTs in each module. A count is an absolute number of people or events, not a rate adjusted for time at risk. The record specifies different observation windows by module: the first 28 days for Module 1 and the first 56 days for Module 2. A participant whose follow-up does not cover the full window may have less opportunity for an event to be observed, but the registry does not report individual follow-up or how incomplete observation was handled. The primary outcome description does not include the actual DLT counts.

There is also a wording distinction in the record: the outcome title refers to participants with DLTs, while the description says the outcome measure is the number of DLTs per module. General statistical interpretation distinguishes a count of affected participants from a count of events, because one participant can experience multiple events. The record does not resolve which quantity was tabulated or provide enough information to reconcile the two descriptions.

How should small cohort counts be understood?

When cohort sizes are small, each participant can have a substantial effect on the observed count or proportion. A reported count should therefore be read with its denominator and observation period, rather than as a stable estimate of risk. Confidence intervals, when available, describe uncertainty around an estimate under specified assumptions; they do not remove design limitations or show whether a result is clinically important. No confidence interval for the primary DLT endpoint is reported in the registry record.

For counts of events, a Poisson model is a general option when events occur independently at a stable average rate over an appropriate exposure period. Over-dispersion means the observed variability is greater than such a model would expect; it can make model-based uncertainty too narrow if ignored. These are general concepts only. The record does not state that a Poisson model, an over-dispersion adjustment, or any other count model was used. It also does not report exposure-adjusted event rates.

What do the sample-size assumptions describe?

The sample-size planning illustration is described as using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect expressed as a fraction of the observed effect. The stated approach is a planning illustration based on the observed effect, not the study's own design. Such an illustration asks what sample size might be required under chosen assumptions; it is not evidence that a study had a particular probability of detecting an effect after the fact. It is not observed power.

The registry record does not report numerical sample-size illustrations or the observed effect used to generate them. It also does not report a sample-size justification for the trial itself. The design is non-randomized, and its modules are not like-for-like arms, so assumptions of equal allocation between two comparable arms do not describe the actual cohort structure. Any planning illustration should be kept separate from the enrolled participant counts and from claims about the study's design adequacy.

What analyses can be evaluated from the record?

The registry lists 3 outcome measures and 0 analyses. It gives the primary outcome name and assessment timing, and names objective response rate and disease control rate as secondary outcomes. It does not report an analysis population for the secondary outcomes, statistical tests, model specifications, adjustment variables, confidence intervals, or p-values. No treatment-effect estimate for an efficacy outcome is posted. Without these details, the statistical analysis cannot be reproduced or evaluated beyond the descriptive safety counts.

The adverse-event summaries use at-risk and affected participant counts for each module, with a list of selected serious-event terms and percentages. These summaries provide descriptive information, not an adjusted comparison between regimens. General guidance is to consider the denominator, time period, event definition, and attribution rules for any safety summary. The registry record does not provide all of those details for the listed terms.

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("Module 1 (NUC-3373 + LV + Pembrolizumab)", "Module 2 (NUC-3373 + LV + Docetaxel)")
n      <- c(13, 4)
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  Module 1 (NUC-3373 + LV + Pembrolizumab)  13  0  0.0  0.0  24.7  0.0  22.8  0.2  23.2
ARM  Module 2 (NUC-3373 + LV + Docetaxel)  4  0  0.0  0.0  60.2  0.0  49.0  0.5  52.2

11. Multiplicity, Missing Data and Analysis Populations

The study lists several outcomes: the primary DLT measure and secondary outcomes for objective response rate and disease control rate. When multiple outcomes or comparisons are assessed, the chance of observing a seemingly notable result by chance can increase if many tests are treated as independent opportunities for a finding. Statistical plans can address this through prespecified testing order or multiplicity adjustments. The registry record does not report a multiplicity strategy, the order in which outcomes were to be tested, or an inferential analysis for the secondary outcomes. Because no analyses are listed, no adjusted or unadjusted efficacy results are available to interpret.

Missing-data handling is also not reported in the registry record. The safety population is defined as participants receiving at least one dose, but the record does not explain how participants with incomplete DLT observation, early discontinuation, missing tumour assessments, or unavailable outcome data were handled. It does not report whether missing outcomes were excluded, imputed, or treated under another rule. These choices can affect estimates, particularly when completion differs across participants.

The record distinguishes the overall enrollment of 19 from the safety populations of 13 in Module 1 and 4 in Module 2, but it does not account for the remaining enrolled participants. It also does not provide analysis populations for the response outcomes. The meaning of each denominator, including whether it represents all treated participants or only those with an evaluable assessment, is therefore not available for those outcomes.

In general, analysis populations should be specified in advance and tied to the endpoint: safety analyses often include treated participants, whereas tumour-response analyses may require an evaluable assessment. These are general considerations, not a description of the procedure used in this study. The registry record does not report a statistical analysis plan or enough detail to determine the study's prespecified population rules.

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: vomiting (25.0%), infection (25.0%), pyrexia (25.0%), diarrhea (25.0%), hypercalcemia (25.0%).

The serious adverse-event summary lists 7 participants affected among 13 at risk in Module 1 and 3 among 4 at risk in Module 2. The same summary lists other adverse events affecting 13 of 13 participants in Module 1 and 4 of 4 in Module 2. Death counts are listed as 10 and 3, respectively. These are separate descriptive counts in the registry record; they should not be added together or treated as mutually exclusive categories. A participant may contribute to more than one type of summary.

The registry also lists selected serious-event terms with percentages: vomiting, infection, pyrexia, diarrhea, and hypercalcemia are each listed at 25.0%, and upper abdominal pain at 7.7%. The record does not explain the denominator or provide event counts for each term alongside those percentages. It does not report whether these events were considered related to treatment, when they occurred, how long they lasted, or whether a participant experienced more than one occurrence.

These figures describe reported safety events, not the primary DLT endpoint. DLT counts are not reported in the registry record, and the DLT definition is not included. The death counts are not accompanied by cause or attribution information, so they cannot be interpreted as treatment-related deaths from this record. Module sizes, treatment combinations, tumour populations, and primary safety observation windows differ; the summaries do not support a comparative safety conclusion between modules.

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

The posted record establishes that the trial was designed to examine NUC-3373 combinations in separate cohorts and that safety was a central part of its dose-validation stage. It identifies the primary endpoint, the module-specific DLT assessment windows, and the number of participants in each safety population. It also reports descriptive adverse-event summaries. These details give a limited account of what the study set out to assess and which safety counts were recorded.

The record does not report the primary DLT counts, despite naming that endpoint. It also does not report results for objective response rate or disease control rate. As a result, the available record does not show the observed result for its primary endpoint or the listed tumour-response outcomes. The presence of an outcome in the registry is not itself evidence of an outcome finding.

The safety summaries do not establish that study treatment caused the listed events or deaths. They also do not provide the information needed to compare risk across modules, which differ in treatment and patient population. A non-randomized design can describe outcomes in its cohorts, but it cannot isolate the effect of a treatment from differences in who received it and the circumstances of care without suitable design features and analysis. The registry record does not report adjusted estimates that would address such differences.

The study is marked terminated, but the reason is not reported in the registry record. Termination should not be treated as evidence of benefit, lack of benefit, harm, or an operational explanation without supporting information. The record also does not provide a statistical analysis plan, DLT criteria, missing-data approach, or analysis results needed to judge how complete or precise the endpoint estimates would be.

Accordingly, the posted information supports a description of the trial's structure and some safety counts, but not a conclusion about treatment efficacy or comparative safety. Those are limits of what the registry record reports, not a claim about results that may exist elsewhere.

14. Why This Trial Matters Statistically

This trial illustrates why early-phase studies often separate dose validation from later expansion. A dose-validation stage focuses on safety and tolerability before further evaluation, while expansion can gather additional safety and efficacy information. The registry describes that staged intent for each module, but does not report the DLT results that would allow readers to assess the primary dose-validation outcome.

Its modular design also highlights an important statistical distinction between parallel cohorts and comparative arms. The two modules use different combinations and address different tumour settings. Since allocation is non-randomized, the cohorts are not balanced by random assignment and should not be treated as if they were a controlled head-to-head comparison. Descriptive differences between their event counts would mix treatment differences with population and follow-up differences.

The record further shows why endpoint definitions and denominators matter. It names a count of participants with DLTs but describes the measure as a number of DLTs, and it specifies different observation windows by module. For clear interpretation, readers need the operational DLT definition, the counted unit, the analysis population, and handling of incomplete observation. Those details are not reported in the registry record.

Finally, listing a secondary outcome is not the same as reporting its result. The absence of analysis entries and response results prevents evaluation of efficacy estimates, uncertainty, and multiplicity. The record can still inform readers about the planned questions and the descriptive safety data, but its statistical contribution is limited by the missing endpoint results and analysis detail.

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 counts. It also omits the criteria used to define a DLT, leaving the endpoint's operational meaning uncertain. The title and description differ in whether the measure is a count of participants or a count of DLTs, and the record does not resolve that distinction.

The safety populations are small: 13 participants in Module 1 and 4 in Module 2. The cohorts have different combinations, tumour settings, and DLT assessment windows, so their safety counts are not directly comparable. Enrollment is 19, but the registry does not explain the difference between overall enrollment and the module-specific safety populations.

The record lists objective response rate and disease control rate but reports no results for them. It lists 0 analyses and provides no statistical analysis plan, confidence intervals, inferential tests, missing-data rules, or endpoint-specific analysis populations. This limits assessment of precision, robustness, and the potential influence of incomplete outcome data.

The adverse-event information is descriptive and does not include attribution, event timing, duration, or sufficient details to interpret the listed percentages fully. The death counts are not accompanied by cause or relationship to treatment. The status is terminated, but the reason is not reported in the registry record. These gaps prevent attributing the status to any particular outcome or event.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: NUC-3373 in Combination With Other Agents in Patients With Advanced Solid Tumours — NCT05714553.
• Registry record last updated 2026-07-23; status last verified 2026-07.
• Results first posted 2026-07-23.
• 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

The registry record describes NCT05714553 as a Phase Ib/II, open-label, non-randomized, parallel-cohort study of NUC-3373 combinations in advanced solid tumours. Module 1 combines NUC-3373 and leucovorin with pembrolizumab; Module 2 combines NUC-3373 and leucovorin with docetaxel. Overall enrollment is 19, and the safety populations are 13 and 4, respectively.

The primary endpoint concerns DLTs, assessed during the first 28 days in Module 1 and the first 56 days in Module 2. The DLT counts are not reported in the registry record. Objective response rate and disease control rate are listed as secondary outcomes, but their results are also absent. The record includes descriptive adverse-event counts, lists the study as terminated, and does not report the reason for termination or a statistical analysis plan.