A Trial to Evaluate the Safety and Efficacy of the Combination of the Oncolytic Immunotherapy Pexa-Vec With the PD-1 Receptor Blocking Antibody Nivolumab in the First-line Treatment of Advanced Hepatocellular Carcinoma (HCC): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Trial to Evaluate the Safety and Efficacy of the Combination of the Oncolytic Immunotherapy Pexa-Vec With the PD-1 Receptor Blocking Antibody Nivolumab in the First-line Treatment of Advanced Hepatocellular Carcinoma (HCC) (NCT03071094), a non-randomized phase 1, phase 2 study. The primary outcome is Phase I: Number of Participants With Dose Limiting Toxicities (DLTs).

2. Clinical Question

3. Trial Design

This was a Phase I/IIa, non-randomized, single-group trial of Pexa-Vec combined with nivolumab in first-line advanced hepatocellular carcinoma. The registry record reports enrollment of 14 participants and lists the study status as terminated. The start date was 2017-07-27 and the primary completion date was 2020-09-30. The sponsor was Transgene.

The registry describes a Phase I group and a Phase IIa group. Both groups received the same stated regimen: 3 bi-weekly intratumoral injections of Pexa-Vec at day 1 and weeks 2 and 4, with intravenous nivolumab every 2 weeks starting from week 2. Although the record labels these as separate phases, it does not describe a randomized assignment between them or a distinct comparator group. The design is therefore not a head-to-head comparison of the two phases.

The primary outcome is specifically labelled as a Phase I measure: participants with dose-limiting toxicities. Its assessment window was 4 weeks from the first study drug administration. The registry also lists three outcome measures overall, but the details of the other measures are not reported in the registry record.

Termination status alone does not explain why the study ended, whether the planned enrollment was reached, or whether the study stopped early relative to its intended schedule. Those details are not reported in the registry record. The protocol, enrollment targets by phase, and the rationale for the study design are likewise not reported in the registry record. Without a randomized control group, observed outcomes can describe participants treated in this study, but cannot isolate the effect of the combination from the course of disease, participant selection, or other influences.

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: Of 14 screened participants, 12 met eligibility criteria and were included in the trial. This was a Phase I/IIa trial with Phase I: single cohort of 6 patients assessing the safety of standard Pexa-Vec and nivolumab doses and Phase IIa: extension of the Phase I to up to 30 patients, assessing the efficacy and safety of Pexa-Vec and nivolumab. The trial was terminated prematurely during the Phase IIa due to the failure of Pexa-Vec and nivolumab in their respective pivotal trials in HCC.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Participants who received at least one dose of either study drug (excluding one patient who did not complete the 4 week-period from the first study drug administration).

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: Phase I and Phase IIa: Participants who received at least one dose of either study drug.

6. Primary Endpoint

The registry lists the primary outcome as Phase I: Number of Participants With Dose Limiting Toxicities (DLTs), measured over 4 weeks from the first study drug administration.

The primary outcome is the number of Phase I participants with dose-limiting toxicities (DLTs), assessed during 4 weeks from the first study drug administration. A DLT is a prespecified safety event that can inform early evaluation of a treatment regimen. Restricting assessment to a defined window makes the timing of the safety measure explicit, while the event criteria set out which toxicities count.

The registry definition covers several categories: specified severe non-hematologic toxicity relative to baseline, acute immune-related events involving major organs, injection-site reactions, liver enzyme and bilirubin changes, toxicity causing a treatment delay of 2 or more weeks, selected blood-count complications, and cardiac findings. The definition also lists exclusions and qualifications, including certain events that resolve within 72h. These criteria matter because the endpoint is not a count of every symptom or adverse event; it is a count of participants meeting the registry's DLT definition.

The analysis population is described as participants who received at least one dose of either study drug, excluding one patient who did not complete the 4 week-period from the first study drug administration. The record does not report how many participants in this population met the DLT definition. It also does not report a confidence interval or inferential analysis for this endpoint. The endpoint can therefore be explained as a planned safety measure, but its observed result and precision cannot be assessed from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is a binary participant-level outcome: each participant either met the DLT definition during the stated assessment window or did not. Reporting the count is a direct way to describe how many participants experienced the defined event. To interpret such a count fully, readers also need the analysis population and denominator. The record describes the Phase I population as participants who received at least one dose of either study drug, excluding one patient who did not complete the 4 week-period from the first study drug administration, but it does not report the number of DLTs or the denominator used in a result.

What does a confidence interval add?

General statistical explanation: a confidence interval describes uncertainty around an estimated outcome. For an event frequency, it helps distinguish a result that is estimated precisely from one that remains compatible with a wider range of underlying risks. A count without an interval can be difficult to interpret, particularly in a small group. The registry record does not report a confidence interval for the primary endpoint or for the adverse event counts, so their statistical precision cannot be quantified from the registry information.

Why does the design affect interpretation?

General statistical explanation: random allocation helps balance participant characteristics between treatment groups on average, supporting a causal comparison. This study is listed as non-randomized and single-group. Its Phase I and Phase IIa groups are phases of the study, not randomized alternatives. Consequently, comparing their event counts cannot establish that one phase or treatment exposure caused a different risk. There is no separate control group in the registry design to account for background events or the course of the underlying condition.

What do the adverse-event counts represent?

The serious adverse event figures distinguish participants at risk from participants affected in each phase group. The other adverse event figures are listed separately. They are descriptive summaries, not adjusted estimates of treatment effect. Participant counts for serious and other events should be interpreted within their own categories. A person could experience more than one event, and the same person may appear in more than one category; the registry entries do not establish whether event categories overlap. The listed serious-event terms and percentages are also descriptive. Their denominator and counting context are not reported clearly in the registry record, so they should not be converted into participant-level event probabilities.

How should planning illustrations be read?

General statistical explanation: a sample-size calculation asks how many participants a future study might need under specified assumptions. It is not a measure of the evidence actually observed in the completed study. The registry's planning assumptions describe an illustration based on the observed effect, a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is defined as a stated fraction of the observed effect. Such an illustration depends on those assumptions and does not show that a study had a particular probability of detecting an effect. It is not observed power. The posted planning values should therefore be treated as hypothetical planning quantities, not as outcomes or validation of the trial's design.

What can be inferred from the reported analysis information?

The registry lists no analyses. It does not report a model, adjusted estimates, hypothesis tests, p-values, or confidence intervals for the outcomes described. Without these results, it is not possible to assess statistical evidence against a null hypothesis or to compare an estimated effect with its uncertainty. This is especially important for the primary endpoint: the registry names and defines the DLT outcome, but does not report the number of affected participants. No result should be inferred from the endpoint definition or from the adverse-event summaries.

General statistical explanation: for binary outcomes, the number of participants with an event is often presented alongside the denominator and an uncertainty interval. Model choice can matter when observations are clustered, repeated, or otherwise more variable than a simple model assumes; this is the general reason over-dispersion may matter in some settings. The registry record does not report such a model or an over-dispersion adjustment, and there is no basis to claim that one was used.

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("Pexa-Vec Combined With Nivolumab - Phase I")
n      <- c(6)
events <- c(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  Pexa-Vec Combined With Nivolumab - Phase I  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 three outcome measures, but the additional outcome names, definitions, and results are not reported in the registry record. The record also lists no analyses. It therefore does not describe a statistical analysis plan, a hierarchy for testing outcomes, or a correction for multiple comparisons. Whether multiplicity was addressed is not reported in the registry record.

Multiplicity matters when several outcomes or repeated analyses are examined, because the chance of a false-positive finding can increase across a collection of tests. This is a general statistical consideration, not evidence that any particular testing approach was used in this trial. With no reported analyses or inferential results, there are no p-values to interpret and no basis to determine how results across outcomes were handled.

The handling of missing outcome data is not reported in the registry record. The primary endpoint population excludes one patient who did not complete the 4 week-period from the first study drug administration, but the record does not explain how that exclusion was determined or whether other participants had incomplete outcome data. It does not report imputation, sensitivity analyses, or assumptions about missingness.

The registry does give an endpoint-specific population description for Phase I, but does not report a broader analysis-population definition for all outcomes. Whether the reported summaries use an intention-to-treat population, a per-protocol population, or another defined set is not reported in the registry record. These omissions limit assessment of the potential effects of missing data, selective outcome reporting, and analytic choices.

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: pyrexia (28.6%), hypertension (28.6%), general physical health deterioration (20.0%), inflammation (20.0%), spinal compression fracture (20.0%).

The registry reports serious adverse events by phase group, with both participants at risk and participants affected. In Phase I, 7 participants were at risk and 6 were affected; in Phase IIa, 5 were at risk and 4 were affected. For other adverse events, 7 participants were at risk and 7 were affected in Phase I, while 5 were at risk and 5 were affected in Phase IIa. These categories should be read separately rather than combined.

The record lists 1 death in each phase group. The death counts do not establish cause or relationship to study treatment; that information is not reported in the registry record. The serious adverse event terms include Pyrexia and Hypertension at 28.6% each, and General Physical Health Deterioration, Inflammation, Spinal Compression Fracture, and Tumour Necrosis at 20.0% each. The denominator and counting context for these term percentages are not reported clearly in the registry record.

These are descriptive safety summaries, not comparative estimates. Events can occur more than once in a participant, and event categories may overlap, so event terms should not be added to infer a count of unique people. The non-randomized design also means that the Phase I and Phase IIa counts do not provide a controlled comparison of safety.

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

The posted information establishes that the trial evaluated Pexa-Vec with nivolumab in first-line advanced hepatocellular carcinoma and that the registry defined a Phase I DLT endpoint. It also provides selected descriptive safety counts for the Phase I and Phase IIa groups. Those details describe the study and some recorded events; they do not answer whether the combination changed clinical outcomes relative to another treatment.

The most important interpretive gap is that the observed number of participants with DLTs is not reported in the registry record. The endpoint's criteria and assessment window are stated, but its result and statistical precision are not. Other outcome results, analyses, confidence intervals, and p-values are also not reported in the registry record. As a result, the primary safety endpoint cannot be quantitatively evaluated from this information.

The serious and other adverse event counts show how many participants were listed as affected in each group, and the record lists deaths and serious-event terms. These summaries do not establish that an event was caused by study treatment. Nor do they permit a sound comparison between phases: the trial was non-randomized and single-group, and the registry does not provide a separate control group. The serious-event percentages also lack a clearly reported denominator and counting context.

The trial status is terminated, but that status does not by itself explain the reason for termination, whether the intended enrollment was achieved, or whether termination was related to safety, efficacy, feasibility, or another factor. Those explanations are not reported in the registry record. The planning assumptions are hypothetical illustrations and should not be treated as trial outcomes or evidence of statistical power.

Accordingly, the registry supports a limited descriptive reading of design and safety reporting. It does not support a causal treatment conclusion, an efficacy conclusion, a comparison of the phases, or a precise estimate of DLT risk.

14. Why This Trial Matters Statistically

This study illustrates why design and outcome reporting must be read together. The registry defines a clinically relevant safety measure with a specified observation window and a detailed event definition. That level of endpoint definition helps readers understand what the study intended to count. Yet the absence of the actual DLT count means the primary outcome cannot be evaluated, regardless of how detailed the definition is.

The study also illustrates the limits of interpreting safety summaries without a control group. Counts of affected participants describe what was recorded among participants in the study, but they do not separate treatment-related events from events that might occur because of the underlying disease or other causes. Because the Phase I and Phase IIa groups were not randomized comparisons, their counts cannot be treated as evidence that risk differed between phases.

Statistically, denominators and analysis populations are as important as event counts. The record identifies the Phase I endpoint population and gives participants at risk for adverse event summaries, but does not report confidence intervals or inferential analyses. The serious-event term percentages also lack a clear denominator and counting context. These omissions make it difficult to judge precision or compare the reported summaries with other studies.

The registry's sample-size assumptions are planning illustrations, not observed evidence. This distinction matters because a planning calculation depends on assumptions about the effect to detect and the analysis, while the trial's actual findings require reported outcome data and appropriate uncertainty measures. The record's terminated status is also not an explanation of why the study ended.

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 primary endpoint is named and defined, but its observed DLT count is not reported in the registry record. Without the result, denominator in the analyzed population, and uncertainty estimate, the central safety outcome cannot be assessed for magnitude or precision.

The registry identifies a non-randomized, single-group design. There is no separate control treatment, and Phase I and Phase IIa should not be treated as like-for-like comparison arms. This restricts causal interpretation and prevents a controlled estimate of the effect of the combination. The participant counts reported for adverse events are small, which makes descriptive counts especially limited as a basis for generalization.

The registry lists three outcome measures, but details of the other measures and their results are not reported in the registry record. It also lists no analyses. The analysis plan, multiplicity approach, missing-data methods, and broader analysis populations are not reported in the registry record. The Phase I endpoint population excludes one patient who did not complete the 4 week-period, but the reason for exclusion and the handling of any other incomplete data are not explained.

For serious adverse event terms, the registry lists percentages but does not make the denominator and counting context clear. The reported death counts do not state cause or relationship to treatment. Termination is recorded, but the reason and its relation to study conduct or findings are not reported in the registry record. These gaps prevent fuller evaluation of safety reporting, study completion, and the potential for selective or incomplete results.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Trial to Evaluate the Safety and Efficacy of the Combination of the Oncolytic Immunotherapy Pexa-Vec With the PD-1 Receptor Blocking Antibody Nivolumab in the First-line Treatment of Advanced Hepatocellular Carcinoma (HCC) — NCT03071094.
• Registry record last updated 2021-11-19; status last verified 2021-10.
• Results first posted 2021-11-19.
• 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 a Phase I/IIa, non-randomized, single-group study of Pexa-Vec with nivolumab for first-line advanced hepatocellular carcinoma. Enrollment was 14, and the study status is terminated. The listed primary outcome is the number of Phase I participants with DLTs during 4 weeks from the first study drug administration.

The record describes the dosing schedule for both phases and provides serious and other adverse event counts, serious-event terms, and deaths by phase group. It does not report the observed DLT count, other outcome details, or statistical analyses. Reasons for termination, missing-data methods, and a comparative control result are not reported in the registry record. The available information therefore supports a descriptive account of design and selected safety reporting, not a causal or efficacy conclusion.