Talimogene Laherparepvec, Chemotherapy, and Radiation Therapy Before Surgery in Treating Patients With Locally Advanced or Metastatic Rectal Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Talimogene Laherparepvec, Chemotherapy, and Radiation Therapy Before Surgery in Treating Patients With Locally Advanced or Metastatic Rectal Cancer (NCT03300544), a na phase 1 study. The primary outcome is Determination of Dose Limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD) of Talimogene Laherparepvec in Combination With Chemotherapy and Radiation in Rectal Cancer..

2. Clinical Question

3. Trial Design

This was a phase I, single-group study sponsored by the National Cancer Institute. The registry lists allocation as not applicable and masking as none. The trial began on 2019-05-14, had a primary completion date of 2022-03-22, and is marked terminated. Enrollment is recorded as 3.

The intervention combined talimogene laherparepvec with chemotherapy and radiation before surgery. The listed drug interventions were capecitabine, fluorouracil, leucovorin, and oxaliplatin, alongside radiation therapy and talimogene laherparepvec. The arm description says talimogene laherparepvec was administered intralesionally via endoscopy on weeks 1, 4, 6, and 8. Fluorouracil, leucovorin, and oxaliplatin were scheduled on weeks 2 and 4; capecitabine was described as oral treatment followed by radiation. A complete radiation schedule is not reported in the registry record.

The study population was described broadly as patients with rectal adenocarcinoma, including locally advanced or metastatic disease. The registry also lists stage III and stage IV rectal cancer categories. It does not provide a control arm or a randomized comparison, so the design can describe experience with the combination but cannot estimate a between-group treatment contrast.

The registry gives poor enrollment due to COVID-19 and a change in standard of care as the reason the study was discontinued. It does not report further operational details about discontinuation, nor does it report a detailed protocol or statistical plan. The planned safety and feasibility objective and the neoadjuvant rectal score objective are listed as secondary outcomes, but their results are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Poor enrollment due to COVID-19 and change in standard of care led to discontinuation of the study

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 Determination of Dose Limiting Toxicities (DLTs) and Maximum Tolerated Dose (MTD) of Talimogene Laherparepvec in Combination With Chemotherapy and Radiation in Rectal Cancer., measured over 4 weeks after surgery.

The primary endpoint concerned dose-limiting toxicities and the maximum tolerated dose of talimogene laherparepvec in combination with chemotherapy and radiation. It was expressed as a count of participants. The registry specifies assessment using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0, and gives the timeframe as 4 weeks after surgery. The primary endpoint result and any dose level associated with it are not reported in the registry record.

In general, a dose-limiting toxicity is a prespecified adverse event or toxicity used in dose-finding to judge whether a dose can be tolerated in the treatment combination under study. The maximum tolerated dose is a dose-finding concept based on the observed toxicity experience and the protocol’s decision rules. Those protocol rules, dose levels, and operational definition of a dose-limiting toxicity are not reported in the registry record, so the endpoint’s label does not establish how those decisions were made in this study.

A phase I dose-finding endpoint is used to characterize safety and guide dose selection, rather than to establish a comparative treatment effect. Here, the absence of a reported endpoint result means the registry record does not establish whether a dose-limiting toxicity occurred or what maximum tolerated dose, if any, was determined. The posted safety counts are separate from a complete report of this primary endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies this as a phase I, single-group study. These design features determine what statistical questions can be answered. A single-group study observes outcomes in a treated group; without a control group, it does not directly estimate a difference between treatments. The registry also reports no masking and allocation as not applicable. No randomized comparison is described.

What does a dose-finding endpoint describe?

In general, early-phase dose-finding studies use observed toxicity to assess whether doses are tolerable and to inform a dose choice for further study. A dose-limiting toxicity is an endpoint category defined by protocol rules. The maximum tolerated dose is a decision that depends on the dose levels studied, the events counted as dose limiting, the period during which events are assessed, and the dose-selection procedure. The registry names dose-limiting toxicities and maximum tolerated dose as the primary objective, and gives a 4 weeks after surgery timeframe for the participant-count endpoint. It does not report the dose levels, detailed toxicity criteria, escalation or decision rules, or the resulting dose assessment.

How should counts be interpreted?

A participant count is a descriptive measure: it states how many participants in the recorded group met a defined outcome. It is not, by itself, a measure of comparative effect. The registry’s safety reporting gives the number at risk and the number affected for serious and other adverse events, as well as deaths. These are useful descriptions of the recorded group, but they do not supply event-level detail or a comparison group. The primary endpoint is also a participant count, but its result is not reported.

In general, estimates based on few observations have substantial uncertainty, especially when events are uncommon. A confidence interval can express uncertainty around an estimate, while a hypothesis test evaluates data against a specified statistical hypothesis. Neither a confidence interval nor a test result for the primary endpoint is reported in the registry record. A count of zero observed events does not establish that the underlying risk is zero; it says only that the registry reports no affected participants for that category in the recorded group.

What is missing from the analysis description?

The registry reports no analyses. A statistical analysis plan would ordinarily clarify how endpoints are defined and summarized, what analysis population is used, how missing observations are handled, and whether any adjustments or sensitivity analyses are planned. Those details are not reported in the registry record. It is therefore not possible to determine from the registry whether the endpoint was analyzed according to a protocol-defined rule or whether any analysis decisions changed during the study.

The record lists CTCAE version 5.0 for toxicity assessment, but does not report the operational definition used to classify an event as dose limiting. A grading system supports consistent description of adverse-event severity; it does not, by itself, specify which grades, event types, or time windows qualify as dose limiting for a particular protocol. That distinction matters because a safety summary and a dose-limiting-toxicity endpoint may not include exactly the same events.

What do the planning assumptions mean?

General sample-size planning asks how much information a proposed study would need to detect a chosen effect under stated assumptions. The registry’s planning description refers to a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect framed as a stated fraction of an observed effect. It distinguishes planning for participants per arm from planning for total events in time-to-event settings.

Those assumptions are explicitly an illustration computed from an observed effect, not the trial’s own design. They do not describe this single-group phase I study as randomized or establish that the trial was planned to enroll the illustrated number of participants. Sample-size illustrations are planning quantities, not observed power. The record does not report a trial-specific sample-size justification, and does not report the endpoint estimate needed to interpret an observed-effect-based illustration as evidence about the trial’s findings.

Overall, the methods that can be confirmed are limited to the phase I single-group design, the endpoint description, the specified toxicity grading system, and the posted safety counts. More detailed statistical procedures are not reported in the registry record, so analyses beyond these descriptions should not be inferred.

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("Treatment (T-VEC, Capecitabine, Chemoradiation)")
n      <- c(3)
events <- c(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  Treatment (T-VEC, Capecitabine, Chemoradiation)  3  3  100.0  29.2  100.0  43.9  100.0  39.8  99.4

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary dose-finding objective and secondary objectives concerning safety and feasibility and the neoadjuvant rectal score. It does not report a statistical analysis plan or describe how multiple outcomes were prioritized or interpreted. In general, when many outcomes are examined, the chance of finding an apparently notable result by chance can increase; prespecified outcome hierarchies or multiplicity procedures can address that issue. Whether any such procedure was planned or used is not reported in the registry record.

The primary endpoint result and the secondary outcome results are not reported. The record lists no analyses, so it does not give outcome-specific estimates, uncertainty intervals, or testing procedures. The registry does not report whether any interim analyses occurred or whether there were protocol amendments affecting the analysis.

The analysis populations are not described beyond the overall enrollment and the safety group’s reported numbers at risk. The registry does not state how participants were included in each endpoint analysis, or whether any participants were excluded from an analysis. Missing-data handling, outcome follow-up completeness, and any imputation or sensitivity analysis are not reported in the registry record. These omissions prevent assessment of whether missing observations could affect an endpoint summary. The listed sample-size assumptions are described as a planning illustration rather than the trial’s own design; they do not supply an analysis population or resolve missing-data questions.

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 non-serious adverse event terms

The safety record reports a single treatment group. For serious adverse events, it gives 3 participants at risk and 0 affected. For other adverse events, it gives 3 at risk and 3 affected. The record reports 0 deaths. These are counts in the registry’s reported categories; the registry does not provide event names in its list of top serious terms.

The counts should be read as descriptive observations, not as a comparison with another treatment. In general, a count of participants affected does not show how many events each participant experienced, when events occurred, how long they lasted, or whether they were judged related to treatment. Those details are not reported in the registry record. The serious-event count also should not be substituted for the primary dose-limiting-toxicity result, which is not reported.

With a small recorded group, the absence of a reported serious event does not rule out a risk of such events in a wider population. The safety figures describe only the observations recorded for this group and cannot establish comparative safety or provide a precise estimate of event frequency.

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

The record documents a phase I study of talimogene laherparepvec with chemotherapy and radiation before surgery for rectal cancer, conducted as a single group and terminated after poor enrollment associated with COVID-19 and a change in standard of care. It reports enrollment of 3 and includes safety counts for serious and other adverse events and deaths. Those are the descriptive findings available in the registry record.

The record does not report the primary endpoint result: the number of participants with dose-limiting toxicities, or a maximum tolerated dose. It also does not report results for the secondary objectives of safety and feasibility or neoadjuvant rectal score. As a result, the registry record does not establish the dose-finding outcome or provide a complete account of the planned clinical outcomes.

Because the design had no comparator, these observations do not estimate how the combination compares with another treatment. They also cannot establish that the regimen caused or prevented a particular event. In general, a single-group study can describe outcomes among the participants observed, while comparative conclusions require a valid reference group and appropriate analysis.

The posted safety counts do not establish that rare harms are absent, and the lack of a reported primary result is not evidence that no dose-limiting toxicity occurred. It means the outcome is not reported in the registry record. The registry also does not report the statistical plan, analysis population details, or missing-data approach, limiting assessment of how complete or precise any endpoint summary would have been.

Planning illustrations based on stated assumptions should be understood as hypothetical design calculations, not as evidence of the trial’s observed power or as a replacement for the missing endpoint results. The most defensible interpretation is therefore limited: the registry records the study design, enrollment, termination rationale, and specified safety counts, but does not report the results needed to answer its main dose-finding question.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of the difference between a study objective and a reported result. The registry identifies a specific phase I dose-finding question, but does not report the primary endpoint result. Naming an endpoint does not establish that it was observed, analyzed, or resolved in the posted record.

The single-group design also illustrates the distinction between descriptive safety reporting and comparative inference. Counts in a treated group can describe recorded events, but without a comparator they cannot estimate a treatment contrast. This matters particularly when readers encounter safety counts without information on event timing, severity detail, or attribution.

Enrollment of 3 and termination for poor enrollment associated with COVID-19 and a change in standard of care are important context for interpreting the record. Limited enrollment constrains the information available, especially for infrequent events, while early discontinuation can leave planned outcomes unreported. The registry does not report further details that would quantify these effects or explain the analysis consequences.

The distinction between a trial’s design and a planning illustration is also important. The listed sample-size assumptions refer to a hypothetical equal-allocation, two-arm calculation, whereas this study is recorded as a single-group phase I trial. The illustration is not the study’s design and does not constitute observed power. Clear separation of these concepts helps prevent a planning calculation from being mistaken for evidence about the completed study.

For clinical researchers and statisticians, this record underscores the value of reporting endpoint results, analysis populations, uncertainty, and prespecified methods alongside adverse-event counts. Without those elements, the registry supports only a limited descriptive reading rather than a complete statistical interpretation.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The principal limitation is that the primary dose-finding result is not reported in the registry record. The record therefore does not show the number of participants meeting the dose-limiting-toxicity definition or the maximum tolerated dose determined, if any. The dose levels, toxicity decision rules, and detailed endpoint definition are also not reported, limiting the ability to assess how the primary question was operationalized.

Enrollment was 3, and the study is marked terminated. The registry attributes discontinuation to poor enrollment due to COVID-19 and a change in standard of care, but does not report additional details about the timing or consequences for outcome follow-up. The small enrollment restricts the amount of information available for describing safety, especially for events not observed in the recorded group.

The single-group design has no direct control comparison. Accordingly, the registry cannot support a between-group estimate from this study. The safety record gives aggregate participant counts but does not report event-level descriptions, timing, duration, severity details, or treatment attribution. No top serious adverse-event terms are listed.

The registry lists secondary objectives but does not report their results, and it lists no analyses. The analysis population, missing-data handling, statistical plan, interim analyses, and multiplicity procedures are not reported. The complete radiation schedule is not reported in the registry record. These limitations are specific to the available description of this study and leave important aspects of its implementation and results unresolved.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Talimogene Laherparepvec, Chemotherapy, and Radiation Therapy Before Surgery in Treating Patients With Locally Advanced or Metastatic Rectal Cancer — NCT03300544.
• Registry record last updated 2024-05-23; status last verified 2024-01.
• Results first posted 2024-05-01.
• 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

NCT03300544 is a National Cancer Institute-sponsored phase I study of talimogene laherparepvec with chemotherapy and radiation before surgery for rectal cancer. It is recorded as a single-group, unmasked study with allocation not applicable, enrollment of 3, and terminated status. The registry gives poor enrollment due to COVID-19 and a change in standard of care as the reason for discontinuation.

The primary objective was dose-limiting toxicities and maximum tolerated dose, assessed using NCI CTCAE version 5.0 at 4 weeks after surgery. The primary endpoint result is not reported. The safety group reports 0 affected by serious adverse events, 3 affected by other adverse events, and 0 deaths. Secondary outcome results and statistical analyses are not reported in the registry record.