Phase Ib/II of TG4001 and Avelumab in HPV16 Positive R/M Cancers: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase Ib/II of TG4001 and Avelumab in HPV16 Positive R/M Cancers (NCT03260023), a randomized phase 1, phase 2 study. The primary outcome is Phase Ib: To Evaluate the Safety and Tolerability of the Combination of TG4001 Plus Avelumab in Participants With Recurrent or Metastatic HPV-16 Positive Advanced Malignancies.

2. Clinical Question

3. Trial Design

NCT03260023 is a phase Ib/II study of TG4001 plus avelumab in HPV-16 positive recurrent or metastatic malignancies. The registry lists an enrollment of 143 and a parallel-group model. The study has several parts, so its design is not a single uniform comparison across all participants.

Phase Ib uses consecutive cohorts of 3 to 6 participants at increasing TG4001 doses in combination with avelumab. The registry describes a 3+3 design for this dose escalation and states that participants do not undergo intra-participant dose escalation. The posted phase I primary endpoint results cover two dose groups: TG4001 5x10e6 Pfu plus avelumab, with 3 participants, and TG4001 5x10e7 Pfu plus avelumab, with 6 participants.

Phase II part 1 is described as a single-arm evaluation of efficacy and further safety for the combination. Phase II part 2 is described as a randomized, open-label controlled study comparing the combination with avelumab alone. Within part 2, Cohort A consists of participants without liver metastases, while Cohort B consists of participants with liver metastases. The posted safety groups include both treatments in each of these cohorts.

Tumor response is assessed locally according to RECIST 1.1 in both phases. Participants are followed until disease progression, death, unacceptable toxicity, or study withdrawal, whichever occurs first. The study began on 2017-09-01, had a primary completion date of 2024-09-18, and is listed as active, not recruiting. The registry record does not report further details about randomization procedures, allocation concealment, or stratification.

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: Out of 361 screened participants, 143 were included in the trial and 142 were administered with trial interventions. 218 participants were not included (main reasons: 48.6% inclusion criterion of having histologically or cytologically documented HPV-16+ cancer, 18.8% inclusion criterion of having adequate hematological, hepatic and renal function)

Only the first 6 of 7 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Phase Ib : All participants included and who received any amount of study treatment were included in the SAF. Any participant who was assigned a participant number, but did not receive any study treatment was not included in the SAF. Phase II part 1 and Phase II part 2: the outcome measure safety and tolerability has not been defined as primary endpoint. Therefore Phase II part 1 and Phase II part 2 are not included in the analysis population for safety and tolerability as primary endpoint.

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: In phase I and phase II part 1: all participants included and who received any amount of study treatment will be included in the SAF. Any participant who is assigned a participants number but does not receive any study treatment will not be included in the SAF. In phase II part 2: all randomized participants who were administered at least one dose of IMP(s) according to the treatment allocated at randomization will be included in the SAF.

Only the first 6 of 8 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Phase Ib: To Evaluate the Safety and Tolerability of the Combination of TG4001 Plus Avelumab in Participants With Recurrent or Metastatic HPV-16 Positive Advanced Malignancies, measured over From Day 1 to Day 28.

The listed phase Ib primary endpoint is the number of dose-limiting toxicities (DLTs) from Day 1 to Day 28. A count endpoint records how many qualifying events occurred in the defined participant group and observation window. In an early dose-escalation study, DLTs are used to characterize whether a dose produces toxicities serious enough to affect decisions about further dose evaluation. They are not a measure of tumor response.

The registry defines DLTs to include a grade 3 or higher drug-related adverse event, subject to listed exceptions. Exceptions include certain symptoms adequately treated or controlled, specified skin or laboratory findings without clinical correlation, asymptomatic grade 3 or higher lipase or amylase elevation, tumor flare, and a transient grade 3 infusion adverse event. The definition also includes specified liver function abnormalities: AST or ALT greater than 5 x ULN; total bilirubin greater than 3 x ULN; or concurrent AST or ALT greater than 3 x ULN and total bilirubin greater than 2 x ULN. A drug-related adverse event requiring treatment interruption for more than 2 weeks also qualifies.

The registry reports zero DLTs in each of the two posted phase Ib groups, with 3 participants in the lower-dose group and 6 in the higher-dose group. These counts describe the endpoint within the stated window; the record does not report an uncertainty interval or a formal comparison for these counts. Efficacy outcomes such as response rate, progression-free survival, overall survival, and duration of response are listed separately as secondary outcomes.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The outcome type is a count: the number of participants meeting the registry definition of a DLT during the stated window. Counts are often a natural way to report safety outcomes, especially when the question is whether qualifying toxicities occurred during dose evaluation. Interpretation depends on the event definition, the time period, the number of participants observed, and how the analysis population is set. Here, the endpoint description specifies a window from Day 1 to Day 28 and defines several kinds of events that qualify, along with exclusions.

What does a 3+3 dose-escalation design do?

As a general explanation, a 3+3 design evaluates successive dose cohorts using a small initial group and may add participants to a cohort depending on observed DLTs. The aim is to guide dose escalation and identify dose levels with tolerability concerns; it is not primarily designed to estimate comparative efficacy. The registry describes consecutive cohorts of 3 to 6 participants at increasing TG4001 doses with avelumab and identifies the design as 3+3. It also states that there is no intra-participant dose escalation. Details of the exact escalation and stopping rules are not reported in the registry record.

The two posted phase Ib groups contain 3 and 6 participants, and both have zero DLTs recorded. The small group sizes matter for precision: a count of zero in a small cohort leaves substantial uncertainty about the frequency of an event in a wider population. General statistical principle: as the number of observed participants increases, estimates can become more precise, but the amount of precision also depends on the event frequency and analysis method. A confidence interval would express uncertainty around an estimated event frequency; such an interval is not reported for these DLT counts.

Why distinguish a count from a rate?

A count is the number of observed events or affected participants. A rate requires an explicit denominator and, for a time-based rate, an amount of person-time. The primary endpoint is specified as a number of DLTs, and the registry lists the participant counts for the two phase Ib groups. It does not report person-time-based DLT rates. Because the observation window is fixed in the endpoint description, the reported counts can be read within that window, but they should not be mistaken for estimates of event rates over longer follow-up.

The adverse-event displays include counts of participants at risk and participants affected for serious and other adverse events. These are group-level descriptive safety summaries. The registry does not provide, in the record summarized, a full account of event timing, recurrent-event handling, exposure duration, or statistical comparisons for those displays. Serious-event terms are also listed with percentages, but their denominator and counting rules are not reported in the registry record.

What do randomized and single-arm parts contribute?

Randomization in phase II part 2 is intended, as a general statistical principle, to support a fair comparison between assigned groups by reducing systematic differences at baseline. The registry describes this part as randomized and open-label, comparing the combination with avelumab alone. Open-label means the study is not masked, as indicated in the record. The registry record does not report the randomization sequence method, allocation concealment, stratification factors, or details of the planned comparative model.

Phase II part 1 is single-arm. General statistical principle: a single-arm study can describe outcomes among participants receiving the study regimen, but without a concurrent control it cannot isolate the treatment contribution from other explanations such as participant characteristics or the natural course of disease. The part 2 comparison is distinct from part 1 and from the phase Ib dose cohorts. Combining those parts into one comparison would not preserve the design distinctions.

How should over-dispersion and modeling be understood?

General statistical explanation: count data are sometimes analyzed with models that allow variability to exceed what a simple count model expects. This is called over-dispersion. It matters because a model that assumes too little variability can produce uncertainty estimates that are too narrow. Whether over-dispersion is relevant depends on the outcome structure and the analysis model. The registry record does not report a model for the DLT counts or any assessment of over-dispersion, so no such modeling choice can be attributed to the study.

Likewise, the registry record does not report a formal hypothesis test, confidence interval, covariate adjustment, or model specification for the primary DLT endpoint. The posted counts can be described without assuming that an unreported model was used. The efficacy outcomes listed for phase II include overall response rate, progression-free survival, overall survival, duration of overall response, and proportion of progressive disease. The record summarized does not state the detailed estimators, censoring rules, or analysis models for these outcomes.

What do planning illustrations mean?

General statistical explanation: a sample-size planning illustration describes how many participants might be needed under stated assumptions to detect a specified effect with a chosen error rate and power. It is not an observed result and does not show the power achieved by an already completed study. Any planning illustration associated with these results is explicitly based on the observed effect rather than the trial's own design, using a two-sided significance level of 0.05, equal allocation, and a normal approximation; for time-to-event outcomes, the planning quantity is a total number of events, while other outcomes use participants per arm. These assumptions describe an illustration, not a prospectively reported sample-size justification. The registry record does not report the trial's sample-size justification or its planned target effect.

10. Multiplicity, Missing Data and Analysis Populations

The study has several phases, treatment groups, and outcomes. The registry lists DLT safety assessment in phase Ib; efficacy and further safety in phase II part 1; and randomized comparison in phase II part 2. Listed secondary outcomes include overall response rate, progression-free survival, overall survival, duration of overall response, and proportion of progressive disease, with different phases or cohorts named for different outcomes. This range of questions creates the general possibility of multiplicity: when many outcomes or subgroup comparisons are examined, the chance of at least one apparently notable result can increase.

The registry record does not report whether multiplicity was addressed through a testing hierarchy, adjustment procedure, or prespecified prioritization beyond identifying the primary endpoint and listing secondary outcomes. The posted phase Ib DLT count is descriptive, and no multiplicity adjustment is reported for it. The registry record also does not report whether subgroup analyses by liver metastasis status were prespecified for the efficacy outcomes or how any such analyses would be interpreted.

Missing-data handling is not reported in the registry record. The record does not specify how missing tumor assessments, incomplete follow-up, withdrawal, or unavailable outcome measurements were handled in efficacy analyses. It also does not report censoring rules for time-to-event outcomes. The stated follow-up ends at disease progression, death, unacceptable toxicity, or study withdrawal, whichever occurs first, but that description does not itself establish the analysis rules for each outcome.

The phase Ib safety population is described as participants who received any amount of study treatment; participants assigned a number but receiving no study treatment were excluded from that safety population. The phase II population description in the primary outcome record is incomplete, so its analysis-population definition is not reported in the registry record. Intent-to-treat, per-protocol, and other analysis populations are not specified. These omissions limit assessment of how exclusions, missing observations, and repeated assessments may affect the reported outcomes.

11. 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: pneumoperitoneum (33.3%), pneumonia aspiration (33.3%), respiratory distress (33.3%), disease progression (29.4%), pancreatitis acute (20.0%).

The registry reports serious adverse events and other adverse events separately by group. In phase Ib, serious adverse events affected 1 of 3 participants in the TG4001 5x10e6 Pfu plus avelumab group and 4 of 6 in the 5x10e7 Pfu group. In phase II part 1, the corresponding count was 18 of 34. In phase II part 2 Cohort A, serious adverse events affected 16 of 46 participants receiving the combination and 18 of 44 receiving avelumab. In Cohort B, the counts were 2 of 5 for the combination and 0 of 4 for avelumab.

For other adverse events, the registry reports 3 of 3, 6 of 6, 34 of 34, 46 of 46, 43 of 44, 5 of 5, and 4 of 4 participants affected across the listed groups in the same order. These are participant counts, not a comparison adjusted for differences in group size or exposure. The registry also lists deaths by group, but does not establish treatment causality in those counts.

The serious-event terms listed with percentages include Pneumoperitoneum, Pneumonia aspiration, Respiratory distress, Disease progression, Pancreatitis acute, and General physical health deterioration. The registry record does not report the denominator or event-counting basis for those percentages. Serious adverse events should not be equated with DLTs: DLTs follow the specific phase Ib definition and Day 1 to Day 28 window, whereas the serious-event summaries are separate safety listings.

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

The registry results support a narrow descriptive statement: no DLTs were recorded in either of the two posted phase Ib dose groups during the endpoint window. The groups contained 3 participants at the 5x10e6 Pfu TG4001 dose and 6 participants at the 5x10e7 Pfu dose, each given with avelumab. This is information about observed events in those groups, under the registry's DLT definition; it is not evidence that such events cannot occur or that the combination is free of toxicity.

The phase Ib count does not quantify tumor response, progression-free survival, overall survival, or duration of response. Those outcomes are listed separately as secondary outcomes for specified parts or cohorts. Numerical efficacy results and the associated uncertainty measures are not reported in the registry record described. Consequently, the DLT counts cannot be used to draw conclusions about efficacy.

Nor do the posted phase Ib counts compare the combination with avelumab alone. The randomized comparison is in phase II part 2, with participants grouped according to liver metastasis status and treatment. The registry record's design description identifies that comparison, but the primary results are not a phase II efficacy comparison. Descriptive adverse-event counts across groups should not be interpreted as causal treatment effects without the relevant randomized analyses and their uncertainty.

The record does not report confidence intervals or a formal statistical test for the DLT counts. It also does not report the trial's sample-size justification, detailed analysis plan, missing-data procedures, or multiplicity strategy. Those gaps mean that the precision and inferential scope of the posted results cannot be fully assessed from the registry record. The most defensible reading is therefore limited to the reported counts, their endpoint definition, and the study's distinct phase-specific designs.

In general, a small observed count can be compatible with a range of underlying event frequencies. A zero count should not be interpreted as proof of zero risk, and counts from groups of different sizes are not directly comparable by inspection alone. These statistical cautions apply to the posted safety summaries and do not add an unreported clinical conclusion.

13. Why This Trial Matters Statistically

The trial is statistically notable for combining dose-finding and controlled evaluation within one study record. Phase Ib uses a 3+3 design to examine increasing TG4001 doses with avelumab, while phase II part 1 is single-arm and phase II part 2 is randomized and open-label. Those parts answer different statistical questions. Treating all participants as though they belonged to one comparison would blur the distinction between dose evaluation, single-arm outcome description, and randomized treatment comparison.

The primary endpoint is also specific to the phase Ib task: a count of DLTs over a defined window, under a detailed event definition. This illustrates why endpoint definitions and observation periods matter. A safety count is not interchangeable with a broader adverse-event summary, and neither is a direct measure of efficacy. The posted zero DLT counts need to be understood alongside the small phase Ib groups and the scope of the endpoint.

Phase II part 2 adds a comparator and separates cohorts by presence or absence of liver metastases. These design features make the questions more specific than a single overall comparison, while also making it important to know which analyses were planned and how multiplicity was addressed. Those analysis details are not reported in the registry record.

The record highlights a common challenge in interpreting multi-part clinical trials: the same intervention can be evaluated using different designs, populations, and outcomes across phases. Statistical interpretation requires keeping those components separate and distinguishing descriptive safety observations from comparative estimates. The registry describes that structure and lists several outcomes, but the available result details do not establish a full efficacy comparison or provide the precision information needed to characterize such a comparison.

14. 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 result information described for phase Ib consists of DLT counts in two small dose groups. The registry record does not report confidence intervals, a statistical test, or a modeled estimate for these counts. The observation window is specified as Day 1 to Day 28, so the endpoint does not capture all possible later toxicities. The registry record does not report further detail about the timing of events or whether all participants completed that window.

The study has several distinct components, including a phase Ib dose-escalation component, a single-arm phase II component, and randomized phase II part 2. The primary endpoint result described is not a result from the randomized efficacy comparison. Numerical results for the listed phase II efficacy outcomes are not reported in the registry record described, and detailed phase-specific analysis methods are not reported.

The adverse-event summaries are descriptive. The registry record does not report the exposure duration, recurrent-event handling, or adjustment methods needed to make more detailed comparisons across groups. Percentages for serious-event terms are listed without their denominator and event-counting basis. Counts of deaths are reported, but causal attribution to treatment is not established by the registry information.

Further limitations include absent details on missing-data handling, censoring, analysis populations beyond the phase Ib safety description, multiplicity, and the trial's sample-size justification. The phase II population description in the primary outcome record is incomplete. The registry's description of a randomized, open-label part does not provide the randomization procedure or allocation concealment details. These reporting gaps limit assessment of precision, bias, and the robustness of comparative findings.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Phase Ib/II of TG4001 and Avelumab in HPV16 Positive R/M Cancers — NCT03260023.
• Registry record last updated 2026-02-05; status last verified 2026-01.
• Results first posted 2025-12-02.
• 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.

18. Record Summary

NCT03260023 is a phase Ib/II study of TG4001 plus avelumab in participants with HPV-16 positive recurrent or metastatic malignancies. It includes phase Ib dose escalation, single-arm phase II part 1, and randomized open-label phase II part 2 comparing the combination with avelumab alone. Part 2 distinguishes participants with and without liver metastases. The registry lists an enrollment of 143 and a parallel-group model.

The phase Ib primary endpoint is the number of DLTs from Day 1 to Day 28. The two posted dose groups report zero DLTs, with 3 and 6 participants, respectively. The registry also lists safety summaries and secondary efficacy outcomes, but numerical results for the listed phase II efficacy outcomes and detailed statistical analysis methods are not reported in the registry record described. The study is listed as active, not recruiting.