A Study of Tilsotolimod in Combo With Ipilimumab vs Ipilimumab Alone in Subjects With Anti-PD-1 Refractory Melanoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of Tilsotolimod in Combo With Ipilimumab vs Ipilimumab Alone in Subjects With Anti-PD-1 Refractory Melanoma (NCT03445533), a randomized phase 3 study. The primary outcome is Summary of Independent Reviewer-Assessed Objective Response Rate (ORR) by RECIST v1.1.

2. Clinical Question

3. Trial Design

This is a randomized, Phase 3, parallel-group comparison of ipilimumab with and without IMO-2125 in people described as having anti-PD-1 refractory melanoma. The registry lists metastatic melanoma as the condition. One group received ipilimumab 3 mg/kg intravenously; the other received IMO-2125 by intratumoral injection plus ipilimumab 3 mg/kg intravenously. The study is identified as ILLUMINATE-301, and the sponsor is Idera Pharmaceuticals, Inc.

The registry reports enrollment of 481. The study start date is 2018-05-30, primary completion is recorded as 2021-06-01, and the status is TERMINATED. The record does not state a reason for termination in the information presented, so the status alone does not explain why the study ended or what happened to its planned analyses.

Allocation was randomized, the model was parallel, and masking was listed as none. These features describe how participants were assigned and how the groups were organized, but the record does not report further operational details such as the randomization procedure, allocation concealment, or the conduct of treatment and outcome assessment beyond identifying an independent reviewer for the primary response assessment.

The primary outcome was independent reviewer-assessed objective response rate by RECIST v1.1. Its stated timeframe begins at randomization and continues until disease progression, death, or the start of new anti-cancer therapy, up to 36 months. The registry lists two outcome measures and two analyses, but that count does not supply the missing numerical primary outcome comparison. The result categories and their group-specific counts or percentages 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.

Before assignment: The study was an open-label comparison of ipilimumab with and without intratumoral IMO-2125 (tilsotolimod) in participants with advanced melanoma who had disease progression while on or after PD-1 directed therapy. Study participants were randomized 1:1 to ipilimumab alone (Arm A) or ipilimumab with tilsotolimod given intratumorally (Arm B). Randomization was stratified on the duration of prior anti-PD-1 therapy, metastasis stage, and BRAF mutation status.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All percentages were based on the number of participants in the Intent-to-Treat (ITT) analysis set within each group. Participants with no disease assessment in the study were included in the Not Evaluable category under Best Overall Response.

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 Summary of Independent Reviewer-Assessed Objective Response Rate (ORR) by RECIST v1.1, measured over Response is measured from the date of randomization, until disease progression, death, or start of new anti-cancer therapy (up to 36 months)..

The primary endpoint is an objective response rate based on each participant’s best overall response, assessed by an independent reviewer using RECIST v1.1. The registry describes complete response as disappearance of all target lesions and partial response as at least a 30% decrease from baseline in the sum of target-lesion diameters. Stable disease does not meet the criteria for complete response, partial response, or progression. Progressive disease is described as a 20% increase in the sum of target-lesion diameters.

Measurements are based on target-lesion diameters recorded at baseline and at intervals during or after treatment. The response category is assigned according to the observed decrease or increase. The endpoint timeframe runs from randomization until disease progression, death, or start of new anti-cancer therapy, up to 36 months.

Objective response is used to summarize whether participants experienced a measurable tumor response under defined assessment criteria. In general, a response endpoint can provide a direct measure of tumor change, while not by itself describing survival, symptom relief, or longer-term disease control. The registry says that all percentages use the ITT analysis set within each group and that participants without a disease assessment are classified as Not Evaluable. However, the category counts and percentages needed to evaluate the response-rate contrast are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does randomization contribute?

Random assignment is intended to make the treatment groups comparable at the point of assignment, on average, with respect to both measured and unmeasured characteristics. That design can support a causal comparison when outcomes are collected and analyzed appropriately. It does not guarantee identical groups in a particular trial, and it does not remove the need to examine how participants were included in the analysis or how missing outcomes were handled. The registry identifies the study as randomized, but the specific sequence-generation and allocation-concealment methods are not reported in the registry record.

The parallel-group structure means that participants were assigned to one of the two treatment groups rather than being described as crossing between them. The record lists no masking. In general, masking can limit differences in care or assessment that might arise when group assignment is known. The primary outcome is described as independently reviewer-assessed, which identifies the assessor for response, but the registry record does not provide enough detail to characterize every aspect of assessment procedures or any safeguards against bias.

How should the response endpoint be understood?

Best overall response assigns a participant a response category based on tumor assessments over the stated assessment period. RECIST v1.1 supplies standardized rules for classifying target-lesion change. Complete and partial response represent objective response categories; stable disease and progressive disease are distinct categories, and participants without an assessment are classified as Not Evaluable according to the registry description. A group-level objective response rate is a proportion of participants meeting the response definition within that group. The actual category counts and percentages are not reported in the registry record, so no such rate or between-group contrast can be reconstructed.

Using an independent reviewer can reduce the influence of knowledge about treatment assignment on response classification, but the registry description alone does not establish how disagreements were resolved or what review procedures were used. These details are not reported in the registry record. The timeframe begins at randomization and ends at progression, death, or start of new anti-cancer therapy, up to 36 months. This defines the stated window for measuring response; it is not a report of how long each participant was followed.

What do uncertainty measures add?

In general, a confidence interval describes the range of effect sizes compatible with the observed data under the assumptions of the analysis. It conveys precision as well as direction and magnitude. A p-value, in general, assesses how compatible the data are with a specified null hypothesis under a statistical model; it does not measure the probability that a treatment works or that the null hypothesis is true. No primary-endpoint estimate, confidence interval, or p-value is reported in the registry record, so these aspects of the response comparison cannot be assessed.

The posted sample-size assumptions describe a planning illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. The effect to detect is defined as a stated fraction of the observed effect. Such calculations are planning illustrations, not observed power and not a record of the trial’s original design justification. The registry record does not report the original sample-size justification or the numerical planning results in the information presented. A planning calculation cannot substitute for the observed treatment estimate and its uncertainty.

How should the safety counts be compared?

Adverse-event counts describe how many participants had events under the registry’s reporting conventions. The serious-event and other-event counts have group-specific participant totals listed alongside them. A direct comparison of counts alone does not account for differences in follow-up, event timing, repeat events, or the characteristics of participants who remained under observation. In general, a risk comparison requires a clearly defined outcome, denominator, and observation period. The registry information presented gives participant counts but does not report all details needed to interpret exposure time, event attribution, or adjusted safety analyses.

More than one statistical analysis may be relevant to a trial, including analyses of primary and safety outcomes. The registry lists two analyses, but the results described do not provide their methods, hypotheses, or numerical outputs. The analysis plan, handling of interim analyses, and prespecified hierarchy of outcomes are not reported in the registry record. Consequently, no claim about which inferential procedure was used or how it governed interpretation should be made.

10. Multiplicity, Missing Data and Analysis Populations

The registry identifies an independent reviewer-assessed objective response rate as the primary outcome, and lists two outcome measures and two analyses. The record presented does not give the primary response-category counts or percentages by group, nor does it report a treatment-effect estimate, confidence interval, or p-value. As a result, the primary comparison cannot be interpreted quantitatively from the posted results.

When a study evaluates multiple outcomes, response definitions, time points, or analyses, the chance of a false-positive finding can increase if each is tested separately without a prespecified approach. In general, multiplicity methods can control that risk through an ordered testing strategy, adjusted significance levels, or other procedures. Whether such methods were planned or used for this trial is not reported in the registry record. The record also does not report interim analyses or a statistical analysis plan, so their role cannot be characterized.

The endpoint description states that all percentages are based on the ITT analysis set within each group and that participants without a disease assessment are included in the Not Evaluable category. This is important because missing assessments can affect interpretation of a response proportion. However, the number of participants with missing assessments, the category-specific results, and any sensitivity analyses are not reported in the registry record. The ITT description alone does not show how missing outcomes affected the estimate.

In general, the ITT principle analyzes participants according to randomized group and preserves the comparison created by randomization. The registry’s statement about the ITT denominator is relevant, but further details about analysis populations and departures from assigned treatment are not reported. Without the full results and analysis methods, the impact of missing data, multiplicity, and analysis choices remains uncertain.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: colitis (5.3%), pyrexia (5.0%), immune-mediated enterocolitis (4.6%), diarrhoea (3.7%), general physical health deterioration (2.5%).

The registry lists serious adverse events for 108 of 243 participants in the ipilimumab group and 119 of 238 participants in the IMO-2125 plus ipilimumab group. Other adverse events are listed for 218 of 243 and 226 of 238 participants, respectively. Deaths are listed for 166 and 165 participants in the same group order. These figures should be read as reported counts with their listed participant totals, not as adjusted treatment comparisons.

The serious adverse-event terms with reported percentages are colitis at 5.3%, pyrexia at 5.0%, immune-mediated enterocolitis at 4.6%, diarrhoea at 3.7%, general physical health deterioration at 2.5%, and immune-mediated hepatitis at 2.5%. The registry information presented does not give group-specific percentages for each term, event timing, exposure-adjusted rates, or attribution to treatment. It also does not explain whether the deaths were considered adverse events, treatment-related, or occurring within a particular follow-up window.

In general, safety interpretation depends on definitions, duration of observation, and whether events are counted by participant or by occurrence. The registry counts are informative as descriptive reports, but those missing details limit direct comparisons. They should not be treated as proof that one regimen caused more or fewer events.

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

The posted information establishes that the trial was designed as a randomized comparison of ipilimumab alone with IMO-2125 plus ipilimumab in anti-PD-1 refractory melanoma. It also specifies the primary response measure, RECIST v1.1 categories, the assessment timeframe, and the way the ITT population’s Not Evaluable category was treated. These details describe what the study set out to measure and how response was classified.

The registry results presented do not include the group-specific objective response results. Therefore, they do not establish whether response was more common in either group, how large any difference was, or how precisely it was estimated. No primary-endpoint confidence interval or p-value is reported in the registry record. The endpoint definition cannot stand in for those outcome data.

The safety listing describes participant counts for serious adverse events, other adverse events, and deaths, along with several serious-event terms and percentages. These are descriptive counts. Without event attribution, follow-up details, and the analysis methods, they do not by themselves establish a causal safety difference between treatment groups. Nor do the death counts alone provide a survival comparison: the registry information presented does not include time-to-event estimates or the methods needed to interpret deaths as a survival endpoint.

The TERMINATED status is a factual study status, not an explanation of the study’s results or the reason it ended. The reason for termination is not reported in the registry record. Likewise, the record does not report the original sample-size justification, interim analyses, or a full statistical analysis plan. Those gaps prevent reconstruction of the intended inferential framework.

In general, a randomized design can support a meaningful treatment comparison when outcomes, analysis populations, and missing-data handling are clearly reported. Here, the available record supports description of the design and some safety information, but it does not support a quantitative conclusion about the primary response question. Any interpretation should remain within those limits rather than infer an unreported efficacy result.

13. Why This Trial Matters Statistically

This trial raises a common statistical question in oncology research: how to interpret a randomized treatment comparison when the endpoint is a categorized tumor response and the posted record does not include the group-level response results. The definition of the endpoint matters because it shows what counts as response, progression, stable disease, or non-evaluability. Yet clear definitions are only one part of an interpretable result; estimates and their uncertainty are also needed.

The study’s independent reviewer assessment is relevant to outcome measurement. In general, an independent assessment may help limit bias in classifying tumor response, especially when the study is listed as having no masking. The registry description does not report the detailed review procedures, so the extent of that safeguard cannot be fully evaluated from the information presented.

The stated ITT approach and explicit Not Evaluable category also highlight how analysis population and missing assessments affect response-rate interpretation. A response proportion depends on its denominator and on how participants without assessments are handled. Reporting those choices is important, but the category-specific counts and percentages are not reported in the registry record, leaving the primary comparison unresolved.

The safety summaries illustrate a related distinction between descriptive counts and comparative inference. Participant counts can communicate the scale of reported events, while causal interpretation requires clear definitions, observation periods, attribution, and methods. The registry status of TERMINATED adds context but does not explain the study’s course or its statistical consequences.

Statistically, the record is a reminder that trial design and outcome definitions do not substitute for a complete results presentation. A reader needs the treatment-effect estimate, its precision, and the analysis context to judge the primary comparison. When those are absent, the most defensible interpretation is to identify what is documented and state plainly what remains unknown.

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 main limitation for interpreting the primary endpoint is that the registry record does not report the category-level response results by group. The response-rate estimate and its uncertainty therefore cannot be described. The endpoint description says that participants without a disease assessment were classified as Not Evaluable, but the number of such participants and the distribution of the other response categories are not reported in the registry record.

The record does not report the full statistical analysis plan, the rationale for the original sample size, or whether interim analyses were conducted. The planning assumptions describe an illustration based on an observed effect, but the numerical planning outputs and original design justification are not reported in the information presented. It is not possible to determine whether the posted analyses followed prespecified methods or how any multiplicity across outcomes was handled.

Although the primary response assessment is identified as independent reviewer-assessed, further details about review procedures, assessment timing, and handling of disagreements are not reported in the registry record. The registry states a response timeframe up to 36 months, but does not report individual follow-up duration or the completeness of assessments.

The safety counts also have interpretive limits. Event definitions, treatment attribution, observation time, and exposure-adjusted analyses are not reported in the information presented. The listed deaths are not accompanied by a time-to-event analysis or context about cause. The registry status is TERMINATED, but the reason for termination is not reported in the registry record. These omissions limit conclusions about efficacy, safety comparisons, and the conduct of the study.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study of Tilsotolimod in Combo With Ipilimumab vs Ipilimumab Alone in Subjects With Anti-PD-1 Refractory Melanoma — NCT03445533.
• Registry record last updated 2022-11-08; status last verified 2022-10.
• Results first posted 2022-11-08.
• 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

The registry record describes ILLUMINATE-301, a randomized Phase 3 parallel-group study comparing ipilimumab alone with IMO-2125, also called tilsotolimod, plus ipilimumab in anti-PD-1 refractory melanoma. The study lists enrollment of 481, no masking, and TERMINATED status. Its primary endpoint is independent reviewer-assessed objective response rate by RECIST v1.1, measured from randomization until progression, death, or start of new anti-cancer therapy, up to 36 months.

The endpoint description specifies the response categories and states that participants without a disease assessment were classified as Not Evaluable in the ITT population. However, group-specific response results and a numerical primary comparison are not reported in the registry record. Safety information lists serious adverse events, other adverse events, deaths, and several serious-event terms. The record does not report the full analysis plan, original sample-size justification, interim analyses, or reason for termination.