A Study of the Intra-Patient Escalation Dosing Regimen With IMCgp100 in Patients With Advanced Uveal Melanoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of the Intra-Patient Escalation Dosing Regimen With IMCgp100 in Patients With Advanced Uveal Melanoma (NCT02570308), a non-randomized phase 1, phase 2 study. The primary outcome is Number of Participants With a Dose Limiting Toxicity (DLT) in Phase 1.

2. Clinical Question

The study was designed to examine a dosing sequence that sought higher exposure and maximal plasma concentration after Cycle 1 Day 15 and thereafter. That is the stated rationale for the regimen, not evidence that a particular exposure was achieved or that the regimen had a particular clinical effect. The record also lists secondary outcomes including objective response rate in Phase 1, progression-free survival, disease control rate, duration and time to response, overall survival, minor response rate, and treatment dose interruptions or reductions. Results for these outcomes are not reported in the registry record.

3. Trial Design

This was a Phase I/II, open-label, multicenter study. Its allocation is listed as non-randomized, its masking as none, and its model as single group. The registry record gives an enrollment of 146 and a completed status. It lists uveal melanoma as the condition and IMCgp100 as the intervention.

The study summary describes weekly treatment with IMCgp100 as a single agent. Participants received 2 weekly doses below the identified weekly recommended Phase II dose, with escalation starting at the third weekly dose, Cycle 1 Day 15. The Phase I testing was intended to achieve higher exposure and maximal plasma concentration after that point and thereafter. The record describes dose-escalation cohorts and a dose-expansion cohort using the recommended Phase II dose of the intra-patient escalation regimen.

The dose-escalation cohorts are listed at 54 mcg, 64 mcg, 73 mcg, and 68 mcg. The Phase II dose-expansion cohort is also listed at 68 mcg. These cohorts represent stages and dose groups in the study, not randomized treatment arms. Without random allocation or a control group, differences between cohorts cannot be read as unbiased comparative treatment effects. Cohorts may differ in ways the registry record does not describe.

The primary outcome is a Phase I count of participants with a dose-limiting toxicity. Its registry timeframe is listed as up to 49 months, while its definition specifies events occurring within the first cycle of treatment. The record does not explain this relationship. It reports 15 outcome measures and no analysis entries. Details of the statistical plan, including any planned comparisons or interim analyses, 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 data cut-off date for this analysis was on 20 Mar 2020. The first patient was enrolled on 29 Feb 2016 in the Phase 1 dose escalation cohorts and on 19 Jan 2017 in the Phase 2 dose expansion cohort.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Safety Analysis Set (SAS) included all participants who received at least 1 full or partial dose of tebentafusp.

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: The full analysis set (FAS) comprised all participants assigned to study drug and who received at least 1 full or partial dose of tebentafusp.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With a Dose Limiting Toxicity (DLT) in Phase 1, measured over Up to 49 months.

The primary endpoint is the number of participants with a dose-limiting toxicity in Phase I. It is a participant count, not a rate, time-to-event measure, or summary of all adverse events. The registry definition includes an adverse event or abnormal laboratory value suspected to be related to study drug, unrelated to disease, disease progression, inter-current illness, or concomitant medications, occurring within the first treatment cycle and meeting pre-specified criteria.

In general, dose-limiting toxicity is used in early-phase dose evaluation to identify toxicity that reaches a protocol-defined threshold during a specified observation window. It can help inform decisions about dose escalation and selection of a dose for further study. The interpretation depends on the exact criteria, observation period, and number of participants evaluable for the endpoint. The criteria themselves are not itemized in the registry record.

The registry lists the primary endpoint population as the Safety Analysis Set, defined as participants who received at least 1 full or partial dose of tebentafusp. The study intervention is listed as IMCgp100; the registry record does not clarify this difference in terminology. Although the outcome definition and timeframe are posted, the observed number of Phase I participants with a dose-limiting toxicity is not reported in the registry record. The endpoint therefore cannot be interpreted as a reported finding.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The study combines an early dose-escalation component with a dose-expansion component. In the escalation regimen, participants received 2 weekly doses below the identified weekly recommended Phase II dose, then escalation began at the third weekly dose, Cycle 1 Day 15. The expansion cohort used the recommended Phase II dose of the intra-patient escalation regimen. The registry describes this sequence as intended to achieve higher exposure and maximal plasma concentration after Cycle 1 Day 15 and thereafter. That objective describes the regimen’s rationale; the record does not report pharmacokinetic results that would show whether the objective was achieved.

The primary outcome is a count of participants meeting a dose-limiting toxicity definition in Phase I. As a general statistical concept, a count records how many people meet a specified event definition. To interpret one, a reader needs the number of eligible or evaluable participants and the precise rules for deciding whether an event qualifies. Here, the registry describes the Safety Analysis Set as including all participants who received at least 1 full or partial dose of tebentafusp, and defines dose-limiting toxicity in terms of a suspected relationship to study drug, specified exclusions, occurrence within the first cycle, and pre-specified criteria. The detailed criteria are not reported in the registry record. The observed primary count is also not reported, so neither a count nor a participant-level frequency can be interpreted from this record.

The record labels the design non-randomized, open-label, and single group. General statistical context: randomization helps balance measured and unmeasured participant characteristics between assigned groups, on average, while masking can reduce some forms of assessment or reporting bias. Neither feature is listed for this study. The dose cohorts are not randomized controls, and comparisons across them could reflect differences in cohort membership, dose, timing, or other factors not described in the registry. Descriptive differences between cohorts should therefore not be interpreted as causal effects of dose.

The adverse-event display presents counts at risk and counts affected for serious and other events in each cohort, alongside deaths. These are descriptive safety summaries. General statistical context: an event count depends on the size of the group and the period in which events were collected. Rates or time-to-event analyses may answer different questions, but the record does not report those analyses for the displayed figures. The serious-event terms and percentages listed in the safety display should be read as posted descriptions, not as proof that the intervention caused the events. The registry does not report the ascertainment rules or event-specific denominators behind each listed percentage.

The record lists 15 outcome measures, including response, disease-control, survival, duration, and treatment-modification outcomes. It has no analysis entries. This means the registry record does not contain posted analysis results; it does not establish that no analyses were performed elsewhere. The statistical analysis plan, model specifications, handling of censoring, covariate adjustment, and any planned subgroup analyses are not reported in the registry record.

General statistical context: a confidence interval communicates uncertainty around an estimate under its assumptions, while a p-value assesses compatibility of observed data with a specified null model. Neither can be interpreted without the estimate, method, and analysis population. No confidence intervals, p-values, or other analysis estimates for the primary outcome are reported. The sample-size section accompanying the page is a planning illustration based on an observed effect, not a report of the trial’s original design justification or observed power. Such planning illustrations do not repair missing trial results and should not be mistaken for results of this study.

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("Phase 1 Dose Escalation Cohort 1: 54 mcg Tebentafu", "Phase 1 Dose Escalation Cohort 2: 64 mcg Tebentafu", "Phase 1 Dose Escalation Cohort 3: 73 mcg Tebentafu", "Phase 1 Dose Escalation Cohort 4: 68 mcg Tebentafu")
n      <- c(3, 6, 4, 6)
events <- c(0, 1, 2, 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  Phase 1 Dose Escalation Cohort 1: 54 mcg Tebentafu  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Phase 1 Dose Escalation Cohort 2: 64 mcg Tebentafu  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  Phase 1 Dose Escalation Cohort 3: 73 mcg Tebentafu  4  2  50.0  6.8  93.2  15.0  85.0  14.7  85.3
ARM  Phase 1 Dose Escalation Cohort 4: 68 mcg Tebentafu  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 lists 15 outcome measures. These include the primary Phase I dose-limiting toxicity count and secondary measures covering response, progression-free survival, disease control, duration and time to response, overall survival, minor response, and dose interruptions or reductions. Looking at multiple outcomes can raise a multiplicity issue: in general, the more statistical tests performed, the greater the chance that at least one result appears notable by chance if tests are treated as independent opportunities for discovery. Whether and how that concern was addressed depends on the analysis plan.

The registry record does not report a multiplicity strategy, a hierarchy among secondary outcomes, or an analysis plan. It also has no analysis entries, so there are no posted estimates or tests from which to assess how outcomes were analyzed. It would be inappropriate to infer that an adjustment was or was not used in the study itself.

Missing-data handling is not reported in the registry record. The record does not describe whether outcome data were incomplete, how participants without evaluable data were handled, or how censoring was addressed for time-to-event outcomes. These details matter because the analysis population and assumptions about unavailable observations can affect interpretation.

The primary endpoint population is described as the Safety Analysis Set, including participants who received at least 1 full or partial dose of tebentafusp. The registry does not clarify how that terminology relates to the listed IMCgp100 intervention, nor does it give a separate endpoint-specific evaluable count. Thus, the population definition is available, but the number contributing to the primary result and any exclusions are not reported in the registry record.

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: bone pain (33.3%), hypotension (33.3%), aphasia (33.3%), infusion-related reaction (25.0%), alanine aminotransferase increased (25.0%).

The safety display separates serious adverse events, other adverse events, and deaths by cohort. For serious adverse events, the registry lists 2 of 3 participants in the 54 mcg cohort, 2 of 6 in the 64 mcg cohort, 3 of 4 in the 73 mcg cohort, 3 of 6 in the 68 mcg dose-escalation cohort, and 42 of 127 in the 68 mcg dose-expansion cohort. The other-adverse-event counts match the number at risk in each displayed cohort. These figures describe what is listed in the registry; they do not establish that an event was caused by treatment.

The death counts shown by cohort are 1, 5, 4, 4, and 69. The record does not provide a cause or treatment attribution for these deaths, so they should not be described as treatment-related. It lists serious-event terms including bone pain, hypotension, aphasia, infusion-related reaction, increased alanine aminotransferase, and increased aspartate aminotransferase, with percentages in the safety display. The record does not provide enough detail to establish the denominator or attribution for each term’s percentage.

General statistical context: small cohorts can yield unstable descriptive estimates, and cohort sizes differ in this study. These figures are not a randomized comparison and do not by themselves establish relative safety across doses or groups.

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

This record documents a completed, non-randomized Phase I/II study of a weekly intra-patient escalation regimen of IMCgp100 in advanced uveal melanoma. It describes the treatment sequence, dose-escalation cohorts, dose-expansion cohort, primary endpoint definition, and selected safety summaries. Those details help readers understand what the trial set out to study and what its registry currently displays.

However, the primary endpoint result is not reported in the registry record. The record does not state how many Phase I participants had a dose-limiting toxicity. It also contains no analysis entries and does not report results for the listed secondary outcomes. As a result, this record cannot answer whether the study met its primary objective, estimate the primary endpoint’s uncertainty, or support conclusions about response, progression, survival, or other efficacy outcomes.

The safety figures can be described as cohort-level counts, but they should not be used to compare doses as if participants had been randomized. Nor do the displayed death counts show that deaths were caused by the study intervention. The serious-event terms are descriptive listings, not proof of causation. The registry record does not provide the analysis detail needed to make stronger comparative or causal claims.

General statistical context: a trial’s design and its results are distinct. A protocol-defined endpoint can clarify what investigators intended to measure, but an endpoint definition is not evidence of the observed outcome. Similarly, a planning illustration based on an observed effect is not a trial result and is not observed power. Interpretation of the trial’s effects requires posted outcome estimates, the relevant analysis population, and information about uncertainty and missing data; these are not reported in the registry record.

14. Why This Trial Matters Statistically

This study is statistically notable for its intra-patient escalation sequence and its combination of Phase I dose escalation with Phase II dose expansion. The regimen began below the identified weekly recommended Phase II dose and escalated from the third weekly dose, Cycle 1 Day 15. The registry states that the Phase I regimen was designed to achieve higher exposure and maximal plasma concentration after that point. These features make the exact timing and definition of the primary dose-limiting toxicity outcome important to interpretation.

The primary endpoint focuses on a participant count within a defined early treatment window, while the registry lists a timeframe of up to 49 months. The definition says qualifying events occur within the first cycle. Since the record does not explain how these timeframe descriptions relate, readers should keep both statements in view rather than assuming an interpretation not stated in the registry.

The non-randomized, open-label, single-group design also sets limits on the kinds of statistical conclusions the record can support. Dose cohorts are not equivalent to randomized arms, and descriptive comparisons cannot isolate the effect of dose from other differences among cohorts. The safety display is useful as a record of posted counts, but it is not a controlled comparison.

Finally, the primary result and analysis estimates are absent from the registry record. That absence is statistically consequential: without the observed outcome and its uncertainty, readers cannot judge the precision of the primary endpoint or relate it to the study’s stated rationale. The record can inform readers about the design and reporting gaps, but it cannot serve as a complete account of the trial’s outcome evidence.

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 registry record does not report the observed result for the primary endpoint, despite providing its definition and timeframe. It also lists 15 outcome measures but contains no analysis entries. Results for the listed secondary outcomes, including response and survival outcomes, are not reported in the registry record. This prevents interpretation of efficacy estimates and their precision from this record.

The study was non-randomized, open-label, and single group. The dose-escalation and dose-expansion cohorts are not randomized control groups, so their descriptive figures do not support a direct causal comparison. Cohort-level safety counts are posted, but the registry record does not provide a treatment attribution for the listed deaths or enough context to establish causality for serious-event terms.

Several methodological details are not reported in the registry record: the specific pre-specified criteria for dose-limiting toxicity; the statistical analysis plan; any multiplicity strategy; missing-data handling; endpoint-specific evaluable counts; and analysis methods for time-to-event outcomes. The endpoint population is defined using the term tebentafusp, while the intervention is listed as IMCgp100; the registry does not clarify this terminology.

The primary outcome description refers to events within the first treatment cycle, while its listed timeframe is up to 49 months. The record does not explain this distinction. The safety summaries also require caution because the cohort sizes vary and are not randomized comparisons. These limitations concern what can be concluded from the registry record; they do not establish what analyses or information may exist outside it.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study of the Intra-Patient Escalation Dosing Regimen With IMCgp100 in Patients With Advanced Uveal Melanoma — NCT02570308.
• Registry record last updated 2023-03-21; status last verified 2023-02.
• Results first posted 2021-09-01.
• 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

The registry record describes NCT02570308, a completed Phase I/II, open-label, multicenter, non-randomized, single-group study of weekly IMCgp100 using an intra-patient escalation regimen in advanced uveal melanoma. Enrollment is listed as 146. The regimen used 2 weekly doses below the identified weekly recommended Phase II dose before escalation at the third weekly dose, Cycle 1 Day 15. Dose-escalation cohorts and a dose-expansion cohort are described.

The primary outcome is the number of Phase I participants with a dose-limiting toxicity, but the observed result is not reported in the registry record. Fifteen outcome measures are listed, and no analysis entries are present. The registry does display cohort-level adverse-event and death counts. These are descriptive figures, not randomized comparisons, and the record does not attribute deaths to treatment.