Combination Therapy With Nivolumab and PD-L1/IDO Peptide Vaccine to Patients With Metastatic Melanoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Combination Therapy With Nivolumab and PD-L1/IDO Peptide Vaccine to Patients With Metastatic Melanoma (NCT03047928), a na phase 1, phase 2 study. The primary outcome is Number of Participants With Adverse Events.

2. Clinical Question

The central clinical question is whether the combination of nivolumab and a PD-L1/IDO peptide vaccine can be administered to patients with metastatic melanoma while documenting adverse events. The registry identifies safety as the primary objective and defines the primary outcome as the number of participants with adverse events, recorded for all patients over 0 - 75 weeks. Adverse events were to be reported according to CTCAE v. 4.0.

The treatment description says that nivolumab is given every second week for as long as there is clinical benefit. The vaccine begins with nivolumab; the registry summary describes vaccine administration every second week for the first 6 vaccines and every fourth week thereafter up to 1 year. This is a combination-treatment study, not a comparison of the combination against a separate control treatment.

Objective response rate, overall survival, progression-free survival, and vaccine-specific responses in peripheral blood mononuclear cells are listed as secondary outcomes. Numerical results for those outcomes are not reported in the registry record. The safety figures therefore cannot answer whether the combination changes tumor response or survival, nor can they establish how safety compares with another treatment.

3. Trial Design

This is a phase 1 and phase 2, completed clinical trial with a single-group model. The registry lists enrollment of 48 participants and metastatic melanoma as the condition. Allocation is recorded as NA, and masking is recorded as none. The record describes all patients as receiving the same treatment, so it does not describe randomized treatment assignment or a blinded comparison.

The combination consists of nivolumab and a PD-L1/IDO peptide vaccine. The registry summary describes nivolumab every second week for as long as there is clinical benefit. It describes the vaccine as starting with nivolumab, given every second week for the first 6 vaccines and then every fourth week up to 1 year. The arm description also refers to outpatient intravenous nivolumab infusions of 3 mg/kg biweekly until progression. The registry record does not give further detail about treatment exposure for each participant.

The listed start date is 2018-02-22, and the listed primary completion date is 2022-12-31. The status is completed. These dates describe the registry record; they do not give participant-level follow-up or treatment duration.

Although the study is described as single-group, the safety record presents figures under Arm A, Arm B, and Arm C. The registry does not explain how these labels relate to the single-group design or whether they represent different subsets, time points, or another grouping. They should not be read as randomized comparison groups. The record itself cautions that the arms are not a like-for-like control comparison. Differences among their counts cannot establish comparative treatment effects.

The registry lists five outcome measures and no analyses. It names objective response rate, overall survival, progression-free survival, and vaccine-specific responses as secondary outcomes, but their numerical findings are not reported in the registry record. The protocol details, planned statistical analysis, and sample-size justification are also 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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Adverse Events recorded for all patients

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 Number of Participants With Adverse Events, measured over 0 - 75 weeks.

The primary endpoint is the number of participants with adverse events. Its unit is participants, and its stated timeframe is 0 - 75 weeks. The description says adverse events are reported according to CTCAE v. 4.0, with the population defined as adverse events recorded for all patients.

This count-based endpoint is used to describe how many participants experienced an adverse event during the specified period. Counting participants is different from counting the total number of event episodes: one participant can experience more than one event, but a participant count records that person as a participant with an event. The registry's endpoint title specifies participants with adverse events, while the safety figures separately distinguish serious adverse events and other adverse events. These categories should be interpreted according to the recorded definitions; the record does not give further detail on how recurrent events were handled.

General: Safety endpoints are useful for describing the occurrence of harms during a study. The count alone does not indicate the timing, duration, severity, or clinical course of each event. Those details require event-level reporting and the relevant grading information. CTCAE v. 4.0 is the classification version named in the registry, but the posted primary endpoint does not provide a full event-by-event account.

The registry does not report a numerical result for the primary endpoint. Consequently, the record does not establish the overall number of participants with any adverse event within the primary timeframe. The serious and other adverse-event figures are available by the listed arm labels, but those group-specific counts do not substitute for a complete primary-endpoint result or a controlled safety comparison.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a phase 1/phase 2, single-group study. Allocation is NA and masking is none. These features matter because the safety counts are not presented as results from a randomized, blinded comparison. The record identifies all patients as receiving the same combination, while its safety listing uses Arm A, Arm B, and Arm C labels. The relationship between those labels and the single-group description is not reported in the registry record. The record cautions against treating the arms as a like-for-like control comparison.

What does a participant count measure?

The primary endpoint is the number of participants with adverse events, rather than the total number of event episodes. A participant-level count asks whether each participant experienced an event during the defined period. It does not show how many distinct events an affected participant experienced. The listed timeframe is 0 - 75 weeks, and the registry says the events are reported according to CTCAE v. 4.0.

The safety figures distinguish participants with serious adverse events from those with other adverse events. These are displayed as counts at risk and counts affected within each arm label. A count is straightforward to interpret as a number of people, but it does not by itself describe event severity beyond the serious/non-serious distinction, timing, duration, recurrence, or causal relationship to treatment. The registry's primary description does not report those details for each event.

Why does the study design affect interpretation?

A single-group study can describe outcomes observed among people who received the study treatment. Without a separate control group, it cannot by itself distinguish outcomes associated with treatment from outcomes that might also occur because of the disease, other care, or other influences. This is a general limitation of uncontrolled comparisons. Here, the registry also explicitly warns that Arm A, Arm B, and Arm C are not a like-for-like control comparison. Their counts should therefore be read descriptively, not as evidence that one group had a better or worse outcome than another.

The posted record gives no numerical result for the primary endpoint across all patients. It also lists no analyses. Therefore, no sponsor analysis, adjusted comparison, or statistical test for the primary endpoint is available to interpret. The secondary outcome names are present, but numerical results and analyses for them are not reported in the registry record.

What can uncertainty measures add?

General: A confidence interval describes uncertainty around an estimate under a specified statistical method. It is not a guarantee that the true value falls within the interval, and it does not remedy design limitations such as a lack of a control group. Confidence intervals can help readers distinguish a relatively precise estimate from one that is uncertain. No confidence intervals for these outcomes are reported in the registry record.

General: Statistical tests assess compatibility between data and a specified null model, given assumptions. A p-value does not measure the size or importance of an effect. The registry record lists no analyses, p-values, or effect estimates for the outcomes. It is therefore not possible to evaluate statistical evidence for treatment effects from such measures in this record.

How should planning calculations be understood?

General: Sample-size calculations depend on assumptions about the outcome, the effect to detect, the significance level, allocation, and statistical method. A planning illustration is not a study result and does not describe the number of participants who actually experienced an outcome. The record describes its sample-size assumptions as an illustration based on an observed effect, with two-sided significance level 0.05, equal allocation between two arms, and a normal approximation. For time-to-event tables, the stated quantity is total events; for other tables it is participants per arm. These are planning assumptions, not evidence that the trial enrolled those planning numbers or achieved a particular power.

The record does not report a sample-size justification for the trial's original design. It also does not report the effect estimates underlying any planning illustration in the information available for interpretation. As a result, no conclusion about the adequacy of the original enrollment target or the precision of the trial's results can be drawn from the planning description alone.

What remains unavailable?

The registry does not report the statistical analysis plan, the handling of missing data, analysis populations beyond the primary endpoint's all-patients description, or interim analyses. It does not explain how adverse events were attributed, how repeated events were summarized, or how the three safety group labels were assigned. These details would be needed for a fuller assessment of the analysis. General statistical principles can explain why they matter, but they cannot fill in what is absent from the registry record.

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("Arm A", "Arm B", "Arm C")
n      <- c(30, 10, 4)
events <- c(30, 10, 4)
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  Arm A  30  30  100.0  88.4  100.0  88.6  100.0  88.8  99.9
ARM  Arm B  10  10  100.0  69.2  100.0  72.2  100.0  71.5  99.8
ARM  Arm C  4  4  100.0  39.8  100.0  51.0  100.0  47.8  99.5

11. Multiplicity, Missing Data and Analysis Populations

The registry lists several outcomes: the primary count of participants with adverse events and secondary outcomes for objective response rate, overall survival, progression-free survival, and vaccine-specific responses in peripheral blood mononuclear cells. It also lists five outcome measures in total. Numerical results for the secondary outcomes are not reported in the registry record, and the record lists no analyses.

Multiplicity arises when several outcomes or statistical tests are considered. General: If many hypotheses are tested, the chance of obtaining at least one apparently notable result by chance can increase. Statistical plans sometimes address this by prioritizing outcomes or adjusting inference across tests. The registry record does not report a multiplicity strategy, a hierarchy among secondary outcomes, or which analyses were planned. It is therefore not possible to determine how multiple outcomes would have been handled.

The record does not report the amount or pattern of missing outcome data, the rules for handling missingness, or the number of participants included in each outcome analysis. The primary endpoint description says adverse events were recorded for all patients, but no participant-level completeness information is given. General: Missing data can affect an estimate when the availability of observations is related to participant characteristics or outcomes; its impact depends on the reasons for missingness and the analysis method. Those reasons and methods are not reported.

The registry does not report analysis populations beyond its description of the primary adverse-event population as all patients. It also does not report interim analyses or a statistical analysis plan. These omissions limit assessment of how outcomes were selected, how observations were included, and how uncertainty was handled. They do not justify assuming that a particular method was used.

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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: melaena (25.0%), staphylococcal infection (25.0%), hypophysitis (7.1%), bacteraemia (7.1%), pneumonitis (6.7%).

The safety figures are grouped under Arm A, Arm B, and Arm C. For serious adverse events, the record reports 11 affected participants among 30 at risk in Arm A, 2 among 14 in Arm B, and 1 among 4 in Arm C. For other adverse events, it reports 30 among 30 in Arm A, 13 among 14 in Arm B, and 4 among 4 in Arm C. Death counts are 12 for Arm A, 6 for Arm B, and 2 for Arm C.

These numbers are group-specific descriptive counts. The registry describes the overall trial as single-group and explicitly cautions that the arm labels are not a like-for-like control comparison. It does not explain how the group labels were formed. Thus, differences between these counts cannot be interpreted as comparative treatment effects.

The serious adverse-event term list includes Melaena and Staphylococcal infection at 25.0%, Hypophysitis and Bacteraemia at 7.1%, and pneumonitis and Pneumonia at 6.7%. The denominator for these term-level percentages is not reported in the registry record. These percentages should not be assumed to represent the proportion of all enrolled participants with each event.

The listed death counts do not, by themselves, establish cause or relationship to treatment. The record does not provide event-level timing, attribution, or a complete account of severity and recurrence. The primary endpoint is a participant count for adverse events over 0 - 75 weeks; the displayed serious and other event counts should be understood within those reporting limitations.

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

The record documents a completed phase 1/phase 2 study of nivolumab combined with a PD-L1/IDO peptide vaccine in metastatic melanoma, with enrollment of 48. Its primary outcome is the number of participants with adverse events over 0 - 75 weeks, and its stated safety reporting standard is CTCAE v. 4.0. The registry includes serious and other adverse-event counts under three arm labels, as well as a list of serious adverse-event terms and percentages.

Those posted counts describe events recorded in the listed groups; they do not establish a comparative safety effect. The trial is described as single-group, and the registry says the arm labels are not a like-for-like control comparison. In addition, the relation between those labels and the single-group design is not reported. The numerical primary endpoint result across all patients is not reported in the registry record, nor are confidence intervals or statistical analyses.

The registry lists objective response rate, overall survival, progression-free survival, and vaccine-specific responses as secondary outcomes. Their numerical results are not reported in the registry record. As a result, the record does not establish whether the combination changed tumor response, survival, or immune response. It also does not permit comparison with nivolumab alone or another treatment.

General: A study can provide useful descriptive safety information without establishing causation or comparative effectiveness. Interpreting a treatment effect generally requires a design and analysis that address what outcomes would have occurred under a relevant comparison condition. Counts from a single-group study cannot supply that counterfactual by themselves. Likewise, a count without an uncertainty estimate offers limited information about how precisely it represents a broader population.

The findings should therefore be read as registry-reported safety counts and event terms within a study record that lacks outcome analyses and essential interpretive details. They do not constitute medical advice and should not be used alone to make an individual treatment decision.

14. Why This Trial Matters Statistically

This trial is statistically notable because its registry record combines a single-group description with safety counts labeled as three arms. That contrast highlights an important interpretive principle: group labels do not create a valid comparison by themselves. The registry explicitly says the groups are not a like-for-like control comparison, so the counts are descriptive rather than evidence of differences caused by treatment.

The primary outcome is a participant-level safety count over a stated timeframe, an outcome that can communicate how many people were recorded with adverse events. Yet the registry does not report a numerical result for that primary endpoint across all patients. The available group-specific counts and event-term percentages do not replace a complete outcome estimate or explain the basis of each percentage. This illustrates why outcome definitions, denominators, and analysis populations are important to statistical interpretation.

The record also lists efficacy and immune-response outcomes, including objective response rate, overall survival, progression-free survival, and vaccine-specific responses in peripheral blood mononuclear cells. Their numerical results are not reported in the registry record. Listing an outcome is not the same as reporting an estimate, uncertainty, or analysis. Readers should distinguish the existence of an outcome measure from evidence about its result.

General: Transparent reporting allows readers to assess how outcomes were defined, which participants contributed data, how missing observations were handled, and how uncertainty was quantified. Those details matter for both safety and efficacy interpretation. In this record, several such statistical details are not reported, making the limits of inference as important as the observed counts.

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 for interpretation is that the registry describes a single-group study rather than a randomized controlled comparison. It explicitly cautions that the three arm labels in the safety listing are not a like-for-like control comparison, and it does not explain how those labels relate to the single-group design. The group-specific counts should therefore not be used to infer comparative treatment effects.

The primary endpoint is described, but its overall numerical result is not reported in the registry record. The record gives selected serious and other adverse-event counts, death counts, and serious-event terms with percentages, but it does not report the denominator for the percentages. It also does not provide event-level details about timing, recurrence, severity grades, or attribution to treatment.

Although secondary outcomes are named, their numerical results are not reported. The record lists no analyses and does not provide confidence intervals, effect estimates, or p-values. It does not report the statistical analysis plan, interim analyses, a multiplicity strategy, missing-data methods, or the analysis populations for the secondary outcomes. These details cannot be inferred from the outcome names or the fact that the study is completed.

The registry lists enrollment of 48, but the available information does not give participant-level outcome completeness or the numbers contributing to each secondary analysis. It also does not provide a sample-size justification for the original study design. Planning assumptions described in the record are not a substitute for a design rationale or observed outcome results.

Finally, the safety information is limited to the registry's stated time window and reporting categories. The record does not establish how long each participant was observed or provide a complete account of exposure and follow-up. These limitations restrict how far the posted counts can be generalized or used to compare treatment strategies.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Combination Therapy With Nivolumab and PD-L1/IDO Peptide Vaccine to Patients With Metastatic Melanoma — NCT03047928.
• Registry record last updated 2025-02-20; status last verified 2025-02.
• Results first posted 2025-02-20.
• 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 NCT03047928, a completed phase 1/phase 2, single-group study of nivolumab with a PD-L1/IDO peptide vaccine in metastatic melanoma. Enrollment is listed as 48. The primary outcome is the number of participants with adverse events during 0 - 75 weeks, reported according to CTCAE v. 4.0.

Safety counts are presented for Arm A, Arm B, and Arm C, alongside serious adverse-event terms and death counts. The registry cautions that these are not like-for-like control groups. Although objective response rate, overall survival, progression-free survival, and vaccine-specific responses are listed as secondary outcomes, numerical results are not reported in the registry record. The record lists no analyses, and does not report a full primary endpoint result, statistical analysis plan, missing-data methods, or multiplicity approach.