Phase II Safety Study of Vemurafenib Followed by Ipilimumab in Subjects With V600 BRAF Mutated Advanced Melanoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase II Safety Study of Vemurafenib Followed by Ipilimumab in Subjects With V600 BRAF Mutated Advanced Melanoma (NCT01673854), a na phase 2 study. The primary outcome is Percentage of Participants Who Received Ipilimumab and Who Had Grade 3-4 Drug-related Skin Adverse Events (AEs).

2. Clinical Question

3. Trial Design

This completed Phase II study evaluated a treatment sequence in advanced melanoma with a V600 BRAF mutation. The official title specifies previously untreated participants. The registry lists an enrollment of 70 and identifies the design as single-group and open-label, with no masking and allocation listed as NA. Bristol-Myers Squibb is named as the sponsor.

Participants received vemurafenib, 960 mg, twice daily for 6 weeks. After a washout period of 3-10 days, they received ipilimumab, 10 mg/kg, every 3 weeks for a maximum of 4 doses. The arm description then refers to treatment at Week 24, with ipilimumab, 10 mg/kg, every 12 weeks until disease progression or a further condition that is cut off in the registry record. That full condition is not reported in the registry record.

The study start date is 2012-09-13, and the primary completion date is 2014-07-25. Its primary focus was safety, including the percentage of ipilimumab-treated participants with grade 3-4 drug-related skin adverse events. The registry lists 5 outcome measures, including gastrointestinal and hepatobiliary adverse-event outcomes. It lists 0 analyses. An outcome measure being listed does not establish that its numerical result or a formal statistical analysis is available in the registry record.

Because this was not a randomized comparison, outcome frequencies describe participants in the study rather than a treatment effect relative to a control group. The design can describe observed safety events in the enrolled group, but by itself cannot distinguish events associated with the treatment sequence from events that might also occur under another condition.

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: A total of 70 patients were enrolled, and 46 received treatment.

Vem 1 Phase (Vemurafenib, 960 mg)

Ipilimumab Phase (Ipilimumab, 10 mg/kg)

Reasons for not completing this period:

Vem 2 Phase (Vemurafenib Retreatment)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All participants who received at least 1 dose of ipilimumab

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 Percentage of Participants Who Received Ipilimumab and Who Had Grade 3-4 Drug-related Skin Adverse Events (AEs), measured over From the first dose date of Vem1 to the last dose of ipilimumab (to a maximum of 3 years) + 90 days or to the first dose date of Vem2, whichever occurred first.

The primary endpoint is the percentage of participants who received ipilimumab and had grade 3-4 drug-related skin adverse events. The endpoint population includes all participants who received at least 1 dose of ipilimumab. The registry defines an adverse event as a new unfavorable symptom, sign, or disease, or worsening of a preexisting condition; it notes that an event may not have a causal relationship with treatment. “Drug-related” includes events judged to have a certain, probable, possible, or unknown relationship to study drug.

The grade identifies severity: Grade 1 is mild, Grade 2 moderate, Grade 3 severe, Grade 4 life-threatening or disabling, and Grade 5 death. The endpoint focuses on severe skin events judged to have a relationship to study drug; it is not a measure of every skin event or every adverse event. The observation period begins with the first dose date of Vem1 and continues through the last ipilimumab dose, to a maximum of 3 years plus 90 days, or until the first dose date of Vem2, whichever occurred first.

A percentage describes how common the specified event was in the defined population over that observation period. A 95% confidence interval is listed as the measure of uncertainty. The endpoint result and its interval are not reported in the registry record, so the event frequency and its precision cannot be characterized from that record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a percentage measure?

For a binary outcome, each participant is classified according to whether the defined event occurred during the specified observation period. The percentage expresses the frequency of participants with the event in the relevant analysis population. Its interpretation depends on the event definition, the population included, and the period during which events could be counted. Here, the endpoint concerns grade 3-4 drug-related skin adverse events among participants who received at least 1 dose of ipilimumab. The registry describes the definition and observation window, but the endpoint percentage is not reported in the registry record.

What does a confidence interval convey?

A confidence interval describes statistical uncertainty around an estimate, under the method used to construct it. It is not a guarantee that the true value lies within the interval, and it does not address every source of uncertainty. For a participant percentage, the interval would help readers judge how precisely the event frequency was estimated. The registry specifies a 95% confidence interval for the primary endpoint, but does not report its limits or the endpoint estimate. The interval's width and the precision of the estimate therefore cannot be evaluated.

Why does the study design matter?

A single-group study can report the frequency of events observed in its participants. A randomized comparison serves a different purpose: it provides groups assigned to different conditions, allowing a direct comparison subject to the design and analysis assumptions. This study is identified as single-group, with allocation listed as NA and no masking. There is no concurrent control group in the registry description. Therefore, even if a safety frequency were available, it would describe the enrolled group and would not estimate a randomized difference between treatment conditions.

Open-label design means masking was absent, as the registry explicitly records. That design feature does not by itself determine whether an event occurred or whether it was related to treatment. It is relevant context when interpreting outcomes involving clinical observation and attribution, because assessment is not described as blinded. The registry record does not report further assessment procedures.

How should event severity and relatedness be read?

The registry grades adverse events from mild through death. The primary endpoint selects Grade 3-4 events, defined as severe, life-threatening, or disabling, and requires a drug-related assessment. The registry's definition of drug-related includes certain, probable, possible, or unknown relationship to study drug. These categories are not equivalent to proof that a drug caused an event. The broader adverse-event definition explicitly allows an event to be recorded without a causal relationship to treatment.

This distinction matters because the primary endpoint is a narrower measure than all adverse events. A serious adverse event listing, a grade 3-4 event, and a drug-related skin event are not interchangeable categories. The registry's serious-event summary should be read on its own terms, not treated as the result for the primary endpoint. The record does not report enough endpoint detail to connect the serious-event entries to the primary skin outcome.

What does the planning illustration mean?

The sample-size assumptions describe a planning illustration based on an observed effect, not the design of this single-group trial. The illustration assumes a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; its target effect is a stated fraction of the observed effect. Such planning estimates ask how many participants per arm might be needed under those assumptions to detect a specified effect. They are hypothetical design calculations, not observed outcomes and not evidence that the trial had a particular probability of detecting an effect.

The equal-allocation, two-arm assumptions do not describe this study's single-group design. The record does not report a sample-size justification for the trial, and it does not report a primary endpoint effect from which readers could evaluate the planning illustration. Sample-size calculations also do not repair the absence of a comparator or replace outcome results. Any planning quantity should be understood as conditional on its assumptions rather than as an empirical finding.

What analyses are reported?

The registry record lists 0 analyses. It does not report a statistical model, adjustment strategy, interim analysis, or analysis details for the primary endpoint. The presence of an endpoint definition and a confidence interval label does not establish which calculation method was used. Without an estimate, interval limits, and analysis description, it is not possible to reconstruct the inferential analysis or assess its assumptions.

In general, statistical methods should match the data structure and the question. A binary percentage concerns event occurrence, while time-to-event methods account for when an event occurs and how long participants are observed. The primary endpoint is specified as a percentage, not a time-to-event endpoint. The registry's observation period defines the window for counting events, but does not itself imply a time-to-event analysis. No additional model or uncertainty calculation should be inferred from that period alone.

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("Vemurafenib, 960 mg + Ipilimumab, 10 mg/kg")
n      <- c(46)
events <- c(15)
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  Vemurafenib, 960 mg + Ipilimumab, 10 mg/kg  46  15  32.6  19.5  48.0  20.9  47.0  20.9  47.1

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 5 outcome measures, including the primary skin adverse-event percentage and secondary gastrointestinal and hepatobiliary adverse-event percentages. Considering several outcomes can raise a multiplicity question: when many statistical tests are performed, the chance of at least one apparently unusual result can increase. A multiplicity plan might define which outcomes are confirmatory, whether tests are adjusted, or how results should be interpreted. Such a plan is not reported in the registry record. The record lists 0 analyses, so it does not report outcome-specific tests or an adjustment strategy.

The record does not report a missing-data method, a participant disposition breakdown, or the number analyzed for the primary endpoint. It identifies the endpoint population as all participants who received at least 1 dose of ipilimumab, but does not report how participants with incomplete follow-up or unavailable event assessments were handled. For a percentage, excluding participants with unknown event status can affect interpretation if their outcomes differ from those observed among participants with recorded status. This is a general concern, not evidence that missing data occurred or were handled in a particular way in this study.

Likewise, an enrollment of 70 does not establish the number included in each outcome analysis. The registry does not report a statistical analysis population beyond the primary endpoint population definition, nor does it state whether any participants were excluded from that population. These omissions limit assessment of how complete and representative the reported outcome data would be; the endpoint result itself is not reported in the registry record.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

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: malignant neoplasm progression (10.9%), colitis (6.5%), asthenia (6.5%), pain in extremity (6.5%), squamous cell carcinoma (6.5%).

The serious-event summary records 46 participants at risk and 34 affected in the serious-event fields. The other-event fields record 46 at risk and 44 affected. These are participant counts in the safety summary, not the primary endpoint result. The primary endpoint is specifically the percentage with grade 3-4 drug-related skin adverse events among participants who received ipilimumab; its count and percentage are not reported in the registry record.

The listed serious-event terms include malignant neoplasm progression at 10.9%, colitis at 6.5%, asthenia at 6.5%, pain in extremity at 6.5%, squamous cell carcinoma at 6.5%, and back pain at 6.5%. These percentages describe entries in the serious-event summary. The registry does not provide corresponding event counts in the registry record used for this explanation, so the percentages should not be converted to counts. It also does not report whether each listed serious event was considered drug-related.

Deaths are not reported in the registry record. Seriousness, severity grade, and drug relatedness are distinct classifications; the list should not be read as a list of confirmed treatment-caused events or as a substitute for the defined primary outcome.

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

The record establishes that this was a completed Phase II safety study of a treatment sequence for previously untreated advanced melanoma with a V600 BRAF mutation. It specifies the primary safety question, the population definition, the grading framework, and the observation period. It also provides a descriptive serious-event summary. These details identify what was intended to be measured and give context for reading the safety entries.

The record does not report the numerical result for the primary endpoint or its 95% confidence interval. It therefore does not show the percentage of participants who experienced the specified grade 3-4 drug-related skin events or how precise that estimate was. Enrollment of 70 does not fill this gap, because the number enrolled is not the same as a reported endpoint count or estimate.

The single-group, open-label design also limits what the safety data can establish. Any reported frequency would describe the study group under the specified observation conditions. Without a concurrent randomized comparator, that frequency could not establish how it differs from the frequency under another regimen. The design also does not separate the contribution of vemurafenib from that of ipilimumab or from other influences on observed events.

The serious-event entries are useful as descriptive information but are not proof of causation. The registry definition allows adverse events to be recorded without a causal relationship, and drug-relatedness categories include uncertain assessments. The serious-event counts and term percentages should also not be mistaken for the primary skin endpoint, which applies a narrower event definition.

Accordingly, the available record supports a description of the trial design and the safety outcomes it set out to assess, but not a conclusion about the primary endpoint's observed frequency or comparative safety. Those results and analysis details are not reported in the registry record.

14. Why This Trial Matters Statistically

This study is statistically informative as an example of the difference between a clearly defined safety question and a reported analysis result. The registry specifies the primary event, the eligible endpoint population, the severity grades, the drug-relatedness definition, and a defined observation period. Those details are necessary for interpreting a percentage: without a clear event definition and population, even a reported frequency would be difficult to contextualize.

The design also makes the scope of inference clear. A single-group safety study can characterize events observed during a treatment sequence, but it does not produce a randomized comparison. Readers should distinguish a descriptive frequency from an estimate of a treatment difference. The absence of a comparator is a design limitation for causal comparisons, not a defect that can be addressed by a confidence interval around a single-group percentage.

The record's separate serious-event summary illustrates why adverse-event categories must not be conflated. Seriousness, severity grade, event type, and drug relatedness address different aspects of safety reporting. The primary endpoint selects severe skin events judged drug-related, while the serious-event summary lists broader terms. Interpreting one as if it answered the other would change the statistical question.

Finally, the registry record illustrates the importance of reporting the estimate and its uncertainty alongside the planned endpoint. Without the primary percentage, confidence interval limits, analysis population count, or analysis method, readers cannot assess the endpoint's magnitude, precision, or analysis assumptions. The record lists a planning illustration based on two-arm assumptions, but such calculations are distinct from observed trial results and do not substitute for them.

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 primary endpoint result and its 95% confidence interval are not reported in the registry record. The record also lists 0 analyses, leaving the method used to estimate the percentage, the treatment of incomplete observations, and any adjustment strategy unspecified. Although the endpoint population is defined as participants who received at least 1 dose of ipilimumab, the number in that population is not reported.

The study is single-group and open-label, with allocation listed as NA. It has no concurrent comparator in the registry description, so its safety summaries cannot establish a comparative difference. The sequence also combines vemurafenib and ipilimumab, making it impossible to attribute any observed event to one component on the basis of this design alone.

The registry enrollment is 70, but this does not reveal how many participants contributed to the endpoint or how complete their observation was. The registry does not report participant flow, missing outcome handling, or analysis-population details beyond the primary population definition. It also does not report a multiplicity strategy despite listing 5 outcome measures.

The treatment description after the initial ipilimumab course is incomplete: it states dosing at Week 24 every 12 weeks until disease progression or a truncated additional condition. The full stopping condition is not reported in the registry record. The serious-event summary includes participant counts and selected term percentages, but deaths are not reported in the registry record, and the listed terms are not identified as necessarily drug-related. These limitations constrain interpretation of both the endpoint and the broader safety entries.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Phase II Safety Study of Vemurafenib Followed by Ipilimumab in Subjects With V600 BRAF Mutated Advanced Melanoma — NCT01673854.
• Registry record last updated 2018-07-24; status last verified 2018-06.
• Results first posted 2015-10-19.
• 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

NCT01673854 is a completed, open-label, single-group Phase II study sponsored by Bristol-Myers Squibb. It enrolled 70 participants with previously untreated advanced melanoma with a V600 BRAF mutation. The regimen began with vemurafenib, 960 mg, twice daily for 6 weeks, followed after a washout period of 3-10 days by ipilimumab, 10 mg/kg.

The primary endpoint was the percentage of participants who received ipilimumab and had grade 3-4 drug-related skin adverse events. The registry defines the endpoint population and observation period, but the endpoint estimate and its 95% confidence interval are not reported in the registry record. The record lists 5 outcome measures and 0 analyses. Its serious-event summary includes 34 affected participants among 46 at risk, while the primary endpoint remains unreported. The single-group design supports descriptive safety reporting, not a randomized comparison.