Phase I/Ib Study of Pembrolizumab With Vorinostat for Patients With Advanced Renal or Urothelial Cell Carcinoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase I/Ib Study of Pembrolizumab With Vorinostat for Patients With Advanced Renal or Urothelial Cell Carcinoma (NCT02619253), a non-randomized phase 1 study. The primary outcome is Objective Response Rate (Percentage of Patients With Complete Response or Partial Response).

2. Clinical Question

3. Trial Design

This was a Phase I/Ib, open-label study, described in the registry as Phase 1, non-randomized, and single-group. The study title identifies pembrolizumab with vorinostat in advanced renal or urothelial cell carcinoma. The registry lists an enrollment of 52 and a completed status. Its recorded start date is 2016-02-23, and its primary completion date is 2023-03-28.

The design included a dose-finding cohort and expansion cohorts. The dose-finding objective was to estimate a recommended Phase 2 dose (RP2D) for the combination in advanced renal and urothelial cell carcinoma. The description says participants received daily oral vorinostat for 14 days and pembrolizumab 200 mg IV in 21-day cycles, with two vorinostat dose levels. The amounts for those two levels are not reported in the registry record.

After identifying an expansion test dose, the planned expansion phase would test the combination in patients with advanced renal cell or urothelial cell carcinoma. The record describes three expansion cohorts and says the participants would have prior treatments. It gives a planned group of 45 patients across those cohorts, while the cohort descriptions are truncated in the record. That planned cohort description should not be mistaken for a full account of who was ultimately analyzed.

Because treatment allocation was not randomized and there was no control group, the design can describe outcomes observed during treatment but cannot isolate the combination’s effect from other explanations. The study had an open-label design, so masking was absent. No details about blinded outcome review are reported in the registry record. The registry’s objectives include early anti-tumor activity, safety, tolerability, and selection of an RP2D; it does not provide a detailed statistical analysis plan.

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: Patients were considered eligible for this analysis if they were in the expansion cohorts and had at least one follow-up assessment of disease status after completing one cycle of combination therapy.

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 Objective Response Rate (Percentage of Patients With Complete Response or Partial Response), measured over Up to 4.5 years.

The primary endpoint is objective response rate: the percentage of participants with a complete response or partial response, assessed using RECIST v1.1. A complete response is defined in the record as disappearance of all target lesions. A partial response requires at least a 30% decrease in the sum of the longest diameters of target lesions, using the baseline sum as the reference.

Response rate is a binary outcome at the participant level: each eligible participant is classified as having had a response or not having had one. Expressing the result as a percentage gives a direct description of how often a response was recorded in the analyzed population. The planned 95% confidence interval represents uncertainty around that percentage; a wider interval would indicate less precision, while a narrower one would indicate greater precision. This is a general interpretation of confidence intervals, not a claim about the unreported interval in this study.

The stated analysis population was not every enrolled participant. Eligibility required membership in an expansion cohort and at least one follow-up disease-status assessment after completing one cycle of combination therapy. The registry specifies a timeframe of up to 4.5 years. It does not report the observed response percentage, the confidence interval, the number of participants included in this endpoint analysis, or how participants without an eligible assessment were handled.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The endpoint is a proportion: a participant either meets the response definition or does not. In general, a proportion is calculated from the number of participants meeting a criterion relative to the number assessed in the defined analysis population. The registry says the response percentage and its 95% confidence interval would be provided, but it does not report either result or the number assessed. No calculation can therefore be checked against the registry entry.

What does the confidence interval mean?

In general, a confidence interval describes statistical uncertainty around an estimate. It is not a guarantee that the true value lies within the particular interval, and it does not represent a range of individual participant outcomes. Its width depends on factors including the amount of information in the analysis and the observed proportion. Because the interval and analysis count are absent, the precision of the study’s response estimate is not reported in the registry record.

How does the response definition work?

The endpoint uses RECIST v1.1 categories. Complete response is defined as disappearance of all target lesions. Partial response requires at least a 30% decrease in the sum of the longest diameters of target lesions relative to the baseline sum. The primary measure combines these two response categories into one percentage. The registry does not give separate counts for complete and partial response, nor does it report how stable disease or progressive disease contributed to the response-rate denominator.

Why does the analysis population matter?

The stated population is limited to expansion-cohort participants who had at least one follow-up assessment of disease status after completing one cycle of combination therapy. This definition makes the endpoint dependent on assessment availability and timing, as well as response status. In general, excluding participants without a qualifying assessment can affect the estimate if their outcomes differ from those of participants who are assessed. Whether that occurred in this study cannot be determined: the numbers excluded, reasons for exclusion, and approach to missing assessments are not reported in the registry record.

What can a single-group study estimate?

A single-group study can describe the outcomes recorded among participants receiving the study combination. It lacks a randomized control group for estimating what would have happened to comparable participants under another treatment or without the study combination. General statistical reasoning therefore distinguishes an observed response proportion from a comparative treatment effect. The registry identifies no randomized comparison, and its own notes caution that the arms are not a like-for-like control comparison.

What can be learned from the cohort structure?

The study contains dose-finding and expansion cohorts. Dose finding was intended to estimate an RP2D, while expansion cohorts were intended to test the identified expansion test dose. These are different stages with different purposes. Cohort-specific observations can be useful descriptively, but comparisons among cohorts may be affected by differences in dose, patient characteristics, treatment history, or the stage of the study. The record does not report a prespecified statistical comparison among cohorts or adjustment for such differences.

What statistical details are absent?

The registry lists no analyses and does not provide a detailed statistical analysis plan. The method for constructing the confidence interval, any planned hypothesis tests, missing-data rules, interim analyses, or adjustments for multiple outcomes are not reported in the registry record. General statistical practice may use specific methods for binary outcomes, but it is not possible to attribute any particular method to this study without documentation.

The listed enrollment is not itself evidence of adequate statistical power. A sample-size rationale, target precision for the response estimate, and assumptions used to plan enrollment are not reported in the registry record. Any sample-size illustration based on an observed effect would be a planning exercise rather than observed power, and the primary endpoint effect needed for such an illustration is not reported in the registry entry. The study’s reported enrollment should be read as a design or registry count, not as proof that the primary estimate was precise.

Finally, safety outcomes and response outcomes answer different questions. A response proportion describes tumor response under the stated criteria; serious adverse-event counts describe recorded safety events in cohort groups. Neither measure alone captures the full benefit-risk profile, and the registry’s incomplete outcome reporting limits any combined interpretation.

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("Expansion Cohort A", "Expansion Cohort B", "Expansion Cohort C")
n      <- c(13, 11, 12)
events <- c(1, 0, 2)
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  Expansion Cohort A  13  1  7.7  0.2  36.0  1.4  33.3  1.8  33.9
ARM  Expansion Cohort B  11  0  0.0  0.0  28.5  -0.0  25.9  0.2  26.5
ARM  Expansion Cohort C  12  2  16.7  2.1  48.4  4.7  44.8  5.0  45.4

11. Multiplicity, Missing Data and Analysis Populations

The registry lists four outcome measures and names objective response rate as the primary endpoint. It also lists safety and tolerability outcomes, including the number of patients experiencing grade 3 or 4 adverse events and the number experiencing a dose-limiting toxicity. The reported record does not describe a multiplicity procedure or explain how conclusions across several outcomes would be controlled. In general, evaluating several outcomes can increase the chance of obtaining an apparently notable result by chance; whether or how that concern was addressed in this study is not reported in the registry record.

The record lists no analyses and does not provide a statistical analysis plan. It does not report interim analyses, prespecified subgroup testing, or rules for choosing among analyses. The existence, timing, or absence of these procedures cannot be inferred from the study’s phase or completed status.

For the primary endpoint, the eligible population is defined as expansion-cohort participants with at least one follow-up disease-status assessment after completing one cycle. That definition makes assessment availability relevant to inclusion. The registry does not report the number of enrolled participants who lacked a qualifying assessment, reasons for missing assessments, or any method for handling missing response data. It also does not describe an intention-to-treat analysis or another broader analysis population. The endpoint percentage and its confidence interval are not reported, so the effect of missing data on the reported estimate cannot be assessed.

The safety entries give cohort-specific counts, but the record does not fully explain the analysis population or observation period for each safety measure. The listed deaths should not be taken as treatment-related without a stated attribution. These reporting gaps do not establish that a procedure was or was not used; they mean that the procedure is 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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: anemia (25.0%), death nos (25.0%), atelectasis (25.0%), neoplasms benign, malignant and unspecified (incl cysts and polyps) - other (25.0%), dehydration (25.0%).

The registry lists, for each dose-finding or expansion cohort, the number of participants at risk and the number recorded with serious adverse events, other adverse events, and deaths. These are cohort-level descriptive counts. They should be read within their respective cohorts, not as a randomized comparison between treatment groups. The registry also lists serious-event terms with percentages of 25.0%, including anemia, death NOS, atelectasis, neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, dehydration, and hyperthyroidism. The denominator for those term percentages is not reported in the registry record.

Serious adverse events and other adverse events are distinct reporting categories; “serious” does not mean the same thing as a particular severity grade. The registry’s separate secondary outcome refers to grade 3 or 4 adverse events, but its results are not reported. Serious-event counts therefore should not be substituted for grade 3 or 4 counts. The record does not provide enough information to establish whether any event was caused by pembrolizumab, vorinostat, the combination, or the underlying disease. Death counts likewise do not establish treatment attribution. Differences in cohort counts should be interpreted cautiously because cohort sizes and composition vary, and allocation was not randomized.

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

The registry describes a study designed to investigate the combination of pembrolizumab and vorinostat, first through dose finding and then through expansion cohorts. Its primary question concerns the percentage of eligible expansion-cohort participants with a complete or partial response under RECIST v1.1. The record specifies a confidence interval as part of the intended reporting, but does not state the observed response percentage or interval. It therefore does not provide the numerical primary result needed to judge the response estimate or its precision.

The record does document a completed study, an enrollment of 52, and cohort-level adverse-event counts. These details describe the registry entry, but they do not supply the missing endpoint result. The listed adverse events also do not, on their own, show that study treatment caused the events. The outcomes for the named secondary safety measures—grade 3 or 4 adverse events and dose-limiting toxicities—are not reported in the registry record.

Even if the response result were available, the design would remain important to interpretation. In general, a non-randomized, single-group study can describe what happened among its participants but cannot provide the same controlled comparison as a randomized trial. The observed response proportion would not, by itself, establish how outcomes would compare with another treatment or what portion of the outcomes was attributable to the combination. Differences among dose-finding and expansion cohorts would also require caution rather than a causal interpretation.

The registry does not report the endpoint analysis count, missing-data handling, statistical analysis plan, or sample-size justification. Those omissions limit assessment of precision, potential selection effects, and the planned inferential framework. The available record supports a description of the design and the stated outcome definitions, but not a conclusion about the magnitude or comparative effect of treatment. No medical decision should be based on these incomplete registry entries alone.

14. Why This Trial Matters Statistically

This study illustrates why a clinical trial’s design and analysis population matter alongside its endpoint definition. Objective response rate is a straightforward binary outcome to describe, but the meaning of its estimate depends on who was included, what assessments were available, and how responses were classified. Here, the primary endpoint was restricted to expansion-cohort participants with a post-cycle disease-status assessment. The record does not report how many participants met that definition or the resulting response percentage.

The study also illustrates the distinction between dose finding and expansion. Dose finding was intended to estimate an RP2D, whereas expansion was intended to test the identified expansion test dose. Those stages serve different purposes, and their cohorts are not automatically comparable. A reader should not treat their descriptive outcomes as if they came from a randomized dose comparison.

Another statistical lesson is that a confidence interval is necessary for understanding precision, not just the point estimate. The registry states that a 95% confidence interval would be provided, but neither the interval nor the response result is reported. Without them, the primary endpoint’s uncertainty cannot be judged. The registry’s missing analysis details also show why explicit reporting of analysis populations, missing-data rules, and multiplicity procedures matters when several outcomes are considered.

Finally, a completed study record is not the same as a complete statistical account. The listed design and adverse-event counts provide some information, but important results and methods remain unreported. Clear distinction between what the registry documents, what it leaves unreported, and what a single-group design can establish is essential for responsible statistical interpretation.

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 interpreting efficacy is that the registry does not report the primary endpoint result. It gives the response definition and intended confidence interval, but not the observed percentage, interval, response counts, or number analyzed. The primary endpoint population is restricted to eligible participants in the expansion cohorts with a follow-up disease-status assessment after one cycle; the record does not state how many met that criterion.

The registry’s descriptions of the expansion cohorts are incomplete. It says the expansion was intended to include three cohorts and describes a planned group of 45 patients with prior treatments, but the cohort descriptions are truncated. The dose amounts for the two vorinostat levels are also not reported. The listed enrollment of 52 does not resolve these missing details or establish which participants contributed to each analysis.

There is no randomized control group, allocation was non-randomized, and the study was open label. Consequently, outcomes cannot be interpreted as a controlled estimate of comparative effect, and cohort differences may reflect more than treatment dose or cohort designation. The registry does not report blinded outcome assessment, so that aspect cannot be evaluated.

Important statistical details are absent: the analysis method for the confidence interval, missing-data handling, sample-size justification, interim analyses, and multiplicity procedures are not reported in the registry record. The listed secondary safety outcomes do not include reported results. Serious adverse-event entries have no stated causal attribution, and the denominator underlying the listed event-term percentages is not reported. These limitations constrain both efficacy and safety interpretation without establishing that any unreported procedure was omitted from the actual conduct of the study.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Phase I/Ib Study of Pembrolizumab With Vorinostat for Patients With Advanced Renal or Urothelial Cell Carcinoma — NCT02619253.
• Registry record last updated 2024-11-18; status last verified 2024-09.
• Results first posted 2024-11-18.
• 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 NCT02619253, a completed, open-label Phase I/Ib study of pembrolizumab with vorinostat in advanced renal or urothelial cell carcinoma. It is listed as Phase 1, non-randomized, and single-group, with enrollment of 52. The recorded start date is 2016-02-23, and the primary completion date is 2023-03-28.

The primary endpoint was objective response rate by RECIST v1.1 in eligible expansion-cohort participants, with an intended 95% confidence interval and a timeframe of up to 4.5 years. The observed response result and interval are not reported in the registry record. Cohort-level adverse-event counts are listed, but results for the named grade 3 or 4 adverse-event and dose-limiting-toxicity outcomes are not reported. The record does not include a detailed statistical analysis plan, missing-data approach, or sample-size justification.