Study of Entinostat With Nivolumab Plus Ipilimumab in Previously Treated Renal Cell Carcinoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Entinostat With Nivolumab Plus Ipilimumab in Previously Treated Renal Cell Carcinoma (NCT03552380), a na phase 2 study. The primary outcome is Objective Response Rate (ORR) Via RECIST 1.1.

2. Clinical Question

The clinical question is about response after prior treatment with nivolumab plus ipilimumab, rather than an initial treatment strategy or a comparison against a separate standard-treatment group. The study also aimed to examine safety and pharmacodynamics. Its secondary outcomes include adverse events, response by immune-related response criteria, progression-free survival by RECIST 1.1 and immune-related response criteria, and overall survival.

Because this is an open-label, sequential study without a randomized control comparison, its design can describe outcomes in participants treated with the combination but cannot isolate the effect of entinostat from the other drugs or from other influences. The registry record does not report the primary response result, a confidence interval, or the analysis population used for that endpoint. The central question therefore remains identifiable from the endpoint definition, but the posted record does not provide the result needed to quantify the observed response rate.

3. Trial Design

This is a Phase II, open-label study of entinostat with nivolumab and ipilimumab in people with metastatic renal cell carcinoma previously treated with nivolumab plus ipilimumab and whose disease progressed on that regimen. The registry lists an enrollment of 12 and a status of terminated. The recorded start date is 2018-07-31, and the primary completion date is 2022-06-07. The reason for termination is not reported in the registry record.

The study description says a safety lead-in would precede Phase II, with the aim of establishing the recommended Phase II dose of entinostat in combination with nivolumab and ipilimumab. The Phase II dose groups in the safety record are entinostat 5 mg and 3 mg. The arm description also names entinostat 5 mg, 3 mg, or 2 mg, with nivolumab and ipilimumab; the registry record does not explain how the dose levels were selected or how the lead-in informed them.

The described initial schedule uses weekly oral entinostat and intravenous nivolumab plus ipilimumab every 3 weeks for four 3-week cycles. After those cycles, the description says entinostat would continue weekly with nivolumab every 4 weeks or every 2 weeks according to participant tolerance, while ipilimumab would be discontinued. Treatment was to continue until disease progression or prohibitive toxicity. Tumor assessments were described at baseline and every 6 weeks thereafter using RECIST 1.1.

Allocation is recorded as not applicable, masking as none, and the study model as sequential. Thus, the dose groups are not randomized treatment arms and do not provide a like-for-like comparison. The registry record does not report further details about enrollment by dose group for the primary efficacy analysis, nor a full 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.

Study Treatment

Reasons for not completing this period:

Follow up

Reasons for not completing this period:

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 (ORR) Via RECIST 1.1, measured over From C1D1 until death or up to 31 months..

The primary endpoint is objective response rate by RECIST 1.1, expressed as the percentage of participants with an objective response. The registry defines complete response as disappearance of all target lesions and partial response as a >=30% decrease in the sum of the longest diameters of target lesions. Overall response is defined as complete response plus partial response. The endpoint description says target lesions are assessed by MRI.

Objective response rate is used to summarize whether tumors meet prespecified criteria for shrinkage or disappearance during a defined observation period. It focuses on the proportion of participants who have a complete or partial response; it is not a measure of how long a response lasts, how long participants live, or how long disease remains controlled. Those distinctions matter because the record also lists progression-free survival and overall survival as secondary outcomes.

The stated primary endpoint timeframe is from C1D1 until death or up to 31 months. The posted registry record does not include the observed response percentage or the stated 95% confidence interval. It also does not report the number of participants assessed for the primary endpoint, the response counts, or how missing or unevaluable assessments were handled. Accordingly, the endpoint can be described, but its observed magnitude and precision cannot be determined from the posted results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does an objective response rate describe?

As a general statistical concept, an objective response rate is a proportion: the number of participants meeting the response definition divided by the number in the relevant analysis population. The registry defines response using RECIST 1.1 categories. A complete response requires disappearance of all target lesions, while a partial response requires a specified reduction in the sum of the longest diameters of target lesions. The combined endpoint counts either category as an overall response. It does not, by itself, describe response duration or survival.

To interpret a proportion, readers need both the event count and the denominator. A response percentage without a clearly defined analysis population can be difficult to evaluate, particularly if some participants have no post-baseline assessment or are otherwise not evaluable. The primary outcome description does not state how such cases would be treated, and the posted record does not report the response count, analyzed denominator, or endpoint estimate.

How should a confidence interval be read?

In general, a confidence interval conveys uncertainty around an estimated quantity. For a response proportion, it indicates the range of values compatible with the observed data under the interval method and its assumptions. A narrower interval indicates greater precision than a wider interval, but the interval does not eliminate possible bias from study design, participant selection, outcome assessment, or missing data. The primary endpoint names a 95% confidence interval, but neither the interval nor the method used to calculate it is reported in the registry record.

Precision depends on the amount of information available, including the number of participants assessed and the frequency of the outcome. The registry lists enrollment of 12, but that number alone does not establish how many participants contributed to the primary analysis. It is therefore not possible to infer the endpoint’s precision from enrollment alone.

What does the study structure allow?

In general, random allocation helps balance participant characteristics across treatment groups, supporting a more credible comparison of outcomes. This study is recorded as sequential, open-label, and without applicable allocation. Its dose groups are not randomized controls. Differences between group outcomes, if reported, could reflect dose, participant characteristics, timing, or other influences. The registry does not report an adjusted comparison or a planned statistical test between the dose groups.

Open-label means treatment assignment is not masked. In general, knowledge of treatment can influence care, reporting, or assessment, although the extent depends on the endpoint and trial procedures. The registry describes radiological assessment using RECIST 1.1, but does not report whether imaging was reviewed independently or how assessment disagreements were handled. Those details should not be assumed.

What can be inferred from safety counts?

As a general concept, a participant-level adverse-event count records how many people experienced an event, not how many episodes occurred or how severe each episode was. A person may experience more than one event, so counts of people with events and counts of event terms answer different questions. The registry gives participant counts at risk and affected for serious and other adverse events in the two listed dose groups. It also lists selected serious event terms with percentages. These summaries do not provide event duration, recurrence, timing, severity grades, or attribution to study treatment.

Over-dispersion is a general statistical issue that can arise when event counts vary more than a simple model expects. It is relevant to analyses of repeated event counts, but the registry record does not report a model of that type or enough event-level data to assess it. The posted safety figures are best read as descriptive participant counts and listed event percentages, rather than as a model-based comparison.

What do planning calculations mean?

In general, a sample-size calculation describes the enrollment that would be needed under stated assumptions to detect a specified effect with a chosen significance level and power. It is a planning exercise, not evidence about the trial’s observed results. Any calculations based on an observed effect are illustrative and should not be mistaken for the trial’s original design justification or for observed power. The record does not report the trial’s own sample-size justification or a complete statistical plan. It lists no analyses, and it does not report a primary response estimate from which to assess how an observed effect was defined.

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 II, Dose Level 1:Entinostat 5 mg With Nivolu", "Phase II, Dose Level 2: Entinostat 3 mg With Nivol")
n      <- c(5, 7)
events <- c(1, 3)
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 II, Dose Level 1:Entinostat 5 mg With Nivolu  5  1  20.0  0.5  71.6  3.6  62.4  4.3  64.1
ARM  Phase II, Dose Level 2: Entinostat 3 mg With Nivol  7  3  42.9  9.9  81.6  15.8  75.0  15.7  75.5

11. Multiplicity, Missing Data and Analysis Populations

The registry lists multiple outcomes: objective response rate by RECIST 1.1 as the primary outcome, and adverse events, objective response rate by immune-related response criteria, progression-free survival by RECIST 1.1, progression-free survival by immune-related response criteria, and overall survival among the secondary outcomes. The record also reports six outcome measures, but it does not provide a full analysis plan or explain how the outcomes were prioritized beyond identifying the primary endpoint.

When a study examines several endpoints or makes multiple statistical comparisons, the chance of at least one apparently notable result can increase. As a general method, investigators may prespecify a testing hierarchy or adjustment for multiplicity. Whether either approach was planned or used is not reported in the registry record. The record lists no statistical analyses, so it does not establish which outcomes were formally tested or how any tests were interpreted.

Missing-data rules and analysis populations are also not reported for the primary response endpoint. The registry does not state how participants without an evaluable scan, participants who discontinued early, or participants with incomplete follow-up were handled. It does not specify whether the primary analysis used all enrolled participants, only participants who received treatment, or an evaluable subset. These distinctions can affect a proportion’s numerator and denominator and therefore its interpretation.

The response endpoint timeframe is stated as from C1D1 until death or up to 31 months, but the record does not describe censoring rules, the handling of death before response assessment, or the analysis method for the time-to-event secondary outcomes. Without these details and without posted estimates, neither missing-data effects nor multiplicity-adjusted conclusions can be assessed.

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: platelet count decreased (20.0%), skin infection (20.0%), vomiting (20.0%), adrenal insufficiency (14.3%), gastrointestinal disorders - other, specify (14.3%).

The registry separates serious adverse events from other adverse events and presents participant counts at risk and affected in each dose group. In the entinostat 5 mg group, 3 participants among 5 at risk are listed with serious adverse events, and 5 among 5 are listed with other adverse events. In the entinostat 3 mg group, 3 participants among 7 at risk are listed with serious adverse events, and 7 among 7 are listed with other adverse events. These are descriptive counts. They do not show how many separate events occurred, when events began, how long they lasted, or whether investigators considered them related to study treatment.

The record lists platelet count decreased, skin infection, and vomiting at 20.0% each, and adrenal insufficiency, gastrointestinal disorders - Other, specify, and heart failure at 14.3% each among the top serious adverse event terms. The registry does not give further detail alongside these term percentages about event severity, recurrence, or attribution. The percentages should not be treated as comparative estimates between dose groups without the relevant denominators and analysis context.

Deaths are listed for 3 participants in the 5 mg group and 4 in the 3 mg group. A death count alone does not establish cause, timing, or relationship to treatment. These safety summaries do not support a causal conclusion about the regimen or a direct comparison of dose-related risk.

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

The record establishes that a Phase II study was designed to examine entinostat with nivolumab and ipilimumab in metastatic renal cell carcinoma previously treated with nivolumab plus ipilimumab. It describes a safety lead-in, a sequential open-label design, the planned dosing approach, and RECIST 1.1 as the method for assessing the primary response endpoint. It also records participant counts for adverse events and deaths in two entinostat dose groups.

It does not establish the observed objective response rate. The primary endpoint estimate and its 95% confidence interval are not reported in the registry record. Consequently, the posted information cannot show how frequently participants met the response criteria or how precisely that frequency was estimated. Nor does it show the duration of any responses.

The study design does not include a randomized control group. The dose groups are not like-for-like controls, so descriptive differences between them would not by themselves show that one dose or treatment strategy caused different outcomes. The study also combines entinostat with nivolumab and ipilimumab, preventing attribution of any outcome to entinostat alone based on this record.

Safety counts and listed event terms provide descriptive information, but they do not establish causality. The registry does not report event-level timing, attribution, or severity detail alongside the summarized counts. Similarly, the listed deaths cannot be interpreted as treatment-related or unrelated without further information.

The registry status is terminated, but the reason is not reported in the registry record. Termination alone does not explain whether the study stopped for safety, feasibility, enrollment, administrative, or other reasons. In sum, the record describes the intended research question and some safety observations, but does not post the primary efficacy result or the details needed for a definitive statistical assessment.

14. Why This Trial Matters Statistically

This trial is statistically notable because it asks a response question in a population whose disease had progressed on the nivolumab plus ipilimumab regimen. That setting makes the outcome definition important: the primary endpoint counts complete and partial responses under RECIST 1.1, rather than relying on an unspecified impression of tumor change. The record also lists immune-related response criteria as a secondary outcome, creating a distinct response framework that should not be conflated with RECIST 1.1.

The sequential, open-label design reflects a study with a safety lead-in and dose-level groups rather than a randomized control comparison. This can support descriptive evaluation of safety and response in the enrolled participants, but it limits the strength of causal comparisons. A response estimate in a small study can also be imprecise; however, the registry does not report the primary estimate or confidence interval needed to quantify that uncertainty.

The record is also a useful reminder that an endpoint definition and an endpoint result are different kinds of information. The registry specifies what counts as response and the stated assessment timeframe, but does not post the observed response rate. Without the estimate, denominator, and uncertainty interval, readers cannot judge the magnitude or precision of the primary outcome from this record.

Finally, the listed safety counts are descriptive and should be kept separate from efficacy interpretation. They do not establish why the study was terminated, whether events were treatment-related, or whether one dose group had a different causal risk. Those questions require details not reported in the registry record.

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 limitation for interpreting efficacy is that the registry record does not report the objective response rate, response counts, or 95% confidence interval. The record therefore cannot quantify the primary endpoint, despite identifying its criteria and timeframe. It also does not report the primary analysis population or handling of participants without evaluable assessments.

The study is open-label and sequential, with allocation recorded as not applicable. The dose groups are not randomized controls, so they cannot support a clean causal comparison. The enrollment listed is 12, but the number analyzed for each outcome is not reported. The registry does not provide participant-level characteristics or enough detail to assess how comparable the dose groups were.

The record does not report the reason for termination, the trial’s sample-size justification, a complete statistical analysis plan, or the methods used for confidence intervals and secondary time-to-event outcomes. It also does not state how missing data, multiplicity, or analysis populations were handled. The safety summaries do not provide event-level detail, timing, severity, or attribution alongside the counts and selected terms.

These limitations are specific to the information recorded and should not be treated as evidence that further analyses or explanations do not exist elsewhere. They mean that conclusions about efficacy, precision, comparative dose effects, safety attribution, and the reason for termination cannot be drawn from the registry record alone.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study of Entinostat With Nivolumab Plus Ipilimumab in Previously Treated Renal Cell Carcinoma — NCT03552380.
• Registry record last updated 2024-09-03; status last verified 2024-08.
• Results first posted 2024-09-03.
• 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

NCT03552380 is a Phase II, open-label, sequential study of entinostat with nivolumab and ipilimumab in metastatic renal cell carcinoma previously treated with nivolumab plus ipilimumab. The registry lists 12 participants enrolled and records the study as terminated. Its primary endpoint is objective response rate by RECIST 1.1, with a stated timeframe from C1D1 until death or up to 31 months.

The posted record describes a safety lead-in and dosing schedule and lists serious and other adverse-event counts for entinostat 5 mg and 3 mg groups. It does not report the primary response estimate or confidence interval, a complete statistical analysis plan, the reason for termination, or the analysis populations and missing-data methods. The nonrandomized dose groups are not a like-for-like control comparison.