Phase I of Histone Deacetylase (HDAC) Inhibitor Panobinostat With Ipilimumab With Unresectable III/IV Melanoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase I of Histone Deacetylase (HDAC) Inhibitor Panobinostat With Ipilimumab With Unresectable III/IV Melanoma (NCT02032810), a na phase 1 study. The primary outcome is Maximum Tolerated Dose (MTD).

2. Clinical Question

3. Trial Design

This is a Phase 1, sequential dose-escalation study of panobinostat combined with ipilimumab. The registry record lists allocation as NA and masking as none. The study was conducted in participants with unresectable Stage III or Stage IV melanoma, with enrollment of 17. Its status is completed.

The dose-escalation description specifies panobinostat at 5, 10, 15, or 20 mg, with ipilimumab at 3 mg/kg. The adverse-event groups listed in the record are Panobinostat 5 mg and Panobinostat 10 mg. Results for other dose groups are not reported in the registry record’s adverse-event details. The record does not describe a control group, and the listed dose groups should not be read as randomized comparisons.

The study began on 2014-01-07, and its primary completion date is 2017-09-06. The stated goal was to enroll up to 36 patients for MTD determination. The description says the study would be successfully concluded earlier if 12 patients were accrued at the dose determined to be the MTD, with 3 dose-limiting toxicities (DLTs). These are stated design goals and conditions, not reported findings about what occurred.

The registry record describes safety evaluation through review of adverse-event reports, vital signs, physical examinations, laboratory tests, and triplicate 12-lead ECGs before dosing on Day 1 of induction cycle 1. Further details of the escalation decisions, including the rules used to assign participants among doses, are not reported in the registry record. The record does not establish whether the planned enrollment or early-conclusion condition was met.

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

Analysis population for the primary outcome, as defined in the registry: All participants

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 Maximum Tolerated Dose (MTD), measured over Up to 36 months.

The primary endpoint is the maximum tolerated dose of panobinostat, measured in mg, when administered with ipilimumab at 3 mg/kg. The primary outcome description also identifies the recommended Phase 2 dose (RP2D) as a study objective. The stated timeframe is up to 36 months, and the listed population is all participants.

In general, dose-finding studies use safety observations across dose levels to identify a dose considered tolerable under the study’s rules. An MTD is not a direct measure of comparative benefit. Its interpretation depends on how dose-limiting toxicities are defined, which participants count as evaluable, and what escalation or stopping rules are applied. Those details are not reported in the registry record.

The record describes safety review of adverse events, vital signs, physical examinations, laboratory results, and ECGs. It does not report a numeric MTD or RP2D result, the number of DLTs by dose, or an analysis supporting a selected dose. The timeframe and endpoint description therefore establish what the study set out to assess, but do not establish which dose was selected or why.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical interpretation begins with the question the design can answer. This study is described as sequential and dose-escalating, rather than as a randomized comparison. In general, sequential dose-finding studies examine safety as participants receive treatment at different dose levels, with the aim of informing a dose choice. They are not designed in the same way as trials that randomize participants to treatment and control groups to estimate a comparative effect.

What dose escalation can show

In general, dose escalation uses the pattern of observed toxicities at each dose to guide whether a dose is considered for further study. The interpretation depends on predefined dose-limiting toxicity criteria, the number of participants considered evaluable at each level, and the decision rules for escalation, de-escalation, or stopping. The registry record describes the goal of determining an MTD and RP2D, but the detailed DLT definition and dose-escalation algorithm are not reported in the registry record. Without those details, the protocol’s decision process cannot be reconstructed from the registry entry alone.

The study description says the goal was to enroll up to 36 patients and that it could be concluded earlier if 12 patients were accrued at the dose determined to be the MTD, with 3 DLTs. This is a statement of planned study conduct. It is not evidence that the condition occurred, that the MTD was found, or that the selected dose met a particular safety threshold. The record reports enrollment of 17, but does not report whether the earlier-conclusion condition was met.

Why the design is not a dose comparison

In general, a randomized comparison aims to balance participant characteristics across groups through random assignment. Here, allocation is listed as NA and the model is sequential. Dose groups may therefore represent successive stages in the study rather than concurrent groups formed by random assignment. Any observed difference in event counts across those groups could reflect differences in participants, exposure, follow-up, or other factors, as well as dose. The registry record does not report adjusted comparisons or an analysis designed to separate those influences.

Masking is listed as none. In general, masking can limit the influence of knowledge about treatment assignment on some aspects of care, assessment, or reporting. The record does not specify how any potential assessment bias was addressed. The absence of masking does not by itself show that results are biased, but it is relevant context when interpreting subjective outcomes and adverse-event reporting.

Uncertainty and precision

In general, an estimate describes a quantity of interest, while a confidence interval describes the uncertainty around that estimate under a statistical model. A narrow interval indicates greater precision than a wide interval, all else equal. The registry record does not report a primary endpoint estimate or confidence interval, so the precision of an MTD estimate cannot be assessed. It also does not report analyses for the listed secondary outcomes.

Small dose groups can yield imprecise estimates of event frequency. In general, a count from a small group may change noticeably when only a few participant outcomes differ. The safety figures posted for the 5 mg and 10 mg groups are descriptive counts; the record does not supply confidence intervals or a statistical comparison for these figures. They should not be treated as precise estimates of the underlying risk in a broader population.

How to read the planning illustrations

The registry material describes sample-size illustrations as planning calculations based on the observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The target effect is described as a stated fraction of the observed effect. For time-to-event outcomes, the illustrations use total events under the Schoenfeld approach; for other outcomes, they give participants per arm.

In general, such calculations explore how a hypothetical future comparison might be sized under stated assumptions. They are not the study’s observed enrollment, and they are not observed power. Their equal-allocation, two-arm framework is not a description of this sequential, non-randomized dose-escalation design. The record does not report the numerical illustration results in the registry record for interpretation, so no particular planning requirement can be stated.

The statistical analysis plan, including any prespecified models, handling of repeated assessments, missing-data methods, or adjustment for multiple outcomes, is not reported in the registry record. These omissions limit the ability to evaluate how the investigators intended to quantify uncertainty or make the final dose-selection decision.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists a primary endpoint, maximum tolerated dose, and three secondary outcomes: immune-related overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). It lists four outcome measures, but no analyses. The result estimates and statistical tests for these endpoints are not reported in the registry record.

When a study evaluates multiple outcomes, multiplicity refers to the increased chance of obtaining at least one apparently notable result simply because several questions are examined. In general, a statistical analysis plan may specify which outcome is primary, how secondary outcomes are interpreted, and whether any adjustment is used. The registry record does not report a multiplicity strategy, so it is not possible to determine how testing across outcomes was handled.

The record does not report missing-data counts or methods for handling missing outcomes. It also does not report whether participants who discontinued treatment or lacked follow-up were included in each outcome analysis. The primary endpoint population is listed as all participants, and the safety description says participants who receive any study drug therapy will be evaluated for safety. Actual analysis populations and outcome-specific denominators are not reported in the registry record.

In general, missingness can affect interpretation if participants with unavailable outcomes differ from those with observed outcomes. Without the amount and pattern of missing data, or the methods used to address it, the direction and magnitude of any impact cannot be assessed. No interim analyses or stopping boundaries beyond the stated early-conclusion condition are reported in the registry record.

11. 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: investigations - other, hypophysitis (33.3%), acute kidney injury (27.3%), diarrhea (27.3%), nausea (27.3%), fatigue (27.3%).

The registry record lists serious adverse event counts by panobinostat dose. In the 5 mg group, 4 of 6 participants at risk were affected; in the 10 mg group, 7 of 11 participants at risk were affected. For other adverse events, the record lists 6 of 6 participants at risk in the 5 mg group and 11 of 11 in the 10 mg group. Deaths are listed as 1 and 0, respectively.

These counts describe the posted safety groups. They are not a randomized comparison, and the registry record does not report a statistical test or adjusted estimate comparing doses. The counts alone do not establish cause, timing, duration, recurrence, or severity beyond the serious-event classification. The record’s listed serious-event terms and percentages are descriptive summaries; their denominators and participant-level overlap are not explained in the entries. Events may also be related to underlying disease or other factors, but causal attribution is not reported in the registry record.

The record describes planned safety review using adverse-event reports, vital signs, examinations, laboratory tests, and ECGs. The available entries do not report detailed exposure time or follow-up by group. These limitations mean the counts should be interpreted as recorded safety observations, not as precise comparative risk estimates.

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

The study addressed an important early-stage statistical question: how to characterize tolerability across panobinostat dose levels when used with ipilimumab, and how to identify an MTD and a dose for possible Phase 2 study. Its sequential dose-escalation design is suited to a dose-finding objective. The listed adverse-event data describe the number of participants affected in the recorded 5 mg and 10 mg groups.

The record does not report the primary endpoint result, a selected MTD, an RP2D, or DLT counts. It also does not report results for the secondary outcomes. Thus, the posted information cannot establish the dose-selection conclusion, quantify uncertainty around such a conclusion, or characterize response, progression-free survival, or overall survival in this study.

The safety counts do not establish that either study drug caused the listed events. Because the groups are not described as randomized comparison arms, differences in their counts cannot be interpreted as causal dose effects. The counts also cannot by themselves establish the frequency of events in a wider patient population or predict what an individual participant might experience.

In general, an early dose-finding study can inform later research by identifying a dose range and describing safety observations under its study conditions. It does not, by design alone, establish comparative efficacy. In this case, the registry record supplies the study objective and some safety summaries, but not the dose-finding analysis needed to judge what dose was selected or how well that selection was supported. The conclusions should remain limited to the information the record reports.

13. Why This Trial Matters Statistically

This trial illustrates why the design determines which statistical conclusions are justified. A sequential dose-escalation study and a randomized comparative trial answer different questions. The former focuses on dose selection and safety observations across dose levels; the latter can support an estimate of treatment differences under its design and analysis assumptions. Treating dose groups from a sequential study as though they were randomized controls would overstate what the data can establish.

It also shows the difference between a protocol objective and a reported result. The MTD and RP2D are named as goals, and the record gives a planned enrollment target and an early-conclusion condition. But without a posted endpoint result, DLT counts, or analysis, those design details do not reveal the dose-selection outcome. Statistical interpretation depends on reported evidence, not solely on the question a study intended to answer.

The safety entries further demonstrate why denominators and context matter. The record lists affected participants and participants at risk for the 5 mg and 10 mg groups, but does not report a comparative analysis, uncertainty intervals, or detailed event-level context. The counts are informative as descriptions of recorded observations, while remaining insufficient for causal or precise comparative claims.

Finally, planning calculations must be kept separate from observed study results. The registry describes hypothetical sample-size illustrations with assumptions that do not match the sequential design. Such illustrations can support planning for a future comparison, but they are not observed power and do not substitute for the missing primary endpoint analysis. Distinguishing design, observation, and analysis is central to reading early-phase trial records accurately.

14. 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 is that the registry record does not report the primary endpoint result. It names MTD and RP2D as objectives but gives no selected dose, DLT counts, estimate, or uncertainty measure. The statistical analysis plan and the detailed dose-escalation rules are also not reported in the registry record, limiting independent assessment of how the dose decision was to be made.

The recorded enrollment is 17, while the description states a goal of up to 36. The record does not explain why enrollment was lower than the stated goal or whether the early-conclusion condition was met. The adverse-event entries give group counts for Panobinostat 5 mg and Panobinostat 10 mg; corresponding detailed safety entries for the 15 mg and 20 mg doses are not reported in the registry record. No assumption should be made from that absence about whether participants received those doses.

The study is sequential and has no randomized allocation listed, so its dose groups are not a like-for-like control comparison. The posted safety summaries do not include confidence intervals, adjusted comparisons, detailed follow-up, or participant-level event information. They cannot establish causation or precise differences between doses.

The registry record lists secondary outcomes but does not report their results or analysis methods. It also does not report missing-data handling, outcome-specific analysis populations, multiplicity procedures, or interim analyses. These gaps limit assessment of precision, potential bias, and the strength of any outcome conclusions. The stated sample-size illustrations are planning scenarios, not a report of the study’s design rationale or observed power.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Phase I of Histone Deacetylase (HDAC) Inhibitor Panobinostat With Ipilimumab With Unresectable III/IV Melanoma — NCT02032810.
• Registry record last updated 2023-01-20; status last verified 2023-01.
• Results first posted 2019-07-02.
• 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.

18. Record Summary

NCT02032810 is a completed Phase 1 sequential dose-escalation study of panobinostat with ipilimumab in unresectable Stage III or Stage IV melanoma. Enrollment was 17. The dose description lists panobinostat at 5, 10, 15, or 20 mg with ipilimumab at 3 mg/kg; masking is listed as none, and allocation as NA.

The primary endpoint is maximum tolerated dose, with recommended Phase 2 dose also named as an objective. Immune-related ORR, PFS, and OS are listed as secondary outcomes. The record includes adverse-event counts for the 5 mg and 10 mg groups, but does not report a primary endpoint result, DLT counts, or results for the secondary outcomes. The study began on 2014-01-07, and primary completion is dated 2017-09-06.