Study of (1) Everolimus, (2) Estrogen Deprivation Therapy (EDT) With Leuprolide + Letrozole and (3) Everolimus + EDT in Patients With Unresectable Fibrolamellar Hepatocellular Carcinoma (FLL-HCC): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of (1) Everolimus, (2) Estrogen Deprivation Therapy (EDT) With Leuprolide + Letrozole and (3) Everolimus + EDT in Patients With Unresectable Fibrolamellar Hepatocellular Carcinoma (FLL-HCC) (NCT01642186), a randomized phase 2 study. The primary outcome is Efficacy Endpoints for Part 1 of the Study is Progression-free Survival at 6 Months (PFS6).

2. Clinical Question

The study asks whether these treatment strategies are associated with different observed progression-free outcomes in a population with a cancer described in the registry summary as having no effective standard treatment when it cannot be removed by surgery. That statement provides the registry’s context for the research question; it does not establish the comparative effects of the study treatments.

Random assignment is intended to make treatment groups more comparable at the start of a study, on average. The registry record identifies randomized allocation, but does not report the method used to generate or conceal the allocation sequence. It also does not give the primary endpoint counts or a statistical comparison across the arms. Consequently, the clinical question is clear, but the posted record does not provide the outcome information needed to answer it.

3. Trial Design

The registry describes a randomized, open-label, three-arm phase II study with a crossover model. The interventions were everolimus; letrozole plus leuprolide; and everolimus combined with letrozole and leuprolide. Enrollment is listed as 28. The study status is completed. The recorded start date is 2012-07-12, and the primary completion date is 2021-07-16.

Open-label means the registry does not describe masking of treatment assignment. Participants and investigators therefore were not reported as blinded to the assigned treatment. This matters when interpreting outcomes that may involve investigator judgment, including the endpoint’s clinical-progression component. The endpoint also includes radiographic progression and death, but details of assessment procedures are not reported in the registry record.

The registry identifies the study model as crossover, but does not report the crossover sequence, timing, eligibility for crossover, or how data after crossover were handled in the primary analysis. Those details are important for understanding which treatment exposure each participant contributed to an endpoint and how comparisons were constructed. The record does not explain whether the primary endpoint analysis used only Part 1 data or how that part relates to any later treatment period.

Arm descriptions include dosing information for the drugs, but the registry record does not provide a complete statistical analysis plan or a full account of treatment administration and adherence. The enrollment figure should not be interpreted as the number analyzed for the primary endpoint: analyzed group sizes and the analysis population are not reported in the registry record. Nor does the record report a formal sample-size justification or the intended power for the trial’s own design.

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:

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 Efficacy Endpoints for Part 1 of the Study is Progression-free Survival at 6 Months (PFS6), measured over 6 months.

The primary endpoint is described as efficacy for Part 1 measured by progression-free survival at 6 months (PFS6), with the unit reported as participants. The definition identifies a progression event as the first evidence of radiographic disease progression, clinical progression as determined by study investigators, or death. Imaging performed at 6 months is used to determine PFS6. The registry record does not report the number of participants meeting the PFS6 outcome in any arm.

In general, a fixed-time progression-free endpoint asks whether a participant has experienced a specified event by a particular assessment time. It can make the outcome clinically interpretable as a status at a defined time, rather than reporting only a time-to-event summary. This endpoint combines imaging-based assessment, investigator judgment, and death, so its interpretation depends on how those components were assessed and how missing or unevaluable assessments were handled. Those procedures are not reported in the registry record.

The registry also lists median progression-free survival and median overall survival among secondary outcomes, along with stable disease, adverse events or toxicity, and tissue biomarkers collected. Their results are not reported in the registry record for this analysis. A PFS6 count, a median time-to-event measure, and a stable-disease count describe different aspects of outcomes and should not be treated as interchangeable.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The methods information in the registry is limited. It describes randomized allocation, no masking, a crossover model, and a primary endpoint expressed as a count of participants. It does not report the statistical model used for the primary analysis, the planned contrast among arms, the handling of missing assessments, or the analysis population. The methods below explain general statistical concepts relevant to this design; they do not claim that a particular method was used in this trial.

What does randomization contribute?

In general, randomization assigns participants to treatment groups by chance. It can reduce systematic differences between groups at baseline, though it does not guarantee balance in a small study. The registry identifies the allocation as randomized but does not describe sequence generation, allocation concealment, stratification, or the procedures used to implement randomization. Those features cannot be inferred from the word randomized alone.

What does the open-label design mean?

In general, an open-label design means treatment assignment is known to participants and study personnel. Knowledge of assignment can influence care, reporting, follow-up, or outcome assessment. This consideration is particularly relevant when an endpoint includes clinical progression determined by investigators. The PFS6 definition also includes radiographic progression or death, but the registry does not report whether imaging was assessed by blinded reviewers or according to a specified review process. The record therefore does not permit an assessment of how much, if at all, knowledge of assignment could have affected endpoint classification.

How should a participant count be interpreted?

The primary outcome is categorized as a count of participants. A count is not, by itself, an estimate of the chance of an outcome: it needs an appropriate denominator and a clear definition of who was eligible for analysis. Comparisons between groups also need a stated statistical approach and measures of uncertainty. The record provides neither primary outcome counts nor their analysis denominators, so an outcome proportion or between-arm estimate cannot be described from it. No values should be inferred from the enrollment or safety figures.

What can confidence intervals and p-values tell readers?

In general, a confidence interval describes the range of effect estimates compatible with the data and the assumptions of the analysis. Its width conveys precision; it does not by itself determine whether a result is clinically important. A p-value evaluates how compatible the observed data are with a specified null hypothesis under the analysis assumptions. It does not measure the probability that a treatment works, nor does it describe the size of an effect. Neither confidence intervals nor p-values for the primary endpoint are reported in the registry record.

Why does the crossover model need more detail?

In general, crossover designs can expose a participant to more than one treatment over time. Interpretation depends on sequence, timing, the outcomes used in each period, and whether effects from an earlier period could carry into a later one. The registry labels the model crossover but does not describe these features or the primary analysis’s handling of them. It is therefore not possible to determine how crossover affected the primary comparison or whether the PFS6 endpoint was assessed before or after a crossover for any participant.

What does the sample-size illustration represent?

The stated sample-size assumptions describe a planning illustration based on an observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is described as a stated fraction of the observed effect. For time-to-event tables, the assumptions specify a total event count; for other outcomes, they specify participants per arm. These are planning assumptions, not the trial’s own design justification and not observed power. The registry record does not report a numerical illustration, the observed effect used for it, or a formal sample-size rationale for the study. Such calculations should not be interpreted as evidence that the trial had adequate power or as a substitute for observed treatment-effect estimates.

In general, over-dispersion occurs when variation in count data exceeds what a simple statistical model assumes. If present and ignored, uncertainty estimates can be too optimistic. The registry does not report a model for count outcomes or evidence about over-dispersion; this general consideration cannot be used to infer what analysis was performed.

10. Multiplicity, Missing Data and Analysis Populations

The registry flags the primary outcome as having several categories or time points and not being reduced to one comparison. It also lists 0 analyses. As a result, the record does not identify a single reported primary contrast or show how any multiple comparisons or repeated endpoint assessments were handled.

In general, multiplicity arises when several hypotheses or outcome comparisons are examined. Without an appropriate prespecified strategy, the chance of at least one apparently unusual result can increase. A strategy might define a primary comparison in advance or adjust inference across a set of tests, but the registry record does not report whether either approach was planned or used. It would be inappropriate to assume a particular correction or to infer one from the phase II label.

The record does not report missing-data counts, reasons for missingness, rules for unevaluable imaging, or an imputation or censoring strategy for the primary outcome. These details matter because the PFS6 assessment depends on imaging at 6 months and includes investigator-determined clinical progression. The analysis population is also not reported: it is unclear whether the primary analysis was based on all randomized participants, participants who started treatment, or another defined group.

Although the registry includes a crossover model, it does not report how crossover was handled in analyses, or whether outcome assessment after crossover contributed to the primary endpoint. It also does not provide a statistical analysis plan describing endpoint hierarchy, stopping rules, or interim analyses. These items are not reported in the registry record; their absence from the record does not establish what may have been specified elsewhere.

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 5% reporting threshold.

Most frequent non-serious adverse event terms

The registry safety figures list serious adverse-event counts and other adverse-event counts by arm. The at-risk counts for serious events are 9 in Arm A, 9 in Arm B, and 10 in Arm C; the affected counts are 0 in each arm. For other adverse events, the at-risk counts are 9, 9, and 10, and the affected counts are 9, 9, and 9. The death counts listed by arm are 0, 2, and 2.

These are counts, not adjusted comparisons. The record does not provide event types for serious adverse events, severity details for the other-event counts, exposure time, attribution to treatment, or statistical comparisons. It lists no top serious-event terms. Therefore, the figures should be read as registry-reported descriptive counts rather than as a complete account of all harms or as evidence that one treatment has a safer profile.

The death counts are listed separately and should not automatically be interpreted as treatment-related deaths or as the number of deaths due to progression. The registry record does not report cause or timing in these figures. Nor does it explain how the safety denominators relate to the primary efficacy analysis population.

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

The record does establish that a randomized, open-label phase II study evaluated three strategies in patients with unresectable fibrolamellar hepatocellular carcinoma. It specifies the primary endpoint for Part 1 as PFS6 and defines progression events to include radiographic progression, clinical progression determined by investigators, or death. The registry also reports selected safety counts and secondary outcomes that were intended to be assessed.

However, the registry record does not report the primary outcome counts or comparative efficacy estimates. It therefore cannot show how many participants in each arm were progression-free at 6 months, how the arms compared, or how precise any difference may have been. No conclusion that a treatment did or did not work follows from the absence of posted efficacy results.

The safety counts have similarly limited meaning. They describe affected participants and deaths by arm, but lack the clinical details and analysis needed to attribute events to treatment or compare risk reliably. Counts alone do not account for differences in exposure or follow-up, and the record does not provide those details.

Completion status indicates that the study is recorded as completed; it does not supply missing efficacy findings or establish that all planned analyses are available in the registry. The study’s crossover label also does not, on its own, explain the treatment sequence or the analysis. The distinction is important: the design and endpoint definition describe what investigators set out to study, while results and their uncertainty are needed to assess what the observations show.

13. Why This Trial Matters Statistically

Statistically, this study raises a useful interpretation issue: a clearly named endpoint is not enough to evaluate a trial when the endpoint results and analysis are absent. PFS6 is defined with a fixed assessment time and specified progression events, but the registry does not report the participant counts needed to interpret that endpoint or compare treatment arms.

The three treatment strategies also make the choice of comparison important. A randomized study can support meaningful comparisons when the target contrast and analysis are clearly specified. Here, the record identifies three arms but does not report a single primary contrast, and it flags multiple categories or time points without reducing the outcome to one comparison. Without the analysis plan and results, readers cannot tell which comparison was intended to carry the main inference.

The crossover model adds another design feature that needs explanation. In general, treatment sequence and timing can shape how exposure and outcomes are interpreted. Since those details are not reported in the registry record, the model label alone is insufficient to understand how the primary endpoint was analyzed.

The record also illustrates why descriptive safety counts should be kept separate from comparative conclusions. The counts give some information by arm, but not the event details, exposure, attribution, or inference required for a safety comparison. Taken together, these limitations make the distinction between a registered research question and a reported statistical result especially important. The record documents the former, but does not provide enough outcome evidence to answer the latter.

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.

Several limitations arise from the information recorded for this trial. The primary endpoint is defined, but its arm-specific results and analysis are not reported in the registry record. The record lists enrollment as 28, while the safety figures use arm-specific at-risk counts; it does not report the primary endpoint denominators or explain how participants moved through enrollment, treatment, and analysis.

The registry describes the study as crossover without reporting the sequence, timing, crossover rules, or treatment of post-crossover observations. It identifies no masking, and the endpoint includes clinical progression determined by investigators. The record does not explain whether radiographic assessments were independently reviewed or how outcome assessment was standardized.

The registry does not report the analysis population, missing-data procedures, handling of unevaluable imaging, or the planned method for comparing the three arms. It also does not describe a multiplicity strategy despite noting several categories or time points. The listed sample-size assumptions concern a planning illustration, not a reported trial-specific design justification; the record does not provide the numerical illustration or its input effect.

Safety reporting is also limited to counts. The record does not provide serious-event terms, causes or timing of deaths, treatment attribution, exposure duration, or a comparative safety analysis. These limitations restrict interpretation of the registry record; they do not establish that the study did not collect further information.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Study of (1) Everolimus, (2) Estrogen Deprivation Therapy (EDT) With Leuprolide + Letrozole and (3) Everolimus + EDT in Patients With Unresectable Fibrolamellar Hepatocellular Carcinoma (FLL-HCC) — NCT01642186.
• Registry record last updated 2022-12-29; status last verified 2021-07.
• Results first posted 2022-12-29.
• 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

NCT01642186 is a completed, randomized, open-label phase II study with a crossover model, sponsored by Memorial Sloan Kettering Cancer Center. It enrolled 28 and evaluated everolimus, leuprolide plus letrozole, and the combination in unresectable fibrolamellar hepatocellular carcinoma. The recorded start date is 2012-07-12, and the primary completion date is 2021-07-16.

The primary endpoint for Part 1 is PFS6, defined using radiographic progression, investigator-determined clinical progression, or death. The registry record does not report primary endpoint results, comparative efficacy estimates, confidence intervals, or p-values. It records safety counts by arm, but does not provide the event detail and analysis needed for comparative interpretation. It also does not report the primary analysis population, missing-data procedures, multiplicity strategy, or crossover analysis details.