Study of Lenvatinib (E7080) in Participants With Advanced Hepatocellular Carcinoma (HCC): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Lenvatinib (E7080) in Participants With Advanced Hepatocellular Carcinoma (HCC) (NCT00946153), a non-randomized phase 1, phase 2 study. The primary outcome is Phase 1: Maximum Tolerated Dose (MTD) of Lenvatinib.

2. Clinical Question

3. Trial Design

NCT00946153 is identified as a Phase I/II study of lenvatinib, or E7080, in participants with advanced hepatocellular carcinoma. The registry record lists the study as completed and reports enrollment of 66. The study began on 2009-07-24, with primary completion on 2014-06-15. Eisai Co., Ltd. is listed as the sponsor.

The allocation is described as non-randomized, masking as none, and the model as single-group. These design labels matter when interpreting the dose groups: comparisons across them are not randomized comparisons, and the registry record specifically cautions that the arms are not a like-for-like control comparison. No separate control intervention is listed. The presence of groups at different doses does not, by itself, establish a causal comparison between doses.

The primary outcome is a Phase 1 maximum tolerated dose (MTD) measure, expressed in milligrams. The registry defines MTD by the frequency of dose-limiting toxicities (DLTs) at a dose level: the highest dose level at which no more than 1 of 6 participants had a DLT. The timeframe is up to 28 days, identified as Cycle 1. The numerical MTD finding is not reported in the registry record.

Outcomes listed for Phase 1 include best overall response, objective response rate, and disease control rate by investigator assessment. Phase 2 outcomes include progression-free survival, objective response rate, and disease control rate by independent review assessment, as well as overall survival. These outcome names identify what was to be assessed; definitions, analysis details, and numerical efficacy results are not reported in the registry record. The registry lists 9 outcome measures and 0 analyses.

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.

Phase 1

Phase 2

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety analysis set (SAS) included all participants who received at least 1 dose of lenvatinib, and had at least 1 post baseline safety evaluation.

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.

Population: All participants who received at least 1 dose of lenvatinib, and had at least 1 post baseline efficacy evaluation.

6. Primary Endpoint

The registry lists the primary outcome as Phase 1: Maximum Tolerated Dose (MTD) of Lenvatinib, measured over Up to 28 days (Cycle1).

The primary endpoint is the Phase 1 maximum tolerated dose of lenvatinib, measured in milligrams. The registry sets its assessment timeframe as up to 28 days during Cycle 1. It defines the MTD as the highest dose level at which no more than 1 of 6 participants had a dose-limiting toxicity. This is a dose-finding endpoint, not a direct measure of tumor response or survival.

The registry’s DLT definition includes specified severe toxicities, such as grade 4 or higher hematologic toxicity, grade 3 or higher nonhematologic toxicity, and grade 4 hypertension uncontrolled by antihypertensive drugs. It also specifies thresholds and monitoring rules for liver enzyme elevations, proteinuria, and gastrointestinal symptoms. Some events are explicitly excluded from being considered DLTs under the definition, including grade 3 proteinuria by dipstick and gastrointestinal symptoms that were managed with supportive therapies.

General statistical context: a dose-finding endpoint helps describe tolerability under a stated rule and assessment window. Its interpretation depends on which events count, when they are assessed, and which participants enter the safety analysis. The registry defines the safety analysis set as participants who received at least 1 dose of lenvatinib and had at least 1 post-baseline safety evaluation. However, the numerical MTD result, dose-level decision details, and participant counts used in that determination are not reported in the registry record. The endpoint definition therefore explains the intended decision rule but does not establish which dose met it.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the dose-finding rule mean?

The primary endpoint uses a rule to identify the highest dose level at which no more than 1 of 6 participants had a DLT. The DLT assessment window is up to 28 days during Cycle 1. This is a threshold-based endpoint: the classification depends on the specified toxicity criteria and the observed number of participants meeting them at each dose level. The registry record states the rule but does not report the resulting MTD or the dose-level DLT counts used to apply it.

The DLT definition is specific. It includes grade 4 or higher hematologic toxicity and grade 3 thrombocytopenia requiring blood transfusion; grade 3 or higher nonhematologic toxicity; and grade 4 hypertension uncontrolled by antihypertensive drugs. It also includes AST/ALT greater than 10.0 times the upper limit of normal, proteinuria 4+ by urine dipstick, and proteinuria greater than 3.5 g for 24 hours. Proteinuria 3+ by dipstick was to be monitored by 24-hour urine collection. Uncontrollable grade 3 or higher diarrhea, vomiting, or nausea despite maximal supportive therapies, and abnormal clinical laboratory values requiring no treatment, are also described in the definition. Grade 3 proteinuria by dipstick and gastrointestinal symptoms managed with supportive therapies are explicitly not considered DLTs.

How should the design affect interpretation?

General statistical context: randomization is used to make treatment groups comparable on average with respect to measured and unmeasured characteristics. This study is recorded as non-randomized and single-group, and the registry cautions that its arms are not a like-for-like control comparison. Dose groups may therefore differ for reasons other than dose, and comparisons between them cannot be interpreted as if dose had been randomly assigned. The record does not report a controlled comparison that would separate dose effects from other differences.

Masking is listed as none. This is relevant context for outcomes assessed by investigators, since assessment without masking can be more susceptible to expectations or knowledge of treatment. Phase 2 response and disease-control outcomes are listed as assessed by independent review, but the registry record does not report further details of that review process. It also does not report the outcome definitions or procedures for resolving differences in assessment.

What can be inferred from the listed outcomes?

The study lists Phase 1 best overall response, objective response rate, and disease control rate by investigator assessment. The Phase 2 list includes progression-free survival, objective response rate, disease control rate by independent review, and overall survival. These endpoints address different questions: response and disease control describe tumor assessments, while progression-free survival and overall survival are time-to-event outcomes. General statistical context: a time-to-event analysis typically accounts for the timing of events and may also need to address participants whose event time is not observed during follow-up. The registry record does not report the analysis methods, censoring rules, follow-up details, or numerical results for these outcomes.

The registry reports 9 outcome measures and 0 analyses. No p-values, confidence intervals, or effect estimates are reported for the outcomes in the registry record of this record. The statistical analysis plan, including any model specifications or handling of repeated assessments, is not reported in the registry record. It is therefore not possible to determine which statistical procedures were used for the listed outcomes.

What do confidence intervals and over-dispersion mean in general?

General statistical context: a confidence interval communicates uncertainty around an estimate under the assumptions of a specified analysis. A narrow interval indicates greater precision than a wide interval, while neither interval width nor the estimate alone establishes clinical importance. No confidence intervals are reported for the outcomes described in this record.

General statistical context: over-dispersion occurs when observed variation is greater than a statistical model expects. If an analysis assumes less variability than the data contain, uncertainty may be understated and inference can be too optimistic. The registry record does not report whether over-dispersion was assessed or relevant to any analysis. It does not report an analysis model from which that question could be evaluated.

What are the limits of planning illustrations?

General statistical context: sample-size planning depends on assumptions about the effect to detect, variability, significance level, allocation, and analysis. The record describes planning illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. For time-to-event outcomes, the stated planning quantity is total events; for other outcomes it is participants per arm. These are planning illustrations, not observed power and not evidence that the original study was designed using those assumptions. The registry record does not report the trial’s own sample-size justification.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists multiple outcomes across Phase 1 and Phase 2, including response, disease control, progression-free survival, overall survival, and the primary MTD endpoint. Several outcomes are assessed in more than one phase, with investigator assessment specified for the Phase 1 response measures and independent review specified for the Phase 2 response and disease-control measures. The registry record does not report whether the analyses were prespecified in a statistical analysis plan or how the multiplicity of outcomes was addressed.

General statistical context: when many endpoints or comparisons are tested, the chance of at least one apparently unusual result can increase. Prespecified testing strategies or other multiplicity adjustments can help define how findings should be interpreted. Whether such a strategy was used in this study is not reported in the registry record. The record lists 9 outcome measures and 0 analyses; it does not provide p-values or other inferential results for assessing a multiplicity procedure.

The registry record does not report how missing outcome data were handled, whether participants who discontinued were followed for later outcomes, or how censoring was defined for time-to-event outcomes. It also does not report imputation methods or sensitivity analyses. These omissions limit assessment of how incomplete observations may affect estimates.

The primary endpoint identifies a safety analysis set as participants who received at least 1 dose of lenvatinib and had at least 1 post-baseline safety evaluation. The record does not report the actual number in that set or how participants outside it were handled in the primary MTD assessment. Analysis populations for the efficacy outcomes are not reported in the registry record. The listed adverse-event group denominators should therefore be read as the group-specific counts reported, not assumed to represent every enrolled participant or a common analysis population.

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: pneumonia (33.3%), hepatic encephalopathy (33.3%), hepatic failure (20.0%), tumour haemorrhage (20.0%), haematemesis (16.7%).

The registry reports serious adverse events, other adverse events, and deaths separately for the listed groups. In Phase 1 Group 1 at 12 mg, serious adverse events affected 2 of 6 participants and other adverse events affected 6 of 6; 0 deaths are reported. In Phase 1 Group 1 at 16 mg, the corresponding counts are 2 of 3, 3 of 3, and 0 deaths. In Phase 1 Group 2 at 8 mg, the counts are 3 of 6, 6 of 6, and 1 death; at 12 mg, they are 3 of 5, 5 of 5, and 1 death. In Phase 2 at 12 mg, serious adverse events affected 22 of 46 participants, other adverse events affected 46 of 46, and 32 deaths are reported.

The listed serious adverse event terms include Pneumonia and Hepatic encephalopathy, each at 33.3%; Hepatic failure and Tumour haemorrhage, each at 20.0%; and Haematemesis and Hyperbilirubinaemia, each at 16.7%. The denominator and counting method for these percentages are not reported in the registry record.

These are descriptive counts, not randomized comparisons. The death counts do not establish cause, and the registry record does not state that deaths were treatment-related. General statistical context: event counts are interpreted in light of the group size, event definition, observation period, and analysis population. The information reported does not provide all of those details for each safety measure.

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

This study addresses dose finding and a range of safety and efficacy questions for lenvatinib in advanced HCC. Its primary endpoint is a Phase 1 MTD defined by a DLT rule during Cycle 1, up to 28 days. The registry record supplies the rule and lists dose groups, but it does not report the numerical MTD result or the DLT counts needed to see how the rule was applied. The primary endpoint’s intended meaning can be described, but its result cannot be recovered from the information reported.

The record also lists response and disease-control outcomes, progression-free survival, and overall survival. The listed assessment methods vary by phase: investigator assessment is named for Phase 1 response measures, while independent review is named for Phase 2 progression-free survival, response, and disease control. No numerical efficacy findings or uncertainty estimates are reported in the registry record. The outcome list therefore does not show the size, precision, or direction of any efficacy result.

Safety counts are available for the listed groups, including serious adverse events and deaths. They describe events recorded within those groups, but do not establish that the intervention caused an event. They also do not provide a randomized basis for comparing dose groups. The study is non-randomized, single-group, and unmasked, and the registry explicitly cautions that the arms are not a like-for-like control comparison.

General statistical context: an observed result, if reported, would need to be considered alongside its design, measurement definitions, missing-data handling, and uncertainty. A result from a single-group study cannot by itself provide the same controlled comparison as a randomized trial. In this record, the absence of numerical efficacy results is a limit on interpretation, not evidence of either benefit or lack of benefit. No medical conclusion should be drawn from the outcome names or event counts alone.

13. Why This Trial Matters Statistically

This study is statistically notable for pairing a Phase 1 dose-finding endpoint with Phase 2 outcomes in a non-randomized, single-group design. The primary endpoint is not a conventional comparison between treatment and control. It is a rule-based dose classification: the highest dose level at which no more than 1 of 6 participants had a DLT during the specified Cycle 1 window. Understanding the threshold and the detailed DLT definition is essential to understanding what the endpoint was intended to measure.

The design also illustrates why dose groups should not automatically be read as comparative arms. The registry lists several Phase 1 dose groups and a Phase 2 group, but allocation is non-randomized and the record cautions that the arms are not like-for-like controls. Comparisons of their adverse-event counts are descriptive. Differences may reflect group composition or other factors as well as dose, and no randomized contrast is reported.

The outcome list spans investigator-assessed and independently reviewed measures, as well as response and time-to-event outcomes. Those measures require distinct definitions and analysis choices. The registry record does not report the detailed methods, missing-data handling, multiplicity strategy, or numerical results needed to evaluate those choices. It does report a safety analysis set definition for the primary endpoint, which helps clarify the intended population, but the actual size of that set is not reported.

General statistical context: a registry entry is most informative when the outcome definition, analysis population, estimate, and uncertainty are all available. This record offers important design and endpoint definitions, while its reported numerical outcomes are limited. The distinction between an endpoint being listed and a result being reported is particularly important when interpreting this study.

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 main limitation for interpreting results is that the registry record does not report a numerical MTD finding or numerical results for the listed efficacy outcomes. Without those estimates, their magnitude and precision cannot be assessed. The record also does not report confidence intervals, p-values, or detailed analysis results for the outcomes.

The non-randomized, single-group design and absence of masking limit the interpretation of comparisons across listed dose groups. The registry itself cautions that the groups are not like-for-like control comparisons. There is no separate control intervention listed, so the record does not provide a randomized treatment contrast.

For the primary endpoint, the registry gives a detailed DLT definition and identifies the safety analysis set, but the actual MTD result, dose-level DLT counts, and number of participants in the safety analysis set are not reported. For safety, group-specific counts are listed, but the registry record does not report the observation period or denominator and counting method for the serious-event term percentages. The death counts do not identify cause.

For the efficacy outcomes, definitions, analysis populations, missing-data procedures, censoring rules, and statistical models are not reported in the registry record. The registry does not report a multiplicity strategy or the trial’s own sample-size justification. These details are needed to assess the robustness and precision of any endpoint estimates, and their absence prevents a fuller statistical appraisal.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Study of Lenvatinib (E7080) in Participants With Advanced Hepatocellular Carcinoma (HCC) — NCT00946153.
• Registry record last updated 2019-02-01; status last verified 2018-07.
• Results first posted 2019-02-01.
• 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

NCT00946153, titled Study of Lenvatinib (E7080) in Participants With Advanced Hepatocellular Carcinoma (HCC), is listed as a Phase I/II study sponsored by Eisai Co., Ltd. The registry reports a start date of 2009-07-24, primary completion on 2014-06-15, completed status, and enrollment of 66. The condition is hepatocellular carcinoma.

The study is recorded as non-randomized, unmasked, and single-group. Lenvatinib is the listed intervention. The primary Phase 1 outcome is maximum tolerated dose, with a DLT-based definition and a timeframe of up to 28 days during Cycle 1. Secondary outcomes include Phase 1 investigator-assessed response measures and Phase 2 independently reviewed progression-free survival, response, and disease-control measures, plus overall survival.

The registry lists 9 outcome measures and 0 analyses. It reports descriptive safety counts by group but does not report the numerical primary endpoint result or numerical efficacy results. The registry record therefore supplies the design and endpoint framework, while leaving key outcome estimates and analysis details unreported.