Carcinoma, Hepatocellular
Conditions
Keywords
Unresectable hepatocellular carcinoma, Lenvatinib, E7080
Brief summary
The primary objective of this study is to assess the safety and tolerability of subsequent systemic treatment of physician's choice (TPC) following the first-line lenvatinib treatment in unresectable hepatocellular carcinoma (uHCC) participants.
Interventions
DRUGLenvatinib
Lenvatinib capsules will be administered orally, once daily in continuous 28-day cycles. Body weight (BW) ≥60 kilograms (kg) - Lenvatinib 12 mg (taken as three 4-mg capsules); BW \<60 kg - Lenvatinib 8 mg (taken as two 4-mg capsules)
Sponsors
Eisai Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Participants must have confirmed diagnosis of unresectable Hepatocellular Carcinoma (uHCC) with any of the following criteria: 1. Histologically or cytologically confirmed diagnosis of uHCC 2. Clinically confirmed diagnosis of uHCC according to American Association for the Study of Liver Diseases criteria, including cirrhosis of any etiology or with chronic hepatitis B or C infection criteria * At least one measurable target lesion regardless if hepatic or non-hepatic according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) meeting the following criteria: 1. Hepatic lesion * The lesion can be accurately measured in at least one dimension as ≥1.0 centimeters (cm) (viable tumor for typical; and longest diameter for atypical), and * The lesion is suitable for repeat measurement, 2. Nonhepatic lesion * Lymph node lesion that measures at least one dimension as ≥1.5 cm in the short axis * Non-nodal lesion that measures ≥1.0 cm in the longest diameter Lesions previously treated with radiotherapy or locoregional therapy must show radiographic evidence of disease progression to be deemed a target lesion. * Participants categorized on the Barcelona Clinic Liver Cancer staging system to Stage B (not applicable for transarterial chemoembolization) or Stage C * Adequate bone marrow function, liver function, blood coagulation function, renal function, and pancreatic function as assessed by laboratory tests. * Adequately controlled blood pressure (BP) with up to 3 antihypertensive agents, defined as BP ≤150/90 millimeters of mercury (mmHg) at Screening and no change in antihypertensive therapy within 1 week prior to Cycle 1/Day 1 * Child-Pugh A * Eastern Cooperative Oncology Group Performance Status of 0 or 1 * Survival expectation of 12 weeks or longer before starting study drug Key
Exclusion criteria
* Imaging findings for HCC corresponding to any of the following: 1. HCC with ≥50% liver occupation 2. Clear invasion into the bile duct 3. Portal vein invasion at the main portal branch (Vp4) * Participants who have received any systemic chemotherapy, including sorafenib, regorafenib or other anti-vascular endothelial growth factor therapy, nivolumab, or any systemic investigational anticancer agents, including lenvatinib, for advanced/uHCC. * Participants who have received any anticancer therapy (including surgery, percutaneous ethanol injection, radio frequency ablation, transarterial \[chemo\] embolization, hepatic intra-arterial chemotherapy, biological, immunotherapy, hormonal, or radiotherapy) or any blood enhancing treatment (including blood transfusion, blood products, or agents that stimulate blood cell production, e.g., granulocyte colony-stimulating factor) within 28 days prior to the first dose of lenvatinib study treatment. * Participants who have not recovered from toxicities as a result of prior anticancer therapy such as the local hepatic injection chemotherapy or any prior therapy for other cancer types. * Significant cardiovascular impairment within 6 months of the first dose of study drug * Prolongation of QT interval corrected for heart rate using Fridericia's correction (QTcF) to \>480 milliseconds (ms) * Gastrointestinal malabsorption or any other condition that might affect the absorption of lenvatinib in the opinion of the investigator * Bleeding or thrombotic disorders or use of anticoagulants such as warfarin or similar agents requiring therapeutic international normalized ratio monitoring * Gastrointestinal bleeding event or active hemoptysis (bright red blood of at least half teaspoon) within 28 days prior to the first dose of lenvatinib study treatment * Gastric or esophageal varices that require treatment * Active malignancy (except for HCC or definitively treated melanoma in-situ, basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix) within the past 36 months * Any history of or current brain or subdural metastases * Participants having \>1+ proteinuria on urine dipstick testing will undergo 24-hour urine collection for quantitative assessment of proteinuria. Participants with urine protein ≥1 grams/24 hour will be ineligible * Arterial-portal venous shunt or arterial-venous shunt preventing proper diagnosis of tumor * Any medical or other condition that in the opinion of the investigator would preclude the participant's participation in a clinical study * Known intolerance to lenvatinib or any of the excipients * Human immunodeficiency virus positive or active infection requiring treatment (except for hepatitis virus) * Any history of drug or alcohol dependency or abuse within the prior 2 years * Major surgery within 3 weeks prior to the first dose of lenvatinib study treatment or scheduled for surgery during the study * Participant has had a liver transplant * Females who are breastfeeding or pregnant at Screening or Baseline * Females of childbearing potential who within 28 days before study entry did not use a highly effective method of contraception or do not agree to use a highly effective method of contraception throughout the entire study period
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | From the first dose of study drug up to 28 days after the last dose of study drug (approximately 3 months) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From first dose date until date of death from any cause (approximately 3 months) | OS is defined as the time from the date of first dose of study treatment to the date of death from any cause. Participants who are lost to follow-up are censored at the last date the participant was known to be alive, and participants who remain alive are censored at the time of data cutoff. OS was to be calculated using Kaplan-Meier estimate and presented with 2-sided 95% confidence interval. |
| Progression-free Survival (PFS) | From first dose date until PD or date of death from any cause (approximately 3 months) | PFS based on modified Response Evaluation Criteria in Solid Tumors (mRECIST) (and including the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 conventions for non-hepatic lesions) is defined as the time from the date of the first dose of first-line lenvatinib treatment to the date of the first documentation of PD, or the date of death during the subsequent systemic TPC, whichever occurs first. PD is defined at least 20% increase (including an absolute increase of at least 5 millimeter \[mm\]) in the sum of diameters of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. PFS was to be calculated using Kaplan-Meier estimate and presented with 2-sided 95% confidence interval. |
| Time to Progression (TTP) | From first dose date until PD (approximately 3 months) | TTP based on mRECIST (and including the RECIST 1.1 conventions for non-hepatic lesions) is defined as the time from the date of the first dose of first-line lenvatinib treatment to the date of the first documentation of disease progression during subsequent systemic TPC. PD is defined at least 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. TTP was to be calculated using Kaplan-Meier estimate and presented with 2-sided 95% confidence interval. |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 3 investigative sites in the United States from 26 April 2018 to 07 January 2019.
Pre-assignment details
A total of 8 participants were enrolled, of these, 6 were screen failures and 2 were treated. Upon completion of lenvatinib treatment, eligible participants were to receive commercially available systemic treatment of physician choice (TPC). However, because of early termination of study no participants received TPC.
Participants by arm
| Arm | Count |
|---|---|
| Lenvatinib Participants received lenvatinib 8 or 12 mg, capsule, orally, once daily in 28 day continuous cycles until PD, development of unacceptable toxicity, participant request, withdrawal of consent, or study termination by the sponsor. BW \>=60 kg - lenvatinib 12 mg (taken as three 4 mg capsules); BW \<60 kg - lenvatinib 8 mg (taken as two 4 mg capsules). | 2 |
| Total | 2 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Study terminated by Sponsor | 2 |
Baseline characteristics
| Characteristic | Lenvatinib |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 2 |
| other Total, other adverse events | 1 / 2 |
| serious Total, serious adverse events | 1 / 2 |
Outcome results
Primary
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Time frame: From the first dose of study drug up to 28 days after the last dose of study drug (approximately 3 months)
Population: The safety analysis set (full analysis set) included all participants who received at least 1 dose of the lenvatinib treatment.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lenvatinib | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 1 Participants |
| Lenvatinib | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 1 Participants |
Secondary
Overall Survival (OS)
OS is defined as the time from the date of first dose of study treatment to the date of death from any cause. Participants who are lost to follow-up are censored at the last date the participant was known to be alive, and participants who remain alive are censored at the time of data cutoff. OS was to be calculated using Kaplan-Meier estimate and presented with 2-sided 95% confidence interval.
Time frame: From first dose date until date of death from any cause (approximately 3 months)
Population: The safety analysis set (full analysis set) included all participants who received at least 1 dose of the lenvatinib treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenvatinib | Overall Survival (OS) | NA months |
Secondary
Progression-free Survival (PFS)
PFS based on modified Response Evaluation Criteria in Solid Tumors (mRECIST) (and including the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 conventions for non-hepatic lesions) is defined as the time from the date of the first dose of first-line lenvatinib treatment to the date of the first documentation of PD, or the date of death during the subsequent systemic TPC, whichever occurs first. PD is defined at least 20% increase (including an absolute increase of at least 5 millimeter \[mm\]) in the sum of diameters of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. PFS was to be calculated using Kaplan-Meier estimate and presented with 2-sided 95% confidence interval.
Time frame: From first dose date until PD or date of death from any cause (approximately 3 months)
Population: The safety analysis set (full analysis set) included all participants who received at least 1 dose of the lenvatinib treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenvatinib | Progression-free Survival (PFS) | NA months |
Secondary
Time to Progression (TTP)
TTP based on mRECIST (and including the RECIST 1.1 conventions for non-hepatic lesions) is defined as the time from the date of the first dose of first-line lenvatinib treatment to the date of the first documentation of disease progression during subsequent systemic TPC. PD is defined at least 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. TTP was to be calculated using Kaplan-Meier estimate and presented with 2-sided 95% confidence interval.
Time frame: From first dose date until PD (approximately 3 months)
Population: The safety analysis set (full analysis set) included all participants who received at least 1 dose of the lenvatinib treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenvatinib | Time to Progression (TTP) | NA months |