| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Unresectable Hepatocellular Carcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the Liver that cannot be treated with surgery |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019828 |
| E.1.2 | Term | Hepatocellular carcinoma non-resectable |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of the study is to compare overall survival (OS) in subjects treated with lenvatinib versus sorafenib as a first-line treatment in subjects with unresectable heptocellular carcinoma (HCC) |
|
| E.2.2 | Secondary objectives of the trial |
- Compare PFS, TTP and ORR of subjects treated with lenvatinib vs sorafenib using mRECIST
- Compare safety and tolerability of subjects treated with lenvatinib versus sorafenib
- Characterize the PK of lenvatinib using the population approach
- Assess the PK/PD relationship between exposure and efficacy/ safety
- Compare the impact of treatment on Health Related Quality of Life (HRQoL) of subjects treated with lenvatinib versus sorafenib using the European Organisation for Research and
Treatment of Cancer (EORTC) QLQ-C30 and HCC-specific EORTC QLQ-HCC-18 questionnaire |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Confirmed diagnosis of unresectable HCC with any of the following criteria: histologically or cytologically confirmed diagnosis of HCC, diagnosis of HCC according to the AASLD criteria, including cirrhosis of any etiology or with chronic hepatitis B or C infection criteria
- At least 1 measurable target lesion according to mRECIST meeting the criteria set out in the protocol for the different lesions
-Subjects categorized to stage B or stage C based on BCLC staging system
- Adequate bone marrow function defined as
o Absolute neutrophil count (ANC) ≥ 1.5 × 10e9/L
o Hemoglobin (Hb) ≥ 8.5 g/dL
o Platelet count ≥ 75 × 10e9/L
- Adequate liver function
o Albumin ≥ 2.8 g/dL
o Bilirubin ≤ 3.0 mg/dL
o Aspartate aminotransferase (AST), alkaline phosphatase (ALP), and alanine aminotransferase (ALT) ≤ 5 × the upper limit of normal (ULN)
- Adequate blood coagulation function, defined as international normalized ratio (INR) ≤ 2.3
- Adequate renal function, defined as creatinine clearance > 40 mL/min calculated per the Cockcroft and Gault formula
- Adequate pancreatic function, defined as amylase and lipase ≤ 1.5 × ULN
- Adequately controlled blood pressure (BP) with up to 3 antihypertensive agents, defined as BP ≤
150/90 mm Hg at Screening and no change in antihypertensive therapy within 1 week prior to the Cycle1/Day1.
- Child-pugh score A
- ECOG-PS 0 or 1
- Survival expectation of 12 weeks or longer after starting study drug
- Males or females aged at least 18 years at time of informed consent
- Females must not be lactating or pregnant at Screening or Baseline. A seperate baseline assessment is required if a negative pregnancy test was obtained more then 72 hours before the first dose of study drug.
- All females will be considered to be of childbearing potential unless they are postmenopausal or have been sterilized surgically.
- Females of childbearing potential must not have had unprotected sexual intercourse within 30 days before study entry and must agree to use a highly effective method of contraception (e.g., total abstinence, an intrauterine device, a double-barrier method, a contraceptive implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the entire study period and for 30 days after study drug discontinuation. If currently abstinent, the subject must agree to use a double barrier method as described above if she becomes sexually active during the study period or for 30 days after study drug discontinuation. Females who are using hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product for at least 4 weeks before dosing and must continue to use the same contraceptive during the study and for 30 days after study drug discontinuation.
- Male subjects must have had a successful vasectomy (confirmed azoospermia) or they and their female partners must meet the criteria above. No sperm donation is allowed during the study period and for 30 days after study drug discontinuation.
- Provide written informed consent
- Willing and able to comply with all aspects of the protocol |
|
| E.4 | Principal exclusion criteria |
- Imaging findings for HCC corresponding to any of the following: HCC with greater or equal 50% liver occupation, clear invasion of the bile duct, portal vein invasion at the main portal branch.
- Subjects who have received any systemic chemotherapy or any systemic investigational anticancer agents, including lenvatinib, for advanced/unresectable HCC. Note: Subjects who have received local hepatic injection chemotherapy are eligible.
- Subjects 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 [G-CSF])
within 28 days prior to randomization.
- Subjects who have not recovered from toxicities as a result of prior anticancer therapy, except alopecia and infertility. Recovery is defined as < Grade 2 severity per Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE v4.0).
- Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or stroke within 6 months of the first dose of study drug, or cardiac arrhythmia requiring medical treatment at screening.
- Prolongation of QTc interval to > 480 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 requiring therapeutic INR monitoring, eg, warfarin or similar agents. Treatment with low molecular weight heparin and factor X inhibitors which do not require INR monitoring is permitted. Antiplatelet agents are prohibited throughout the study.
- Gastrointestinal bleeding event or active hemoptysis (bright red blood of at least 0.5 teaspoon) within 28 days prior to randomization.
- Gastric or esophageal varices that require interventional treatment within 28 days prior to randomization. Prophylaxis with pharmacologic (eg nonselective beta-blocker) therapy is permitted.
- 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.
-Subjects whose only target lesion(s) is in bone.
- Meningeal carcinomatosis.
- Any history of, or current, brain or subdural metastases.
- Subjects having > 1 + proteinuria on urine dipstick testing will undergo 24 h urine collection for quantitative assessment of proteinuria. Subjects with urine protein ≥ 1 g / 24 h will be ineligible.
- Surgical arterial-portal venous shunt or arterial-venous shunt.
- Any medical or other condition that in the opinion of the investigator would preclude the subject’s participation in a clinical study.
- Known intolerance to lenvatinib or sorafenib (or any of the excipients).
- Human immunodeficiency virus (HIV) positive or active infection requiring treatment (except for hepatitis virus).
- Any history of drug or alcohol dependency or abuse within the prior 6 months.
- Any subject who cannot be evaluated by either triphasic liver CT or triphasic liver MRI because of allergy or other contraindication to both CT and MRI contrast agents.
- Major surgery within 3 weeks prior to randomization or scheduled for surgery during the study.
- Subject has had a liver transplant. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall survival (OS) measured from the date of randomization until date of death from any cause. Subjects who are lost to follow-up will be censored at the last date the subject was known to be alive, and subjects who remain alive will be censored at the time of data cutoff |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- PFS defined as the time from the date of randomization to the date of first documentation of disease progression, or date of death, whichever occurs first.
- TTP, defined as the time from the date of randomization to the date of first documentation of disease progression.
- ORR defined as the proportion of subjects who have best overall response of complete response (CR) or partial response (PR).
- HRQoL will be assessed using EORTC QLQ-C30, the HCC-specific questionnaire (HC-18), and a generic instrument EQ-5D-3L.
- Plasma PK lenvatinib exposure parameters. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 33 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Belgium |
| Canada |
| China |
| France |
| Germany |
| Hong Kong |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Malaysia |
| Philippines |
| Poland |
| Russian Federation |
| Singapore |
| Spain |
| Taiwan |
| Thailand |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 39 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 39 |
Print
