Study of Lenvatinib (E7080) in Participants With Advanced Hepatocellular Carcinoma (HCC)

• Sponsor: Eisai Co., Ltd.
• Information provided by (Responsible Party): Eisai Inc. ( Eisai Co., Ltd. )

Tracking Information

• First Submitted Date: July 23, 2009
• First Posted Date: July 24, 2009
• Results First Submitted Date: August 27, 2018
• Results First Posted Date: February 1, 2019
• Last Update Posted Date: February 1, 2019
• Actual Study Start Date: July 24, 2009
• Actual Primary Completion Date: June 15, 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 27, 2018)

• Phase 1: Maximum Tolerated Dose (MTD) of Lenvatinib [ Time Frame: Up to 28 days (Cycle1) ]
  The MTD was defined as the highest dose level at which no more than 1 of 6 participants had a dose limiting toxicities (DLT). DLT was defined as any of the following events: grade 4 or higher hematologic toxicity or grade 3 thrombocytopenia that required blood transfusion, grade 3 or higher nonhematologic toxicity, grade 4 hypertension uncontrolled by antihypertensive drug(s), aspartate aminotransferase/alanine aminotransferase (AST/ALT) greater than (>) 10.0*upper limit of normal (ULN), proteinuria 4+ by urine dipstick, proteinuria 3+ by urine dipstick was to be monitored by 24-hour urine collection, proteinuria >3.5 gram (g) for 24 hours, diarrhea/vomiting/nausea of grade 3 or higher that was uncontrollable despite maximal supportive therapies and abnormal clinical laboratory values that required no treatment, grade 3 proteinuria by dipstick, diarrhea/vomiting/nausea that was managed with supportive therapies were not considered as DLT.
• Phase 2: Time to Progression (TTP) by Independent Review Assessment [ Time Frame: From day of registration to the day when PD was first confirmed (approximately up to 6.1 years) ]
  TTP was defined as the time from the date of registration to the date when progressive disease (PD) was first confirmed. PD was evaluated according to modified response evaluation criteria in solid tumors (mRECIST) by an independent imaging review. PD was defined as at least a 20 percent (%) increase in the sum of long diameter (LD) of target lesions as compared with the smallest sum of LD and the increase of LD was at least 5 millimeter (mm) (including new lesions).

Original Primary Outcome Measures (submitted: July 23, 2009)

• Dose-Escalation Component: To determine the MTD defined by dose-limiting toxicity (DLT) of E7080. Safety assessments based on adverse events, physical exams, and selected lab values. [ Time Frame: 4 weeks ]
• Expansion Component: Time to progression. [ Time Frame: From day of registration to the day when progressive disease is first confirmed ]

• Change History: Complete list of historical versions of study NCT00946153 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: August 27, 2018)

• Phase 1: Best Overall Response (BOR) of Lenvatinib by Investigator Assessment [ Time Frame: Every 8 weeks (approximately up to 18.4 months) ]
  BOR was performed using RECIST1.1 and was measured as complete response (CR) defined as when an overall response of CR was obtained 2 or more consecutive times at intervals of at least 28 days (the date when the second overall response of CR was confirmed and the BOR established as CR was regarded as the "CR confirmed date), partial response (PR) defined as when the overall response of PR or better (CR or PR) was obtained 2 or more consecutive times at intervals of at least 28 days (the date when the second overall response of PR was confirmed and the BOR established as PR will be regarded as the "PR confirmed date), PD defined as when the BOR was neither CR, PR, or stable disease (SD), and the overall response was PD, SD defined as when the BOR obtained was neither CR nor PR, but no PD from the initial administration to the end of Cycle 2 and the overall response of SD or better occurred at least once and not evaluable (NE) was when the overall response was NE in all cases.
• Phase 1: Objective Response Rate (ORR) by Investigator Assessment [ Time Frame: From day of registration to the day when PD was first confirmed or death (approximately 6.1 years) ]
  ORR was defined as the percentage of participants who achieved a tumor response measured by RECIST 1.1 of CR defined as disappearance of all target lesions (a short diameter is less than (<)10 mm if it exists in a lymph node) plus PR defined as at least 30% decrease in the sum of the long diameter LD (hereafter referred to as sum of LD) of all target lesions, as compared with Baseline summed LD.
• Phase 1: Disease Control Rate (DCR) by Investigator Assessment [ Time Frame: Up to Week 16 ]
  DCR was measured by RECIST 1.1 and defined as CR which was defined as disappearance of all target lesions (a short diameter was <10 mm if it exists in a lymph node) plus PR which was defined as at least 30% decrease in the sum of the long diameter (hereafter referred to as sum of LD) of all target lesions, as compared with baseline summed LD plus SD which was reduction in tumor volume of less than 50% or an increase in the volume of 1 or more measurable lesions of less than 25% without the appearance of any new lesions which was neither tumor shrinkage corresponding to PR nor tumor expansion corresponding to PD.
• Phase 2: Progression-free Survival (PFS) by Independent Review Assessment [ Time Frame: From day of registration to the day when PD was first confirmed or death (approximately 6.1 years) ]
  PFS was defined as the time from the date of registration until the date when PD was first confirmed or death (whichever occurred first) as determined by mRECIST and PD was defined as at least a 20% increase in the sum of long diameters of target lesions, taking as reference the baseline sum of diameters of target lesions.
• Phase 2: Objective Response Rate (ORR) by Independent Review Assessment [ Time Frame: From day of registration to the day when PD was first confirmed or death (approximately 6.1 years) ]
  ORR was defined as the percentage of participants who achieved a tumor response measured by mRECIST of CR defined as disappearance of all target lesions (a short diameter is <10 mm if it exists in a lymph node) plus PR defined as at least 30% decrease in the sum of the long diameter LD (hereafter referred to as sum of LD) of all target lesions, as compared with Baseline summed LD.
• Phase 2: Disease Control Rate (DCR) by Independent Review Assessment [ Time Frame: Weeks 8 and 16 ]
  DCR was measured by mRECIST and defined as CR which was defined as disappearance of all target lesions (a short diameter is <10 mm if it exists in a lymph node) plus PR which was defined as at least 30% decrease in the sum of the long diameter (hereafter referred to as sum of LD) of all target lesions, as compared with baseline summed LD plus SD which was reduction in tumor volume of less than 50% or an increase in the volume of 1 or more measurable lesions of less than 25% without the appearance of any new lesions which was neither tumor shrinkage corresponding to PR nor tumor expansion corresponding to PD.
• Phase 2: Overall Survival (OS) [ Time Frame: From day of registration to the day of death (approximately 6.1 years) ]
  OS was defined as the time from the date of registration until the date of death.

Original Secondary Outcome Measures (submitted: July 23, 2009)

• Dose-Escalation Component: To evaluate the anti-tumor effect of E7080 using Response Evaluation Criteria in Solid Tumors (RECIST). [ Time Frame: Every 8 weeks ]
• Expansion Component: Progression-free survival [ Time Frame: From day of registration to the day when progressive disease is first confirmed or death ]
• Expansion Component: Objective response rate. [ Time Frame: Every 8 weeks ]
• Expansion Component: Disease control rate. [ Time Frame: At 8 weeks and 16 weeks ]
• Expansion Component: Overall survival. [ Time Frame: From day of registration to the day of death ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Lenvatinib (E7080) in Participants With Advanced Hepatocellular Carcinoma (HCC)
• Official Title: Phase I/II Study of E7080 in Patients With Advanced Hepatocellular Carcinoma (HCC)
• Brief Summary: The purpose of this study is to determine maximum tolerated dose (MTD), efficacy, safety and tolerability, pharmacokinetics, pharmacodynamics, and anti-tumor effect of E7080 when is administered continually once daily in participants with advanced hepatocellular carcinoma.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Hepatocellular Carcinoma

Intervention

Drug: Lenvatinib

In the Dose-Escalation Component of the study, lenvatinib will be administered as continuous once-daily oral dosing. Dose-escalation will occur based on safety information obtained during Cycle 1. The recommended dose for the Expansion Component of the study will use the MTD in Cycle 1.

Other Name: E7080

Study Arms

Experimental: Lenvatinib

Intervention: Drug: Lenvatinib

• Publications *: Ikeda K, Kudo M, Kawazoe S, Osaki Y, Ikeda M, Okusaka T, Tamai T, Suzuki T, Hisai T, Hayato S, Okita K, Kumada H. Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma. J Gastroenterol. 2017 Apr;52(4):512-519. doi: 10.1007/s00535-016-1263-4. Epub 2016 Oct 4.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 14, 2012): 66
• Original Estimated Enrollment (submitted: July 23, 2009): 82
• Actual Study Completion Date: August 13, 2015
• Actual Primary Completion Date: June 15, 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion criteria:

1. Histologically or clinically confirmed diagnosis of advanced HCC.
2. Eastern Cooperative Oncology Group-Performance Status (ECOG-PS): 0-1.
3. Adequate laboratory values/organ function tests.

Exclusion criteria:

1. Simultaneous or metachronous cancers.
2. Pericardial, ascites, or pleural effusion requiring drainage.
3. Brain metastasis/meningeal carcinomatosis presenting clinical symptoms or requiring treatment.
4. Malabsorption syndrome.
5. Artery-portal vein shunt or artery-vein shunt preventing proper diagnosis of tumor.
6. Use of drugs known to inhibit cytochrome P3A4.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 20 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Japan, Korea, Republic of

Administrative Information

• NCT Number: NCT00946153
• Other Study ID Numbers: E7080-J081-202
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Eisai Inc. ( Eisai Co., Ltd. )
• Study Sponsor: Eisai Co., Ltd.
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Eisai Inc.
• Verification Date: July 2018