Study of Lenvatinib (E7080) in Unresectable Biliary Tract Cancer (BTC) Who Failed Gemcitabine-based Combination Chemotherapy

• ClinicalTrials.gov Identifier: NCT02579616
• Recruitment Status: Completed
• First Posted: October 19, 2015
• Results First Posted: December 23, 2020
• Last Update Posted: December 23, 2020
• Sponsor: Eisai Co., Ltd.
• Information provided by (Responsible Party): Eisai Inc. ( Eisai Co., Ltd. )

Tracking Information

• First Submitted Date: October 16, 2015
• First Posted Date: October 19, 2015
• Results First Submitted Date: October 1, 2020
• Results First Posted Date: December 23, 2020
• Last Update Posted Date: December 23, 2020
• Actual Study Start Date: October 23, 2015
• Actual Primary Completion Date: November 22, 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 1, 2020)

Objective Response Rate (ORR) [ Time Frame: From the date of first dose of study drug to the date of last documentation of disease progression or date of death from any cause, whichever occurred first (up to approximately 1 year 1 month) ]

ORR was assessed by the investigator based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. ORR was defined as the percentage of participants with best overall response (BOR) of complete response (CR) or partial response (PR). Confirmation of CR or PR was performed at least 28 days following the initial achievement of the response.

• Original Primary Outcome Measures (submitted: October 16, 2015): Objective response rate (ORR) [ Time Frame: At least 28 days after first dose of study drug ]

Current Secondary Outcome Measures (submitted: December 1, 2020)

• Progression-free Survival (PFS) Rate at 12 Weeks [ Time Frame: From the date of first dose to the date of last documentation of disease progression or death from any cause, whichever occurred first (up to Week 12) ]
  PFS was assessed by the investigator based on RECIST 1.1. PFS was defined as the time from the date of first dose to the date of last documentation of disease progression or death from any cause, whichever occurred first. PFS rate was cumulative probability for event-free participants at 12 weeks. PFS rate at 12 weeks was calculated using Kaplan-Meier method.
• Progression-free Survival (PFS) [ Time Frame: From the date of first dose of study drug to the date of last documentation of disease progression or date of death from any cause, whichever occurred first (up to approximately 3 years 4 months) ]
  PFS was assessed by the investigator based on RECIST 1.1. PFS was defined as the time from the date of first dose to the date of last documentation of disease progression or date of death from any cause, whichever occurred first. For participants who did not have an event, PFS were censored. PFS was calculated using Kaplan-Meier method.
• Overall Survival (OS) [ Time Frame: From the date of first dose of study drug to the date of death from any cause (up to approximately 3 years 4 months) ]
  OS was defined as the time from the date of first dose to the date of death from any cause. For the participants who were alive or unknown, OS was censored on the last date participant was known to be event-free or date of data-cut-off. OS was calculated using the Kaplan-Meier method.
• Disease Control Rate (DCR) [ Time Frame: From the date of first dose of study drug to the date of last documentation of disease progression or date of death from any cause, whichever occurred first (up to approximately 3 years 4 months) ]
  DCR was assessed by the investigator based on RECIST 1.1. DCR was defined as the percentage of participants whose BOR was CR, PR or SD.
• Clinical Benefit Rate (CBR) [ Time Frame: From the date of first dose of study drug to the date of the last documentation of disease progression or death from any cause, whichever occurred first (up to approximately 3 years 4 months) ]
  CBR was assessed by the investigator based on RECIST 1.1.CBR was defined as percentage of participants with BOR of CR, PR or durable SD. Durable SD: Durable SD: duration of SD greater than or equal to (>=23) weeks.
• Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: From signing of informed consent form to 30 days after the decision to discontinue study treatment or 30 days after last dose of study drug, whichever comes later (up to approximately 3 years 4 months) ]
• Plasma Concentrations of Lenvatinib [ Time Frame: Cycle 1 Day 1: 0.5-2 hours post dose (Cycle length is 28 days) ]

Original Secondary Outcome Measures (submitted: October 16, 2015)

• Progression free survival (PFS) [ Time Frame: From the date of first dose of study drug to the date of first documentation of disease progression or date of death from any cause, whichever occurs first, or up to approximately 3 years ]
• Overall survival (OS) [ Time Frame: From the date of first dose of study drug to the date of death from any cause, or up to approximately 3 years ]
• Disease control rate (DCR) [ Time Frame: Cycle 2 Day 8 ]
  DCR is defined as the percentage of participants with complete response (CR) + partial response (PR) + stable disease (SD).
• Clinical benefit rate (CBR) [ Time Frame: From the date of first dose of study drug to the date of the first documentation of disease progression or death from any cause, whichever occurs first, or up to approximately 3 years ]
  CBR is defined as the percentage of participants with CR + PR + durable SD.
• Number of participants with adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: From signing of informed consent form to 30 days after investigator decides discontinuation of this study or 30 days after last dose or off-treatment visit, whichever comes later, or up to approximately 3 years ]
• Blood concentration [ Time Frame: Cycle 1 Day 1, Day 8, and Day 15; Cycle 2 Day 1 ]

• 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 Unresectable Biliary Tract Cancer (BTC) Who Failed Gemcitabine-based Combination Chemotherapy
• Official Title: An Open-Label, Multicenter Phase 2 Study of E7080/ LENVIMA (Lenvatinib Mesylate) in Subjects With Unresectable Biliary Tract Cancer Who Failed Gemcitabine-based Combination Chemotherapy
• Brief Summary: This is a multicenter, single arm, open-label study in participants with unresectable BTC and disease progression or failure following one prior gemcitabine-based doublet chemotherapy regimen (combination of gemcitabine and cisplatin, or gemcitabine and other platinum agent/fluoropyrimidine agent). This study contains 3 phases: a Pre-treatment phase that will last within 21 days; a Treatment phase that will consist of study treatment cycles and tumor assessment conducted every 6-8 weeks; and a Follow-up phase that will begin immediately after the Off-Treatment Visit and will continue as long as the participant is alive, unless the participant withdraws consent, or until the End of Study.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Biliary Tract Cancer

Intervention

Drug: Lenvatinib

Lenvatinib will be administered orally once daily in 28-day cycles. Participants will be treated until disease progression, unacceptable toxicity, withdrawal of consent, participant's choice, etc.

Other Names:

• E7080
• Lenvima
• Lenvatinib Mesylate

Study Arms

Experimental: 24 mg Lenvatinib

Participants with unresectable BTC and disease progression or failure following one prior gemcitabine-based doublet chemotherapy regimen (combination of gemcitabine and cisplatin, or gemcitabine and other platinum agent/fluoropyrimidine agent).

Intervention: Drug: Lenvatinib

• Publications *: Ueno M, Ikeda M, Sasaki T, Nagashima F, Mizuno N, Shimizu S, Ikezawa H, Hayata N, Nakajima R, Morizane C. Phase 2 study of lenvatinib monotherapy as second-line treatment in unresectable biliary tract cancer: primary analysis results. BMC Cancer. 2020 Nov 16;20(1):1105. doi: 10.1186/s12885-020-07365-4.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 1, 2020): 29
• Original Estimated Enrollment (submitted: October 16, 2015): 25
• Actual Study Completion Date: February 27, 2019
• Actual Primary Completion Date: November 22, 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Pathologically or cytologically confirmed adenocarcinoma of biliary tract cancer (intrahepatic, extrahepatic cholangiocarcinoma, gall bladder cancer, and ampulla of Vater cancer)
2. Unresectable (eg, locally advanced or metastatic) BTC

3. One prior gemcitabine-based doublet chemotherapy (eg, gemcitabine and cisplatin) to unresectable BTC and not treated by any other chemotherapy to BTC

   • Participants who received adjuvant chemotherapy are eligible if this therapy was completed and recurrent has not been shown for 6 months after the completion of the therapy

4. Measurable disease meeting the following criteria:

   • At least 1 lesion of ≥ 1.0 cm in the longest diameter for a non-lymph node or ≥ 1.5 cm in the short-axis diameter for a lymph node that is serially measurable according to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST1.1) using computerized tomography/magnetic resonance imaging (CT/MRI)
   • Lesions that have had external beam radiotherapy (EBRT) or locoregional therapies such as radiofrequency (RF) ablation must show evidence of progressive disease based on RECIST 1.1 to be deemed a target lesion
5. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1
6. Survival expectation of 3 months or longer after beginning of study treatment
7. Males or females age ≥ 20 years at the time of informed consent
8. All chemotherapy- or radiation-related toxicities must have resolved to Grade 0-1 per Common Terminology Criteria for Adverse Events (CTCAE v 4.03), except alopecia, infertility, and the adverse events listed in inclusion criteria
9. Adequately controlled blood pressure (BP) with or without antihypertensive medications (defined as BP ≤ 150/90 mm Hg at Screening and no change in antihypertensive medications within 1 week prior to the first dose of study drug)

10. Participants with adequate function of major organs and blood coagulation:

    • Absolute neutrophil count (ANC) ≥ 1500/mm^3 ( ≥ 1.5×103/μl)
    • Platelets ≥ 100,000/mm3 ( ≥ 100×10^9/L)
    • Hemoglobin ≥ 9.0 g/dL
    • Bilirubin ≤ 2.0 mg/dL except for unconjugated hyperbilirubinemia or Gilbert's syndrome
    • Alkaline phosphatase (ALP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) ≤ 3.0 × upper limit of normal (ULN) ( ≤ 5.0 × ULN for participants with the liver metastasis)
    • Creatinine clearance ≥ 40 mL/min per the Cockcroft and Gault formula
    • Prothrombin time-International Normalized Ratio (PT-INR) ≤ 1.5
11. Participants must voluntarily agree to provide written informed consent
12. Participants must be willing and able to comply with all aspects of the protocol

Exclusion Criteria:

1. Any anti-cancer treatment (except BSC) within 21 days prior to the first dose of study drug
2. Major surgery (any surgical procedure that involves anesthesia or respiratory assistance) within 21 days prior to the first dose of study drug or scheduled surgery during the study (except for bile duct drainage)
3. Ascites of moderate, severe, or requiring drainage
4. Proteinuria of ≥ 2+ on dipstick testing (Grade ≤ 1 confirmed by quantitative assessment is eligible)
5. Gastrointestinal malabsorption or any other condition that in the opinion of the investigator might affect the absorption of study drug
6. New York Heart Association congestive heart failure of class II or above, unstable angina, myocardial infarction, or serious cardiac arrhythmia associated with significant cardiovascular impairment within the past 6 months from the first dose of study drug
7. A prolonged QT/QTc interval (QTcF > 480 ms)
8. Known to be human immunodeficiency virus (HIV) positive
9. Active infection requiring systemic treatment
10. Bleeding or thrombotic disorders or chronic systemic use of anticoagulants requiring therapeutic INR monitoring, eg, warfarin or similar agents (treatment with low molecular weight heparin is permitted)
11. Gastrointestinal bleeding event or active hemoptysis (bright red blood of at least 0.5 teaspoon) within 21 days prior to the first dose of study drug
12. Active malignancy (except for BTC or definitively treated melanoma in-situ, basal or squamous cell carcinoma of the skin, carcinoma in-situ of the cervix, or early stage gastric/colorectal cancer) within the past 24 months prior to the first dose of study drug
13. Diagnosed with meningeal carcinomatosis
14. Participants with brain or subdural metastases are not eligible, unless they have completed local therapy and have discontinued the use of corticosteroids for this indication for at least 28 days prior to the first dose of study drug. Any signs (eg, radiologic) or symptoms of brain metastases must be stable for at least 28 days prior to the first dose of study drug.
15. Known intolerance to the study drug or any of the excipients
16. History of drug or alcohol dependency or abuse within the last 24 months prior to the first dose of study drug
17. Any medical or other condition that in the opinion of the investigator(s) would preclude the participant's participation in a clinical study
18. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive human chorionic gonadotropin [hCG or B-hCG]). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 3 days before the first dose of study drug.

19. For either males unless undergoing a successful vasectomy (confirmed azoospermia) or females of childbearing potential, the participant and his/her partner do not agree to use a medically appropriate method of contraception throughout the entire study period

    • the use of condom, contraceptive sponge, contraceptive foam, contraceptive jelly, diaphragm, or intrauterine device, otherwise using oral contraceptive (percutaneous or transvaginal also allowed) for at least 28 days before the first dose of study drug

Sex/Gender

• Sexes Eligible for Study: All

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

Administrative Information

• NCT Number: NCT02579616
• Other Study ID Numbers: E7080-J081-215
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Eisai Inc. ( Eisai Co., Ltd. )
• Original Responsible Party: Same as current
• Current Study Sponsor: Eisai Co., Ltd.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Eisai Inc.
• Verification Date: October 2020