Biliary Tract Cancer
Conditions
Keywords
Lenvatinib, E7080, Unresectable biliary tract cancer, BTC, Gemcitabine-based combination chemotherapy, Lenvima
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.
Interventions
DRUGLenvatinib
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.
Sponsors
Eisai Co., Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | 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) | 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) | 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. |
| Progression-free Survival (PFS) Rate at 12 Weeks | 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. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | 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 | Cycle 1 Day 1: 0.5-2 hours post dose (Cycle length is 28 days) | — |
| Clinical Benefit Rate (CBR) | 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. |
Countries
Japan
Participant flow
Recruitment details
Participants took part in the study at 7 investigative sites in Japan from 23 Oct 2015 to 27 Feb 2019.
Pre-assignment details
A total of 29 participants were screened and enrolled, of which 3 were screen failures and 26 were treated in the study.
Participants by arm
| Arm | Count |
|---|---|
| Lenvatinib 24 mg Participants received lenvatinib 24 mg capsules, orally, once daily in 28-days treatment cycles until disease progression, AEs, withdrawal of consent, or participant's choice (up to Cycle 40). | 26 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Participants did not receive treatment | 3 |
Baseline characteristics
| Characteristic | Lenvatinib 24 mg |
|---|---|
| Age, Continuous | 62.1 years STANDARD_DEVIATION 9.48 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 26 Participants |
| Race (NIH/OMB) Black or African American | 0 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 | 11 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 17 / 26 |
| other Total, other adverse events | 26 / 26 |
| serious Total, serious adverse events | 18 / 26 |
Outcome results
Primary
Objective Response Rate (ORR)
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.
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)
Population: The FAS included the group of participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenvatinib 24 mg | Objective Response Rate (ORR) | 11.5 percentage of participant |
Secondary
Clinical Benefit Rate (CBR)
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.
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)
Population: The FAS included the group of participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenvatinib 24 mg | Clinical Benefit Rate (CBR) | 38.5 percentage of participant |
Secondary
Disease Control Rate (DCR)
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.
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)
Population: The FAS included the group of participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenvatinib 24 mg | Disease Control Rate (DCR) | 84.6 percentage of participant |
Secondary
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)
Population: The safety analysis set included group of participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lenvatinib 24 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 26 participants |
| Lenvatinib 24 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 18 participants |
Secondary
Overall Survival (OS)
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.
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)
Population: The FAS included the group of participants who received at least one dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenvatinib 24 mg | Overall Survival (OS) | 7.35 months |
Secondary
Plasma Concentrations of Lenvatinib
Time frame: Cycle 1 Day 1: 0.5-2 hours post dose (Cycle length is 28 days)
Population: The safety analysis set included group of participants who received at least one dose of study drug. The safety analysis set was used for plasma lenvatinib concentration calculation.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenvatinib 24 mg | Plasma Concentrations of Lenvatinib | 3.90 nanogram per milliliter (ng/mL) |
Secondary
Progression-free Survival (PFS)
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.
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)
Population: The FAS included the group of participants who received at least one dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenvatinib 24 mg | Progression-free Survival (PFS) | 3.19 months |
Secondary
Progression-free Survival (PFS) Rate at 12 Weeks
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.
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)
Population: The FAS included the group of participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenvatinib 24 mg | Progression-free Survival (PFS) Rate at 12 Weeks | 72.2 percentage of participant |