A Study of Ramucirumab (LY3009806) or Merestinib (LY2801653) in Advanced or Metastatic Biliary Tract Cancer
- Conditions
- Biliary Tract CancerMetastatic CancerAdvanced Cancer
- Interventions
- Registration Number
- NCT02711553
- Lead Sponsor
- Eli Lilly and Company
- Brief Summary
The main purpose of this study is to evaluate the efficacy and safety of ramucirumab or merestinib or placebo plus cisplatin and gemcitabine in participants with advanced or metastatic biliary tract cancer.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 309
- Have an Eastern Cooperative Oncology Group performance status of 0 or 1.
- Have a histologically or cytologically confirmed diagnosis of non-resectable, recurrent, or metastatic biliary tract adenocarcinoma (intrahepatic or extrahepatic cholangiocarcinoma, gallbladder cancer, or Ampulla of Vater) .
- Have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST).
- Have adequate biliary drainage.
- Have adequate organ function.
- Males and females are sterile, postmenopausal, or compliant with a highly effective contraceptive method.
- Female participants of childbearing potential must have a negative serum pregnancy test within 7 days prior to first dose.
- Are willing to provide blood/serum/plasma and tumor tissue samples for research purposes. Submission of blood/serum/plasma and tumor tissue samples is mandatory for participation in this study, unless restricted per local regulations.
- Previous systemic therapy for locally advanced or metastatic disease is not allowed.
- Have a history of or have current hepatic encephalopathy of any grade, or ascites of Grade >1, or cirrhosis with Child-Pugh Stage B or higher.
- Have ongoing or recent (≤6 months) hepatorenal syndrome.
- Have had a major surgical procedure or significant traumatic injury including nonhealing wound, peptic ulcer, or bone fracture ≤28 days prior to randomization.
- Anticipate having a major surgical procedure during the course of the study.
- Has documented brain metastases, leptomeningeal disease, or uncontrolled spinal cord compression.
- Within 6 months prior to randomization, have had any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack.
- Have an uncontrolled arterial hypertension with systolic blood pressure ≥150 or diastolic blood pressure ≥90 millimeters of mercury (mm Hg) despite standard medical management.
- Have a previous malignancy within 5 years of study entry or a concurrent malignancy.
- Have a history of gastrointestinal perforation and/or fistulae within 6 months prior to randomization.
- Have a known allergy or hypersensitivity reaction to any of the treatment components.
- Have a history of uncontrolled hereditary or acquired thrombotic disorder.
- Have uncontrolled metabolic disorders or other nonmalignant organ or systemic diseases or secondary effects of cancer that induce a high medical risk and/or make assessment of survival uncertain.
- Have mixed hepatocellular biliary tract cancer histology.
- Have a corrected QT interval >470 milliseconds as calculated by the Fridericia equation.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo IV + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Placebo IV Participants received placebo (indistinguishable and equivalent volume to ramucirumab) plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy). Placebo Oral + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Placebo Oral Participants received placebo (indistinguishable to merestinib) orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days. Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy). Placebo Oral + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Cisplatin Participants received placebo (indistinguishable to merestinib) orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days. Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy). 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Gemcitabine Participants received 8 mg/kg ramucirumab plus 25 mg/square meter (mg/m²) cisplatin and 1000 mg/m² gemcitabine intravenously (IV) on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for ramucirumab therapy). 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Ramucirumab Participants received 8 mg/kg ramucirumab plus 25 mg/square meter (mg/m²) cisplatin and 1000 mg/m² gemcitabine intravenously (IV) on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for ramucirumab therapy). 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Cisplatin Participants received 8 mg/kg ramucirumab plus 25 mg/square meter (mg/m²) cisplatin and 1000 mg/m² gemcitabine intravenously (IV) on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for ramucirumab therapy). Placebo IV + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Gemcitabine Participants received placebo (indistinguishable and equivalent volume to ramucirumab) plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy). Placebo IV + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Cisplatin Participants received placebo (indistinguishable and equivalent volume to ramucirumab) plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy). 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Gemcitabine Participants received 80 mg merestinib orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for merestinib therapy). 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Cisplatin Participants received 80 mg merestinib orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for merestinib therapy). Placebo Oral + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Gemcitabine Participants received placebo (indistinguishable to merestinib) orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days. Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy). 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Merestinib Participants received 80 mg merestinib orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for merestinib therapy).
- Primary Outcome Measures
Name Time Method Progression Free Survival (PFS) Randomization to Progressive Disease or Death from Any Cause (Up To 20 Months) PFS time was measured from the date of randomization until the first radiographic documentation of progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, or death from any cause. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. If a participant does not have a complete baseline disease assessment, then the PFS time was censored at the date of first dose, regardless of whether or not objectively determined disease progression or death has been observed for the participant. If a participant was not known to have died or have objective progression as of the data inclusion cutoff date for the analysis, the PFS time was censored at the last adequate tumor assessment date.
- Secondary Outcome Measures
Name Time Method Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab C1 D8, C2 D1, C3 D1, C4 D1,C5 D1,C7 D1, C9 D1 and C13 D1: Within 3 days Prior to Infusion(PTI) PK was determined by the minimum observed plasma concentration (Cmin). 1 Cycle (C) = 21 days (D).
Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep) Baseline, Follow Up (Up To 48 Months) FACT-Hep consists of 45 items in five subscales (1) physical well-being (PWB) score rage 0 -28; (2) social well-being (SWB) score range 0-28; (3) emotional well-being (EWB) score range 0-24; (4) functional well-being (FWB) score range 0-28; and (5) the hepatobiliary cancer subscale (HCS) Score range 0-72. The Trial Outcomes Index (TOI) is the sum of the PWB, FWB and Hep subscales with a scores range of 0 to 128. The Total FACT-Hep score was the sum of all questions with a scores range of 0 to 180.Total FACT-G score was the sum of the 27 questions in the PWB, SFWB, EWB and FWB with a scores range of 0 to 108. The FACT-Hep Symptoms Index with 8 key questions and scores range of 0 to 32 from the Hep Subscale. Higher score in sub-score or total score indicates better QOL and better health state. Participants were classified as "Improved" if they had positive change from baseline, "Worsened" if they had negative change from baseline, and "Stable" otherwise.
Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score Baseline, Follow Up (Up To 48 Months) EQ-5D-5L is a 2-part questionnaire that assesses general health status for 'today'. The first part is comprised of the following 5 participant-reported dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The responses are used to derive the health state index scores using country-specific algorithms, with scores ranging from less than 0 (where zero is a health state equivalent to death; negative values are valued as worse than dead) to 1 (perfect health). Index values were calculated using the US algorithm (-0.109 to 1). A higher score indicates better health state.
Overall Survival (OS) Randomization to Date of Death from Any Cause (Up To 48 Months) OS defined as the time from from randomization to the date of death due to any cause. For each participant who is not known to have died as of the data-inclusion cutoff date for overall survival analysis, OS time was censored on the last date the participant is known to be alive.
Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR) Randomization to Disease Progression (Up To 30 Months) ORR was the number of participants who achieve a best overall response of CR or PR divided by the total number of participants randomized to the corresponding treatment arm as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the longest diameters (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions.
Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD): Disease Control Rate (DCR) Randomization to Disease Progression (Up To 30 Months) Disease Control Rate (DCR) was the number of participants who achieve a best overall response of CR, PR, or SD divided by the total number of participants randomized to the corresponding treatment arm as per RECIST v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the LD of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD for target lesions, no progression of non-target lesions, and no appearance of new lesions. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions.
PK: Plasma Concentration of Merestinib C1 D8; C2 D1; C4 D1; C6 D1; C8 D1; C2 D8; C4 D8; C6 D8; C8 D8: Morning PK was presented through graphical overlay comparison versus historic data. No numerical summary of data was intended or produced.
Change From Baseline in Participant-Reported EQ-5D-5L Visual Analog Scale (VAS) Score Baseline, Follow Up (Up To 48 Months) EQ-5D-5L is a 2-part questionnaire that assesses general health status 'today'. The second part is assessed using a VAS on which the patient rates their perceived health state, ranging from 0 millimeter (the worst health you can imagine) to 100 millimeter (the best health you can imagine).
Number of Participants With Treatment-Emergent Anti-Ramucirumab Antibodies Predose Cycle 1 Day 1 through Follow Up (Up To 48 Months) Number of participants with positive treatment emergent anti-ramucirumab antibodies (ADA) was summarized by treatment group.
Trial Locations
- Locations (79)
The University of Arizona Cancer Center
🇺🇸Tucson, Arizona, United States
UCSF Medical Center at Mission Bay
🇺🇸San Francisco, California, United States
Georgetown University Medical Center
🇺🇸Washington, District of Columbia, United States
University of Florida School of Medicine
🇺🇸Gainesville, Florida, United States
Karmanos Cancer Institute
🇺🇸Detroit, Michigan, United States
Washington University Medical School
🇺🇸Saint Peters, Missouri, United States
Thomas Jefferson University
🇺🇸Philadelphia, Pennsylvania, United States
Fox Chase Cancer Center
🇺🇸Philadelphia, Pennsylvania, United States
Florida Cancer Specialists
🇺🇸Nashville, Tennessee, United States
Tennessee Oncology PLLC
🇺🇸Nashville, Tennessee, United States
Alexander Fleming
🇦🇷Caba, BS, Argentina
Hospital de Gastroenterologia Udaondo
🇦🇷Capital Federal, Buenos Aires, Argentina
Fundacion Ars Medica
🇦🇷San Salvador de Jujuy, Jujuy, Argentina
Clinica Viedma
🇦🇷Viedma, Río Negro, Argentina
Centro Medico San Roque
🇦🇷San Miguel de Tucumán, Tucumán, Argentina
Fundacion Favaloro
🇦🇷Ciudad de Buenos Aires, Argentina
Fundación CORI para la Investigación y Prevención del Cáncer
🇦🇷La Rioja, Argentina
Centro Polivalente de Asistencia e Inv. Clinica CER-San Juan
🇦🇷San Juan, Argentina
Calvary Mater Newcastle
🇦🇺Waratah, New South Wales, Australia
Royal Adelaide Hospital
🇦🇺Adelaide, South Australia, Australia
Austin Health
🇦🇺Heidelberg, Victoria, Australia
Landesklinikum Wr. Neustadt
🇦🇹Wiener Neustadt, Niederösterreich, Austria
Universitätsklinikum Salzburg
🇦🇹Salzburg, Austria
KH der Barmherzigen Brüder Wien
🇦🇹Wien, Austria
Cliniques universitaires Saint-Luc
🇧🇪Bruxelles, Brussel, Belgium
Universitair Ziekenhuis Gent
🇧🇪Gent, Belgium
Universitaire Ziekenhuizen Leuven - Campus Gasthuisberg
🇧🇪Leuven, Belgium
Masarykuv onkologicky ustav
🇨🇿Brno, Brno-město, Czechia
Fakultni nemocnice Hradec Kralove
🇨🇿Hradec Kralove, Czechia
Fakultni Nemocnice v Motole
🇨🇿Praha 5, Czechia
Aarhus Universitetshospital, Aarhus Sygehus
🇩🇰Aarhus C, Denmark
Odense Universitetshospital
🇩🇰Odense C, Denmark
CHU de Bordeaux Hop St ANDRE
🇫🇷Bordeaux, Gironde, France
Centre Leon Berard
🇫🇷Lyon, Rhône-Alpes, France
CHU de Besancon Hopital Jean Minjoz
🇫🇷Besancon Cedex, France
Hôpital C. HURIEZ
🇫🇷Lille, France
CHRU de Montpellier-Hopital St Eloi
🇫🇷Montpellier Cedex 5, France
Centre Antoine-Lacassagne
🇫🇷Nice, France
Gustave Roussy
🇫🇷Villejuif Cedex, France
Universitätsklinikum Tübingen
🇩🇪Tübingen, Baden-Württemberg, Germany
Universitätsklinikum Ulm
🇩🇪Ulm, Baden-Württemberg, Germany
Universitätsklinikum Erlangen
🇩🇪Erlangen, Bayern, Germany
Medizinische Hochschule Hanover
🇩🇪Hannover, Niedersachsen, Germany
HELIOS Klinikum Berlin-Buch
🇩🇪Berlin, Germany
Universitaetsklinikum Hamburg-Eppendorf
🇩🇪Hamburg, Germany
Debreceni Egyetem Klinikai Kozpont Onkologiai Tanszek
🇭🇺Debrecen, Hajdu-Bihar, Hungary
Del-pesti Centrumkorhaz - Orszagos Hematologiai es Infektologiai Intezet
🇭🇺Budapest, Hungary
Asan Medical Center
🇰🇷Seoul, Korea, Korea, Republic of
Seoul National University Hospital
🇰🇷Seoul, Seoul, Korea, Korea, Republic of
Severance Hospital, Yonsei University Health System
🇰🇷Seoul, Korea, Republic of
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of
Arke Estudios Clinicos S.A. de C.V.
🇲🇽Mexico, DF, Mexico
Centro de Alta Especialidad Reumatologia Inv del Potosi SC
🇲🇽San Luis Potosi, Mexico
Russian Scientific Center of Radiology and Surgical Technologies
🇷🇺St. Petersburg, Sankt-Peterburg, Russian Federation
Arkhangelsk Clinical Oncological Dispensary
🇷🇺Arkhangelsk, Russian Federation
Blokhin Cancer Research Center
🇷🇺Moscow, Russian Federation
Saint-Petersburg City Clinical Oncology Dispensary
🇷🇺Saint-Petersburg, Russian Federation
Hospital Duran I Reynals
🇪🇸Hospitalet De Llobregat, Barcelona, Spain
Hospital Clínico Universitario de Valencia
🇪🇸Barcelona, Spain
Hospital General Universitario Gregorio Marañon
🇪🇸Madrid, Spain
Hospital Clinico de San Carlos
🇪🇸Madrid, Spain
Hospital Universitario 12 de Octubre
🇪🇸Madrid, Spain
Skåne universitetssjukhus
🇸🇪Malmö, Sweden
Karolinska Universitetssjukhuset i Solna
🇸🇪Stockholm, Sweden
Chang Gung Memorial Hospital - Kaohsiung Branch
🇨🇳Kaohsiung, Taiwan
China Medical University Hospital
🇨🇳Taichung, Taiwan
National Cheng-Kung Uni. Hosp.
🇨🇳Tainan, Taiwan
Taipei Veterans General Hospital
🇨🇳Taipei, Taiwan
Chang Gung Memorial Hospital - Linkou
🇨🇳Taoyuan City, Taiwan
Baskent University Dr. Turgut Noyan Research and Training Center
🇹🇷Adana, Turkey
Hacettepe University Faculty of Medicine
🇹🇷Ankara, Turkey
Akdeniz University Medical Faculty
🇹🇷Antalya, Turkey
Trakya University
🇹🇷Edirne, Turkey
Istanbul Universitesi-Cerrahpasa Cerrahpasa Tip Fakultesi Yerleskesi
🇹🇷Istanbul, Turkey
University College Hospital - London
🇬🇧London, Greater London, United Kingdom
The Christie NHS Foundation Trust
🇬🇧Manchester, Greater Manchester, United Kingdom
Hammersmith Hospital
🇬🇧Acton, London, United Kingdom
The Clatterbridge Cancer Centre
🇬🇧Bebbington, Merseyside, United Kingdom
Royal Marsden Hospital
🇬🇧Sutton, Surrey, United Kingdom