A Study of Ramucirumab (LY3009806) or Merestinib (LY2801653) in Advanced or Metastatic Biliary Tract Cancer

Randomized, Double-Blind, Phase 2 Study of Ramucirumab or Merestinib or Placebo Plus Cisplatin and Gemcitabine as First-Line Treatment in Patients With Advanced or Metastatic Biliary Tract Cancer

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Metastatic Cancer; Advanced Cancer; Biliary Tract Cancer
• Intervention / Treatment: Drug: Ramucirumab; Drug: Cisplatin; Drug: Gemcitabine; Drug: Placebo IV; Drug: Merestinib; Drug: Placebo Oral

• Study Type: Interventional
• Enrollment (Actual): 309
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Ciudad de Buenos Aires, Argentina, 1093
    • Fundacion Favaloro
  • La Rioja, Argentina, F5300COE
    • Fundacion CORI para la Investigacion y Prevencion del Cancer
  • San Juan, Argentina, J5402DIL
    • Centro Polivalente de Asistencia e Inv. Clinica CER-San Juan
  • BS
    • Caba, BS, Argentina, 1426
      • Alexander Fleming
  • Buenos Aires
    • Capital Federal, Buenos Aires, Argentina, C1264AAA
      • Hospital de Gastroenterologia Udaondo
  • Jujuy
    • San Salvador de Jujuy, Jujuy, Argentina, Y4600APW
      • Fundación Ars Medica
  • Río Negro
    • Viedma, Río Negro, Argentina, R8500ACE
      • Clinica Viedma
  • Tucumán
    • San Miguel de Tucumán, Tucumán, Argentina, 4000
      • Centro Medico San Roque
• Australia
  • New South Wales
    • Waratah, New South Wales, Australia, 2298
      • Calvary Mater Newcastle
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital
  • Victoria
    • Heidelberg, Victoria, Australia, 3084
      • Austin Health
• Austria
  • Salzburg, Austria, 5020
    • Universitätsklinikum Salzburg
  • Wien, Austria, 1020
    • KH der Barmherzigen Brüder Wien
  • Niederösterreich
    • Wiener Neustadt, Niederösterreich, Austria, 2700
      • Landesklinikum Wr. Neustadt
• Belgium
  • Gent, Belgium, 9000
    • Universitair Ziekenhuis Gent
  • Leuven, Belgium, 3000
    • Universitaire Ziekenhuizen Leuven - Campus Gasthuisberg
  • Brussel
    • Bruxelles, Brussel, Belgium, 1200
      • Cliniques Universitaires Saint-Luc
• Czechia
  • Hradec Kralove, Czechia, 500 05
    • Fakultni Nemocnice Hradec Kralove
  • Praha 5, Czechia, 150 06
    • Fakultni nemocnice v Motole
  • Brno-město
    • Brno, Brno-město, Czechia, 656 53
      • Masarykuv onkologicky ustav
• Denmark
  • Aarhus C, Denmark, 8000
    • Aarhus Universitetshospital, Aarhus Sygehus
  • Odense C, Denmark, 5000
    • Odense Universitetshospital
• France
  • Besancon Cedex, France, 25030
    • CHU de Besancon Hopital Jean Minjoz
  • Lille, France, 59037
    • Hôpital C. HURIEZ
  • Montpellier Cedex 5, France, 34295
    • CHRU de Montpellier-Hopital St Eloi
  • Nice, France, 06189
    • Centre Antoine-Lacassagne
  • Villejuif Cedex, France, 94805
    • Gustave Roussy
  • Gironde
    • Bordeaux, Gironde, France, 33075
      • CHU de Bordeaux Hop St ANDRE
  • Rhône-Alpes
    • Lyon, Rhône-Alpes, France, 69008
      • Centre Leon Berard
• Germany
  • Berlin, Germany, 13125
    • Helios Klinikum Berlin-Buch
  • Hamburg, Germany, 20246
    • Universitaetsklinikum Hamburg-Eppendorf
  • Baden-Württemberg
    • Tübingen, Baden-Württemberg, Germany, 72076
      • Universitätsklinikum Tübingen
    • Ulm, Baden-Württemberg, Germany, 89081
      • Universitätsklinikum Ulm
  • Bayern
    • Erlangen, Bayern, Germany, 91054
      • Universitätsklinikum Erlangen
  • Niedersachsen
    • Hannover, Niedersachsen, Germany, 30625
      • Medizinische Hochschule Hanover
• Hungary
  • Budapest, Hungary, 1097
    • Del-pesti Centrumkorhaz - Orszagos Hematologiai es Infektologiai Intezet
  • Hajdu-Bihar
    • Debrecen, Hajdu-Bihar, Hungary, 4032
      • Debreceni Egyetem Klinikai Kozpont Onkologiai Tanszek
• Korea, Republic of
  • Seoul, Korea, Republic of, 03722
    • Severance Hospital, Yonsei University Health System
  • Seoul, Korea, Republic of, 06351
    • Samsung Medical Center
  • Korea
    • Seoul, Korea, Korea, Republic of, 05505
      • Asan Medical Center
  • Seoul, Korea
    • Seoul, Seoul, Korea, Korea, Republic of, 03080
      • Seoul National University Hospital
• Mexico
  • San Luis Potosi, Mexico, 78213
    • Centro de Alta Especialidad Reumatologia Inv del Potosi SC
  • DF
    • Mexico, DF, Mexico, 06700
      • ARKE Estudios Clínicos S.A. de C.V.
• Russian Federation
  • Arkhangelsk, Russian Federation, 163045
    • Arkhangelsk Clinical Oncological Dispensary
  • Moscow, Russian Federation, 115478
    • Blokhin Cancer Research Center
  • Saint-Petersburg, Russian Federation, 198255
    • Saint-Petersburg City Clinical Oncology Dispensary
  • Sankt-Peterburg
    • St. Petersburg, Sankt-Peterburg, Russian Federation, 197758
      • Russian Scientific Center of Radiology and Surgical Technologies
• Spain
  • Barcelona, Spain, 46010
    • Hospital Clinico Universitario de Valencia
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Marañon
  • Madrid, Spain, 28040
    • Hospital Clinico de San Carlos
  • Barcelona
    • Hospitalet De Llobregat, Barcelona, Spain, 08908
      • Hospital Duran i Reynals
• Sweden
  • Malmö, Sweden, 20502
    • Skåne Universitetssjukhus
  • Stockholm, Sweden, 17176
    • Karolinska Universitetssjukhuset i Solna
• Taiwan
  • Kaohsiung, Taiwan, 83301
    • Chang Gung Memorial Hospital - Kaohsiung Branch
  • Taichung, Taiwan, 40447
    • China Medical University Hospital
  • Tainan, Taiwan, 704
    • National Cheng-Kung Uni. Hosp.
  • Taipei, Taiwan, 11217
    • Taipei Veterans General Hospital
  • Taoyuan City, Taiwan, 33305
    • Chang Gung Memorial Hospital - Linkou
• Turkey
  • Adana, Turkey, 1250
    • Baskent University Dr. Turgut Noyan Research and Training Center
  • Ankara, Turkey, 06100
    • Hacettepe University Faculty of Medicine
  • Antalya, Turkey, 07059
    • Akdeniz University Medical Faculty
  • Edirne, Turkey, 22030
    • Trakya University
  • Istanbul, Turkey, 34098
    • Istanbul Universitesi-Cerrahpasa Cerrahpasa Tip Fakultesi Yerleskesi
• United Kingdom
  • Greater London
    • London, Greater London, United Kingdom, NW1 2BU
      • University College Hospital - London
  • Greater Manchester
    • Manchester, Greater Manchester, United Kingdom, M20 4BX
      • The Christie NHS Foundation Trust
  • London
    • Acton, London, United Kingdom, W12 0HS
      • Hammersmith Hospital
  • Merseyside
    • Bebbington, Merseyside, United Kingdom, CH63 4JY
      • The Clatterbridge Cancer Centre
  • Surrey
    • Sutton, Surrey, United Kingdom, SM2 5PT
      • Royal Marsden Hospital
• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • The University of Arizona Cancer Center
  • California
    • San Francisco, California, United States, 94158
      • UCSF Medical Center at Mission Bay
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University Medical Center
  • Florida
    • Gainesville, Florida, United States, 32608
      • University of Florida School of Medicine
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Institute
  • Missouri
    • Creve Coeur, Missouri, United States, 63141
      • Washington University Medical School
    • Saint Louis, Missouri, United States, 63110
      • Washington University Medical School
    • Saint Louis, Missouri, United States, 63129
      • Washington University Medical School
    • Saint Peters, Missouri, United States, 63376
      • Washington University Medical School
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
    • Philadelphia, Pennsylvania, United States, 19111-2497
      • Fox Chase Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology PLLC
    • Nashville, Tennessee, United States, 37203
      • Florida Cancer Specialists

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² 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).	Drug: Ramucirumab; Administered IV; Other Names: LY3009806; Drug: Cisplatin; Administered IV; Drug: Gemcitabine; Administered IV; Other Names: LY188011
Placebo Comparator: Placebo IV + 25 mg/m² Cisplatin + 1000 mg/m² 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).	Drug: Cisplatin; Administered IV; Drug: Gemcitabine; Administered IV; Other Names: LY188011; Drug: Placebo IV; Administered IV
Experimental: 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² 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).	Drug: Cisplatin; Administered IV; Drug: Gemcitabine; Administered IV; Other Names: LY188011; Drug: Merestinib; Administered orally; Other Names: LY2801653
Placebo Comparator: Placebo Oral + 25 mg/m² Cisplatin + 1000 mg/m² 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).	Drug: Cisplatin; Administered IV; Drug: Gemcitabine; Administered IV; Other Names: LY188011; Drug: Placebo Oral; Administered orally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	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.	Randomization to Progressive Disease or Death from Any Cause (Up To 20 Months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	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.	Randomization to Date of Death from Any Cause (Up To 48 Months)
Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR)	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.	Randomization to Disease Progression (Up To 30 Months)
Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD): Disease Control Rate (DCR)	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.	Randomization to Disease Progression (Up To 30 Months)
Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab	PK was determined by the minimum observed plasma concentration (Cmin). 1 Cycle (C) = 21 days (D).	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: Plasma Concentration of Merestinib	PK was presented through graphical overlay comparison versus historic data. No numerical summary of data was intended or produced.	C1 D8; C2 D1; C4 D1; C6 D1; C8 D1; C2 D8; C4 D8; C6 D8; C8 D8: Morning
Number of Participants With Treatment-Emergent Anti-Ramucirumab Antibodies	Number of participants with positive treatment emergent anti-ramucirumab antibodies (ADA) was summarized by treatment group.	Predose Cycle 1 Day 1 through Follow Up (Up To 48 Months)
Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep)	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.	Baseline, Follow Up (Up To 48 Months)
Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score	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.	Baseline, Follow Up (Up To 48 Months)
Change From Baseline in Participant-Reported EQ-5D-5L Visual Analog Scale (VAS) Score	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).	Baseline, Follow Up (Up To 48 Months)

Collaborators and Investigators

• Sponsor: Eli Lilly and Company
• Investigators: Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

Publications and helpful links

General Publications

• Valle JW, Vogel A, Denlinger CS, He AR, Bai LY, Orlova R, Van Cutsem E, Adeva J, Chen LT, Obermannova R, Ettrich TJ, Chen JS, Wasan H, Girvan AC, Zhang W, Liu J, Tang C, Ebert PJ, Aggarwal A, McNeely SC, Moser BA, Oliveira JM, Carlesi R, Walgren RA, Oh DY. Addition of ramucirumab or merestinib to standard first-line chemotherapy for locally advanced or metastatic biliary tract cancer: a randomised, double-blind, multicentre, phase 2 study. Lancet Oncol. 2021 Oct;22(10):1468-1482. doi: 10.1016/S1470-2045(21)00409-5.

Helpful Links

• A Study of Ramucirumab (LY3009806) or Merestinib (LY2801653) in Advanced or Metastatic Biliary Tract Cancer

Study record dates

Study Major Dates

• Study Start (Actual): May 19, 2016
• Primary Completion (Actual): February 16, 2018
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: March 14, 2016
• First Submitted That Met QC Criteria: March 14, 2016
• First Posted (Estimated): March 17, 2016

Study Record Updates

• Last Update Posted (Actual): August 3, 2025
• Last Update Submitted That Met QC Criteria: July 23, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Biliary Tract Diseases; Biliary Tract Neoplasms; Antineoplastic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Gemcitabine; Ramucirumab
• Other Study ID Numbers: 16329 (Stanford IRB); I3O-MC-JSBF (Other Identifier: Eli Lilly and Company); 2015-004699-31 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.
• IPD Sharing Time Frame: Data are available 6 months after the primary publication and approval of the indication studied in the US and european union (EU), whichever is later. Data will be indefinitely available for requesting.
• IPD Sharing Access Criteria: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR