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

Metastatic Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02711553
• Other study ID #: 16329
• Secondary ID: I3O-MC-JSBF2015-
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: May 19, 2016
• Est. completion date: December 31, 2025

Study information

• Verified date: May 2024
• Source: Eli Lilly and Company
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 309
• Est. completion date: December 31, 2025
• Est. primary completion date: February 16, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Advanced Cancer
• Biliary Tract Cancer
• Biliary Tract Neoplasms
• Metastatic Cancer

Intervention

Drug:
• Ramucirumab
Administered IV
• Merestinib
Administered orally
• Cisplatin
Administered IV
• Gemcitabine
Administered IV
• Placebo Oral
Administered orally
• Placebo IV
Administered IV

Locations

Country	Name	City	State
Argentina	Alexander Fleming	Caba	BS
Argentina	Hospital de Gastroenterologia Udaondo	Capital Federal	Buenos Aires
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	Centro Medico San Roque	San Miguel de Tucumán	Tucumán
Argentina	Fundacion Ars Medica	San Salvador de Jujuy	Jujuy
Argentina	Clinica Viedma	Viedma	Río Negro
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Austin Health	Heidelberg	Victoria
Australia	Calvary Mater Newcastle	Waratah	New South Wales
Austria	Universitätsklinikum Salzburg	Salzburg
Austria	KH der Barmherzigen Brüder Wien	Wien
Austria	Landesklinikum Wr. Neustadt	Wiener Neustadt	Niederösterreich
Belgium	Cliniques universitaires Saint-Luc	Bruxelles	Brussel
Belgium	Universitair Ziekenhuis Gent	Gent
Belgium	Universitaire Ziekenhuizen Leuven - Campus Gasthuisberg	Leuven
Czechia	Masarykuv onkologicky ustav	Brno	Brno-mesto
Czechia	Fakultni nemocnice Hradec Kralove	Hradec Kralove
Czechia	Fakultni Nemocnice v Motole	Praha 5
Denmark	Aarhus Universitetshospital, Aarhus Sygehus	Aarhus C
Denmark	Odense Universitetshospital	Odense C
France	CHU de Besancon Hopital Jean Minjoz	Besancon Cedex
France	CHU de Bordeaux Hop St ANDRE	Bordeaux	Gironde
France	Hôpital C. HURIEZ	Lille
France	Centre Leon Berard	Lyon	Rhône-Alpes
France	CHRU de Montpellier-Hopital St Eloi	Montpellier Cedex 5
France	Centre Antoine-Lacassagne	Nice
France	Gustave Roussy	Villejuif Cedex
Germany	HELIOS Klinikum Berlin-Buch	Berlin
Germany	Universitätsklinikum Erlangen	Erlangen	Bayern
Germany	Universitaetsklinikum Hamburg-Eppendorf	Hamburg
Germany	Medizinische Hochschule Hanover	Hannover	Niedersachsen
Germany	Universitätsklinikum Tübingen	Tübingen	Baden-Württemberg
Germany	Universitätsklinikum Ulm	Ulm	Baden-Württemberg
Hungary	Del-pesti Centrumkorhaz - Orszagos Hematologiai es Infektologiai Intezet	Budapest
Hungary	Debreceni Egyetem Klinikai Kozpont Onkologiai Tanszek	Debrecen	Hajdu-Bihar
Korea, Republic of	Asan Medical Center	Seoul	Korea
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul	Seoul, Korea
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Mexico	Arke Estudios Clinicos S.A. de C.V.	Mexico	DF
Mexico	Instituto Nacional de Ciencias Medicas y Nutrici Salva Zubir	Mexico City
Mexico	Centro de Alta Especialidad Reumatologia Inv del Potosi SC	San Luis Potosi
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	Russian Scientific Center of Radiology and Surgical Technologies	St. Petersburg	Sankt-Peterburg
Spain	Hospital Clínico Universitario de Valencia	Barcelona
Spain	Hospital Duran I Reynals	Hospitalet De Llobregat	Barcelona
Spain	Hospital Clinico de San Carlos	Madrid
Spain	Hospital General Universitario Gregorio Marañon	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Sweden	Skåne universitetssjukhus	Malmö
Sweden	Karolinska Universitetssjukhuset i Solna	Stockholm
Taiwan	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
Turkey	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
United Kingdom	Hammersmith Hospital	Acton	London
United Kingdom	The Clatterbridge Cancer Centre	Bebbington	Merseyside
United Kingdom	University College Hospital - London	London	Greater London
United Kingdom	The Christie NHS Foundation Trust	Manchester	Greater Manchester
United Kingdom	Royal Marsden Hospital	Sutton	Surrey
United States	Washington University Medical School	Creve Coeur	Missouri
United States	Karmanos Cancer Institute	Detroit	Michigan
United States	University of Florida School of Medicine	Gainesville	Florida
United States	Florida Cancer Specialists	Nashville	Tennessee
United States	Tennessee Oncology PLLC	Nashville	Tennessee
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Thomas Jefferson University	Philadelphia	Pennsylvania
United States	Washington University Medical School	Saint Louis	Missouri
United States	Washington University Medical School	Saint Louis	Missouri
United States	Washington University Medical School	Saint Peters	Missouri
United States	UCSF Medical Center at Mission Bay	San Francisco	California
United States	The University of Arizona Cancer Center	Tucson	Arizona
United States	Georgetown University Medical Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Eli Lilly and Company

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Czechia,  Denmark,  France,  Germany,  Hungary,  Korea, Republic of,  Mexico,  Russian Federation,  Spain,  Sweden,  Taiwan,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)

External Links

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