Gemcitabine Plus Cisplatin With or Without Bintrafusp Alfa (M7824) in Participants With 1L BTC

Cholangiocarcinoma Clinical Trial

Official title:

A Phase II/III, Multicenter, Randomized, Placebo-controlled Study of Gemcitabine Plus Cisplatin With or Without Bintrafusp Alfa (M7824) as First-line Treatment of Biliary Tract Cancer

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04066491
• Other study ID #: MS200647_0055
• Secondary ID: 2019-001992-35
• Status: Terminated
• Phase: Phase 2/Phase 3
• Start date: September 20, 2019
• Est. completion date: November 10, 2022

Study information

• Verified date: October 2023
• Source: EMD Serono
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Study consisted of an open-label, safety run-in part and a randomized, double-blind, placebo-controlled Phase 2/3 part. In the Phase 2/3 part, the study was evaluated whether bintrafusp alfa in combination with the current standard of care (SoC) (gemcitabine plus cisplatin) improves overall survival (OS) in chemotherapy and immunotherapy-naïve participants with locally advanced or metastatic Biliary Tract Cancer (BTC) compared to placebo, gemcitabine and cisplatin.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 309
• Est. completion date: November 10, 2022
• Est. primary completion date: May 20, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Are participants with histologically or cytologically confirmed locally advanced or metastatic BTC

• Participants must have available tumor tissue (primary or metastatic) (archival or fresh biopsies) before the first administration of study treatment

• At least 1 measurable lesion according to RECIST 1.1

• Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 at study entry and at Week 1, Day 1 prior to dosing

• Life expectancy of >= 12 weeks, as judged by the Investigator

• Adequate hematological function, hepatic function, renal function, coagulation function as defined in the protocol

• Hepatitis B virus (HBV) deoxyribonucleic acid (DNA) positive participants must be treated and on a stable dose of antivirals

• Other protocol defined inclusion criteria could apply

Exclusion Criteria:

• Previous and/or intercurrent cancers

• Receipt of any organ transplantation, including allogeneic stem-cell transplantation, but with the exception of transplants that do not require immunosuppression

• Participants with symptomatic central nervous system (CNS) metastases

• Significant acute or chronic infection including known history of positive test for human immunodeficiency virus (HIV), active tuberculosis, uncontrolled biliary infection and active bacterial or fungal infection requiring systemic therapy (with the exception of hepatitis B and hepatitis C) requiring systemic therapy at study entry and at Week 1 Day 1 prior to dosing.

• Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent

• History of or concurrent interstitial lung disease

• History of hypersensitivity reactions to bintrafusp alfa, anaphylaxis, or recent (within 5 months) uncontrolled asthma, cardiovascular/cerebrovascular disease

• Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before randomization

• Prior therapy with any antibody/drug targeting T-cell coregulatory proteins (immune checkpoints)

• Other protocol defined exclusion criteria could apply

Related Conditions & MeSH terms

• Biliary Tract Cancer
• Biliary Tract Neoplasms
• Cholangiocarcinoma
• Gallbladder Cancer
• Gallbladder Neoplasms

Intervention

Drug:
• M7824
Participants received intravenous infusion of M7824 at a dose of 2400 milligrams (mg), once every 3 weeks (Q3W) 2 years (in case of Complete Response), otherwise until criterion pre-sepcified in protocol for discontinuation is met, in combination with intravenous infusion of Gemcitabine and Cisplatin at a dose of 1000 milligram per meter square (mg/m^2) and 25 mg/m^2 respectively on Day 1 and Day 8 of 21- day cycle, for 8 cycles every 3 weeks.
• Placebo
Participants received intravenous infusion of M7824 matched placebo, once every 3 weeks (Q3W) until 2 years (in case of CR), otherwise until crtiterion pre-sepcified in protocol for discontinuation is met.
• Gemcitabine
Gemcitabine was received intravenously at a dose of 1000 milligram per meter square (mg/m^2) on Day 1 and Day 8 of 21- day cycle, for 8 cycles every 3 weeks (Q3W).
• Cisplatin
Cisplatin was received intravenously at a dose of 25 mg/m^2 on Day 1 and Day 8 of 21-day cycle, for 8 cycles every 3 weeks (Q3W).

Locations

Country	Name	City	State
Argentina	Hospital de Gastroenterologia Dr. Carlos Bonorino Udaondo	Ciudad Autonoma Buenos Aires
Argentina	Instituto de Investigaciones Metabolicas (IDIM)	Ciudad Autonoma Buenos Aires
Argentina	Instituto Medico Especializado Alexander Fleming	Ciudad Autonoma Buenos Aires
Argentina	Centro Oncologico Riojano Integral (CORI)	La Rioja
Argentina	CEDIT	Salta
Argentina	Centro Medico San Roque S.R.L.	San Miguel de Tucuman
Argentina	Fundacion ARS Medica	San Salvador de Jujuy
Australia	Blacktown Hospital - PARENT	Blacktown
Australia	Monash Health	Clayton
Australia	Epworth Freemasons	Melbourne
Australia	Icon Cancer Care South Brisbane	South Brisbane
Brazil	Hospital de Câncer de Barretos - Fundação Pio XII	Barretos
Brazil	INCA - Instituto Nacional de Câncer	Rio de Janeiro
Brazil	CEPHO - Centro de Estudos e Pesquisas de Hematologia e Oncologia	Santo André
Brazil	Fundação Faculdade Regional de Medicina de São José do Rio Preto	Sao Jose Rio Preto
Brazil	A. C. Camargo Cancer Center	São Paulo
Brazil	ICESP - Instituto do Câncer do Estado de São Paulo Octavio Frias de Oliveira	São Paulo
Chile	IC la serena Research	La Serena
Chile	Centro de Investigación Clínica Bradford Hill	Santiago
Chile	Hospital Clínico Universidad de Chile	Santiago
Chile	Prosalud	Santiago
Chile	Instituto Clinico Oncologico del Sur (ICOS)	Temuco
China	Beijing Cancer Hospital	Beijing
China	Beijing Chao Yang Hospital	Beijing
China	Beijing Friendship Hospital, Capital Medical University	Beijing
China	West China Hospital, Sichuan University	Chengdu
China	Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine	Hangzhou
China	The Affiliated Hospital of Qingdao University	Qingdao
China	Fudan University Shanghai Cancer Hospital	Shanghai
China	The Second Affiliated Hospital of Soochow University	Suzhou
China	Tianjin Medical University Cancer Institute & Hospital	Tianjin
China	Union Hospital Tongji Medical College Huazhong University of Science and Technology	Wuhan
France	ICO - Site Paul Papin - service d'oncologie medicale	Angers Cedex 2
France	Centre Georges François Leclerc - Oncologie Médicale	Dijon cedex
France	CHU Lille - Hôpital Claude Huriez	Lille cedex
France	ICO - Site René Gauducheau	Saint Herblain
France	CHU de Toulouse - Hôpital Ranguei	Toulouse Cedex 9
Germany	Vivantes Klinikum Neukoelln - Haematologie und Onkologie	Berlin
Germany	Universitaetsklinikum Bonn AoeR - Medizinische Klinik I Gastroenterologie	Bonn
Germany	Universitaetsklinikum Carl Gustav Carus TU Dresden - Medizinische Klinik I	Dresden
Germany	Klinikum der Johann Wolfgang Goethe-Universitaet	Frankfurt
Germany	Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz - Medizinische Klinik I - HCC Ambulanz	Mainz
Italy	Fondazione IRCCS Istituto Nazionale dei Tumori Milano	Milano
Italy	IOV - Istituto Oncologico Veneto IRCCS - S.Semplice Dip.Oncologia dei Melanomi	Padova
Italy	Università Campus Bio-Medico di Roma	Roma
Italy	Azienda Ospedaliera Universitaria Integrata Verona (Ospedale Borgo Roma) - UOC Oncologia	Verona
Japan	Chiba Cancer Center	Chiba-shi
Japan	National Cancer Center Hospital - Dept of Hepatobiliary and Pancreatic Oncology	Chuo-ku
Japan	NHO Kyushu Cancer Center - Dept of Gastroenterology/Hepatology/Pancreatology	Fukuoka-shi
Japan	National Cancer Center Hospital East	Kashiwa-shi
Japan	Cancer Institute Hospital of JFCR - Dept of Hepato,Biliary and Pancreatic Medicine	Koto-ku
Japan	Kyorin University Hospital	Mitaka-shi
Japan	Aichi Cancer Center Hospital	Nagoya-shi
Japan	Osaka City University Hospital	Osaka-shi
Japan	Kindai University Hospital	Osakasayama-shi
Japan	Kanagawa Cancer Center	Yokohama-shi
Korea, Republic of	Chungnam National University Hospital - Department of Internal Medicine (Rheumatology)	Daejeon
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam-si
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Korea University Anam Hospital	Seoul
Korea, Republic of	Korea University Guro Hospital	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Korea, Republic of	The Catholic University of Korea, Seoul St. Mary's Hospital	Seoul
Poland	Centrum Onkologii-Instytut im.M.Sklodowskiej Curie	Gliwice
Poland	Pratia	Krakow
Poland	Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - Panstwowy Instytut Badawczy	Warszawa
Poland	ETG Zamosc	Zamosc
Spain	Hospital Clinic i Provincial de Barcelona - Servicio de Oncologia	Barcelona
Spain	Hospital Universitari Vall d'Hebron - Dept of Oncology	Barcelona
Spain	Hospital San Pedro de Alcantara - Servicio de Oncologia	Caceres
Spain	Hospital Universitario Reina Sofia - Dept of Oncology	Cordoba
Spain	ICO l´Hospitalet - Hospital Duran i Reynals	L'Hospitalet de Llobregat
Spain	Hospital General Universitario Gregorio Marañon - Servicio de Oncologia Medica	Madrid
Spain	Hospital Universitario Clinico San Carlos - Servicio de Oncologia	Madrid
Spain	Hospital Universitario HM Madrid Sanchinarro - Servicio de Oncologia	Madrid
Spain	Hospital Clinico Universitario de Valencia - Servicio de Hematologia y Oncologia Medica	Valencia
Spain	Hospital Universitari i Politecnic La Fe - Servicio de Oncologia Medica	Valencia
Taiwan	Kaohsiung Chang Gung Memorial Hospital	Kaohsiung
Taiwan	China Medical University Hospital	Taichung
Taiwan	Taichung Veterans General Hospital	Taichung
Taiwan	National Cheng Kung University Hospital	Tainan
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei
Taiwan	Chang Gung Memorial Hospital, Linkou	Taoyuan
United Kingdom	The Christie - Dept of Oncology	Manchester
United States	Sidney Kimmel Comprehensive Cancer Center at John Hopkins	Baltimore	Maryland
United States	Beverly Hills Cancer Center	Beverly Hills	California
United States	Ironwood Cancer & Research Centers - Chandler II	Chandler	Arizona
United States	Methodist Transplant Physicians	Dallas	Texas
United States	Banner MD Anderson Cancer Center	Gilbert	Arizona
United States	MD Anderson Cancer Center - Unit 429	Houston	Texas
United States	Mayo Clinic in Florida - Department of Neurology	Jacksonville	Florida
United States	Mount Sinai Medical Center	Miami Beach	Florida
United States	Mayo Clinic Arizona	Phoenix	Arizona
United States	Mayo Clinic - Rochester	Rochester	Minnesota
United States	Renovatio Clinical - CENTRAL SITE	The Woodlands	Texas
United States	University of Kansas Medical Center Research Institute, Inc. - University of Kansas Cancer Center/Bloch Pavilion	Westwood	Kansas

Sponsors (2)

Lead Sponsor	Collaborator
EMD Serono Research & Development Institute, Inc.	Merck KGaA, Darmstadt, Germany

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Brazil,  Chile,  China,  France,  Germany,  Italy,  Japan,  Korea, Republic of,  Poland,  Spain,  Taiwan,  United Kingdom, 

References & Publications (1)

Yoo C, Oh DY, Choi HJ, Kudo M, Ueno M, Kondo S, Chen LT, Osada M, Helwig C, Dussault I, Ikeda M. Phase I study of bintrafusp alfa, a bifunctional fusion protein targeting TGF-beta and PD-L1, in patients with pretreated biliary tract cancer. J Immunother C — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety Run-in Part: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs)	A DLT is a toxicity related to the study intervention that meets the following criteria as evaluated in the open-label, safety run-in: Grade 3 or 4 Immune-related adverse event (irAE) that needs permanent discontinuation of M7824 treatment; a malignant skin lesion induced by M7824 that is local and can be resected with a negative resection margin is not a DLT; Grade 3 or 4 nonhematologic toxicity other than irAE, A life threatening hematological toxicity (unless clearly attributable to chemotherapy alone), which is hardly medically manageable, including a bleeding event resulting in urgent intervention and admission to an intensive care unit and Grade 5 toxicity.	Day 1 up to Day 21 of Cycle 1 (each Cycle is of 21 days)
Primary	Double-blind Part: Overall Survival	Overall Survival was defined as the time from study day 1 to the date of death due to any cause. The overall survival was analyzed by using the Kaplan-Meier method.	Time from study day 1 up to data cutoff (assessed up to 609 days)
Secondary	Safety Run-in Part: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs (SAEs) and Treatment Related TEAEs According to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0	Adverse Event (AE) was defined any untoward medical occurrence in a participant administered with a study drug, which does not necessarily had a causal relationship with this treatment. Serious AE was defined AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAE was defined as events with onset date or worsening during the on treatment period. TEAEs included serious TEAEs and non-serious TEAEs.	Time from first treatment up to data cutoff (assessed up to 609 days)
Secondary	Safety Run-in Part: Number of Participants With Grade Greater Than or Equal (>=) 3 Laboratory Abnormalities	Laboratory investigation included hematology and biochemistry. The number of participants with Grade >=3 laboratory abnormalities were reported. Severity of grade 3 or higher TEAEs were graded using NCI-CTCAE v5.0 toxicity grades, as follows: Grade 3 = Severe; Grade 4 = Life-threatening and Grade 5 = Death.	Time from first treatment up to data cutoff (assessed up to 609 days)
Secondary	Double-blind Part: Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) Assessed by Independent Review Committee (IRC)	Progression free survival was defined as the time from randomization of study intervention until the first documentation of disease progression (PD) or death due to any cause in the absence of documented PD, whichever occurred first. PD: At least a 20 percent (%) increase in the sum of the longest diameter (SLD) taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.	Time from randomization of study drug until the first documentation of PD or death, assessed up to 609 days
Secondary	Double-blind Part: Percentage of Participants With Confirmed Objective Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Independent Review Committee (IRC)	Percentage of participants with confirmed objective response that is at least one overall assessment of complete response (CR) or partial response (PR) reported here. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Confirmed CR = at least 2 determinations of CR at least 4 weeks apart and before progression. Confirmed PR = at least 2 determinations of PR at least 4 weeks apart and before progression (and not qualifying for a CR). Confirmed objective response was determined according to RECIST v1.1 and as adjudicated by IRC.	Time from randomization of study drug up to data cut off (assessed up to 609 days)
Secondary	Double-blind Part: Duration of Response (DOR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) as Assessed by Independent Review Committee (IRC)	DOR was defined for participants with objective response, as the time from first documentation of objective response (confirmed Complete Response [CR] or Partial Response [PR]) to the date of first documentation of progression disease (PD) or death due to any cause, whichever occurred first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions. PD: At least a 20 percent (%) increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. DOR was determined according to RECIST v1.1 and assessed by IRC. Results were calculated based on Kaplan-Meier estimates.	From first documented objective response to PD or death due to any cause, assessed up to 609 days
Secondary	Double-blind Part: Durable Response of at Least 6 Months According to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 as Assessed by Investigator	Durable Response was defined as the number of participants with confirmed objective response (CR or PR) according to RECIST 1.1, determined by Investigator with duration of at least 6 months. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions.	Time from first treatment assessed up to 1148 days
Secondary	Double-blind Part: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs (SAEs), Treatment Related TEAEs and Adverse Events of Special Interest (AESIs) According to NCI-CTCAE Version 5.0	AE was defined any untoward medical occurrence in a participant administered with a study drug, which does not necessarily had a causal relationship with this treatment. Serious AE was defined AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAE was defined as events with onset date or worsening during the on treatment period. TEAEs included serious TEAEs and non-serious TEAEs. Adverse events of special interest (AESI) are serious or non-serious AEs that are of clinical interest and should be closely followed. For this study, AESIs include the following: Infusion-related reactions including immediate hypersensitivity; Immune-related AEs; Transforming growth factor beta (TGFß) inhibition mediated skin reactions; Anemia; Bleeding AEs.	Time from first treatment up to data cutoff (assessed up to 609 days)

External Links

•   Trial Awareness and Transparency website