Clinical trial NCT03773302: Phase 3 Study of BGJ398 (Oral Infigratinib) in First Line Cholangiocarcinoma With FGFR2 Gene Fusions/Translocations
Official title: A Phase 3 Multicenter, Open-Label, Randomized, Controlled Study of Oral Infigratinib Versus Gemcitabine With Cisplatin in Subjects With Advanced/Metastatic or Inoperable Cholangiocarcinoma With FGFR2 Gene Fusions/Translocations: The PROOF Trial
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Advanced Cholangiocarcinoma
FGFR2 Gene Mutation
Keywords: cholangiocarcinoma
unresectable cholangiocarcinoma
metastatic cholangiocarcinoma
fibroblast growth factor receptor inhibitor
FGFR2
FGFR2 gene fusions/translocations
BGJ398
Lead sponsor: QED Therapeutics, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Helsinn Healthcare SA
First posted: 2018-12-12
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicenter, Open Label, 2:1 Randomized, Controlled Phase 3
Primary purpose: TREATMENT

Brief summary: Infigratinib is an oral drug which selectively binds to fibroblast growth factor receptor (FGFR) 2 and is being developed to treat participants with FGFR2 mutated cholangiocarcinoma. The purpose of the study is to evaluate the efficacy and safety of the investigational agent oral infigratinib vs standard of care chemotherapy (gemcitabine plus cisplatin) in first-line treatment of participants with unresectable locally advanced or metastatic cholangiocarcinoma with FGFR2 fusion/rearrangement. Subjects will be randomized 2:1 to receive infigratinib or gemcitabine plus cisplatin.


Eligibility criteria: Inclusion Criteria:

* Histologically or cytologically confirmed unresectable locally advanced or metastatic cholangiocarcinoma. Participants with gallbladder cancer or ampulla of Vater carcinoma are not eligible
* Have written documentation of local laboratory or central laboratory determination of a known or likely activating FGFR2 fusion/rearrangement from a sample collected before randomization
* Have an archival tumor tissue sample available with sufficient tumor content for FGFR2 fusion/rearrangement molecular testing by the central laboratory. However, if an archival tumor tissue sample is not available, or does not meet requirements for central testing a newly obtained (before randomization) tumor biopsy may be submitted instead. If a prestudy written documentation of FGFR2 fusion/rearrangement in tumor tissue is available from the central laboratory, an additional tumor sample does not need to be submitted.
* Have an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
* Are able to swallow and retain oral medication
* Are willingness to avoid pregnancy or father children

Exclusion Criteria:

* Received treatment with any systemic anti-cancer therapy for unresectable locally advanced or metastatic cholangiocarcinoma, with following exceptions

  1. Prior neoadjuvant or adjuvant therapy is permitted if completed \> 6 months after the last dose of neoadjuvant or adjuvant therapy.
  2. One cycle of gemcitabine-based chemotherapy for locally advanced or metastatic cholangiocarcinoma is permitted before randomization
* History of a liver transplant
* Received previously or currently is receiving treatment with a mitogen activated protein kinase kinase (MEK) or selective FGFR inhibitor
* Have impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral infigratinib (such as, ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection).
* Current evidence of endocrine alterations of calcium/phosphate homeostasis, e.g., parathyroid disorders, history of parathyroidectomy, tumor lysis, tumoral calcinosis etc.
* History and/or current evidence of extensive tissue calcification including, but not limited to, the soft tissue, kidneys, intestine, myocardium, vascular system and lung with the exception of calcified lymph nodes, minor pulmonary parenchymal calcifications, and asymptomatic coronary calcification
* Current evidence of corneal or retinal disorder/keratopathy
* Receiving and continued treatment or are planning to receive agents or consuming foods that are known moderate or strong inducers or inhibitors of CYP3A4 and medications which increase serum phosphorus and/or calcium concentration
* Clinically significant or uncontrolled cardiac disease
* Recent (≤ 3 months prior to first dose of study drug) transient ischemic attack or stroke
* Severe hearing loss
* Severe neuropathy
* History of another primary malignancy within 3 years except adequately treated in-situ carcinoma of the cervix or non-melanoma skin cancer or other curatively treated malignancy that is not expected to require treatment
* Pregnant or breastfeeding
* Have known microsatellite instability-high (MSI-H) disease and the decision is made by the treating investigator that an alternative, non-study therapy is warranted according to standard of care.
* Have any known hypersensitivity to gemcitabine, cisplatin, calcium-lowering agents, infigratinib, or their excipients
* Have any contraindication to cisplatin or gemcitabine treatment according to local labeling or standard institutional practice.
* Have taken any Chinese herbal medicine or Chinese patent medicine treatments with anticancer activity within 14 days of the first dose of study drug.
* Have received a live vaccine within 30 days before the first dose of study drug or are planning to receive a live vaccine during participation in this study

Primary outcomes:
measure: Progression-free Survival (Central Imaging Assessment)
timeFrame: From the time of randomization to end of treatment due to confirmed disease progression or death. Note: PFS is an event driven endpoint. Subjects without confirmed disease progression at the end of study were censored at their last valid tumor assessment.
Secondary outcomes:
measure: Overall Survival (OS) in Participants Treated With Infigratinib Versus Gemcitabine With Cisplatin
timeFrame: From the time of randomization to time of death. Note: OS is an event driven endpoint. Subjects who had not died (no record of death) or were lost to follow-up were censored at the date of last known to be alive.
measure: Investigator Assessed Progression Free Survival in Participants Treated With Infigratinib Compared to Gemcitabine and Cisplatin
timeFrame: From the time of randomization to end of treatment due to confirmed disease progression or death. Note: PFS is an event driven endpoint. Subjects without confirmed disease progression at the end of study were censored at their last valid tumor assessment.
measure: Overall Response Rate (ORR) Determined by Blinded Independent Central (BICR) and Investigator Assessment
timeFrame: From the time of randomization to end of study treatment (an average of approx.6.5 months [max: 23 months] for the infigratinib arm and approx. 4 months [max: 11-13 months] for the gemcitabine + cisplatin arm up to the time of termination of the study).
measure: Best Overall Response (BOR) Determined by Blinded Independent Central Assessment and the Investigator.
timeFrame: From the time of randomization to end of study treatment (an average of approx.6.5 months [max: 23 months] for the infigratinib arm and approx. 4 months [max: 11-13 months] for the gemcitabine + cisplatin arm up to the time of termination of the study).
measure: Duration of Response (DOR) Determined by Blinded Independent Central Assessment and the Investigator.
timeFrame: From the time of randomization to end of study treatment (an average of approx.6.5 months [max: 23 months] for the infigratinib arm and approx. 4 months [max: 11-13 months] for the gemcitabine + cisplatin arm up to the time of termination of the study).
measure: Disease Control Rate (DCR=PR+CR+SD) Determined by Blinded Independent Central Assessment and the Investigator.
timeFrame: From the time of randomization to end of study treatment (an average of approx.6.5 months [max: 23 months] for the infigratinib arm and approx. 4 months [max: 11-13 months] for the gemcitabine + cisplatin arm up to the time of termination of the study).
measure: Number of Participants With Adverse Events (AEs)
timeFrame: From baseline to last dose date of study treatment + 30 days (an average of 7.5 months for the infigratinib arm and 5 months for the gemcitabine + cisplatin arm).
measure: Number of Participants With Serious Adverse Events (SAEs)
timeFrame: From baseline to last dose date of study treatment + 30 days (an average of 7.5 months for the infigratinib arm and 5 months for the gemcitabine + cisplatin arm).
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Center
state: Arizona
city: Tucson
country: United States
facility: University of Arizona
state: Arizona
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: Fullerton
country: United States
facility: St. Joseph Heritage Healthcare
state: California
city: Los Angeles
country: United States
facility: USC Norris Cancer Center
state: California
city: Los Angeles
country: United States
facility: University of California Los Angeles
state: California
city: Orlando
country: United States
facility: Florida Hospital Medical Group
state: Florida
city: Orlando
country: United States
facility: UF Health Cancer Center at Orlando Health
state: Florida
city: Chicago
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
city: New Orleans
country: United States
facility: University Medical Center - New Orleans
state: Louisiana
city: Frederick
country: United States
facility: Frederick Regional Healthcare Systems/James M. Stockman Cancer Institute
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute - Lawrence and Idell Weisberg Cancer Treatment Center
state: Michigan
city: Grand Rapids
country: United States
facility: Cancer and Hematology Centers of Western Michigan
state: Michigan
city: Royal Oak
country: United States
facility: William Beaumont Hospital
state: Michigan
city: New York
country: United States
facility: NYU Langone Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Charlotte
country: United States
facility: Levine Cancer Institute - Charlotte
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
city: Charleston
country: United States
facility: Charleston Oncology
state: South Carolina
city: Dallas
country: United States
facility: Parkland Health and Hospital System
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Camperdown
country: Australia
facility: Chris O'Brien Lifehouse Hospital
state: New South Wales
city: Darlinghurst
country: Australia
facility: Blacktown Hospital
state: New South Wales
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Bentleigh East
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Frankston
country: Australia
facility: Peninsula & South Eastern Haematology and Oncology Group
state: Victoria
city: Subiaco
country: Australia
facility: St John of God Hospital Subiaco
state: Western Australia
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires Saint-Luc
state: Brussels
city: Charleroi
country: Belgium
facility: Grand Hopital de Charleroi
city: Edegem
country: Belgium
facility: Universitair Ziekenhuis Antwerpen
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Ottawa
country: Canada
facility: Ottawa Hospital
state: Ontario
city: Toronto
country: Canada
facility: St. Josephs Health Centre
state: Ontario
city: Montréal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Beijing
country: China
facility: Peking University People's Hospital
city: Beijing
country: China
facility: Beijing Cancer Hospital
city: Beijing
country: China
facility: Peking University Third Hospital
city: Changsha
country: China
facility: Hunan Cancer Hospital
city: Guangzhou
country: China
facility: Guangzhou First People's Hospital
city: Hubei
country: China
facility: Hubei Cancer Hospital
city: Shenyang
country: China
facility: Liaoning Cancer Hospital & Institute
city: Zhongshan
country: China
facility: The First Affiliated Hospital, Sun Yat-sen University
city: Créteil
country: France
facility: Hopital Henri Mondor
state: Val-de-Marne
city: Dijon
country: France
facility: CHRU Dijon
city: Dijon
country: France
facility: Centre Georges-Francois Leclerc
city: Lille
country: France
facility: Hopital Claude Huriez Rue Michel Polonovski (CHRU) Lille
city: Lyon
country: France
facility: Groupement Hospitalier Edouard Herriot
city: Montbéliard
country: France
facility: Hopital Nord Franche-Comte
city: Nice
country: France
facility: Groupe Hospitalier Archet I Et II
city: Paris
country: France
facility: Hopital Cochin
city: Paris
country: France
facility: Hôpital Saint Antoine
city: Paris
country: France
facility: L'Institut Mutualiste Montsouris
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen
state: Baden-Wurttemberg
city: München
country: Germany
facility: Klinikum rechts der Isar der Technischen Universität München
state: Bayern
city: Dortmund
country: Germany
facility: Klinikum Dortmund gGmbH
city: Heidelberg
country: Germany
facility: University Clinic Heidelberg
city: Cremona
country: Italy
facility: Azienda Socio Sanitaria Territoriale di Cremona (ASST)
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori IRST
city: Milano
country: Italy
facility: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
city: Milano
country: Italy
facility: ASST Grande Ospedale Metropolitano Niguarda
city: Padova
country: Italy
facility: Istituto Oncologico Veneto - I.R.C.C.S.
city: Roma
country: Italy
facility: Policlinico Universitario Campus Biomedico Di Roma
city: Pusan
country: Korea, Republic of
facility: Pusan National University Hospital
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: SMG - SNU Boramae Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea, Seoul St. Mary's Hospital
city: Suwon-si
country: Korea, Republic of
facility: Ajou University Hospital
city: Loures
country: Portugal
facility: Hospital Beatriz Angelo
state: Lisboa
city: Almada
country: Portugal
facility: Hospital Garcia de Orta
city: Coimbra
country: Portugal
facility: Centro Hospitalar E Universitário de Coimbra EPE
city: Coimbra
country: Portugal
facility: Instituto Português de Oncologia Francisco Gentil Centro Regional de Oncologia de Coimbra EPE
city: Lisboa
country: Portugal
facility: Centro Hospitalar Lisboa Norte, E.P.E. - Hospital de Santa Maria
city: Lisboa
country: Portugal
facility: Hospital CUF Descobertas
city: Lisbon
country: Portugal
facility: Instituto Português de Oncologia de Lisboa Francisco Gentil, E.P.E.
city: Porto
country: Portugal
facility: Centro Hospitalar do Porto - Hospital de Santo António
city: Porto
country: Portugal
facility: Instituto Portugues de Oncologia Do Porto Francisco Gentil Epe - PPDS
city: Porto
country: Portugal
facility: Centro Hospitalar de São João, E.P.E.
city: Rio Piedras
country: Puerto Rico
facility: Hospital Oncologico, Puerto Rico Medical Center
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena
state: Andalucia
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
state: Aragon
city: Salamanca
country: Spain
facility: Complejo Asistencial Universitario de Salamanca - Hospital Clinico
state: Castilla Y Leon
city: Badalona
country: Spain
facility: Hospital Universitario Germans Trias i Pujol
state: Cataluna
city: Barcelona
country: Spain
facility: Instituto Catalan de Oncologio ICO I'Hospitalet
state: Cataluna
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebrón - PPDS
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Maranon
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Madrid
country: Spain
facility: Hospital Universitario HM Sanchinarro - CIOCC
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe de Valencia
city: Tainan City
country: Taiwan
facility: National Cheng Kung University Hospital
state: Tainan
city: Huwei
country: Taiwan
facility: National Taiwan University Hospital - YunLin Branch
city: Kaohsiung
country: Taiwan
facility: Chang Gung Memorial Hospital - Kaohsiung
city: Taichung City
country: Taiwan
facility: China Medical University Hospital
city: Tainan
country: Taiwan
facility: Chi Mei Hospital, Liouying
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taoyuan City
country: Taiwan
facility: Chang Gung Memorial Hospital, Linkou
city: Hat Yai
country: Thailand
facility: Songklanagarind Hospital, Prince of Songkla University
state: Songkla
city: Bangkok
country: Thailand
facility: Chulalongkorn University
city: Bangkok
country: Thailand
facility: Ramathibodi Hospital Mahidol University
city: Chiang Mai
country: Thailand
facility: Maharaj Nakorn Chiang Mai Chiang Mai University
city: Khon Kaen
country: Thailand
facility: Srinagarind Hospital
city: Phitsanulok
country: Thailand
facility: Naresuan University
city: Nottingham
country: United Kingdom
facility: Nottingham City Hospital
state: Nottinghamshire
city: Sutton
country: United Kingdom
facility: Royal Marsden Hospital
state: Surrey
city: Bebington
country: United Kingdom
facility: The Clatterbridge Cancer Centre NHS Foundation Trust
state: Wirral
city: London
country: United Kingdom
facility: Guys Hospital
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust - PPDS
Study officials:
affiliation: QED Therapeutics
name: Clinical Development
role: STUDY_DIRECTOR
References:
citation: Makawita S, K Abou-Alfa G, Roychowdhury S, Sadeghi S, Borbath I, Goyal L, Cohn A, Lamarca A, Oh DY, Macarulla T, T Shroff R, Howland M, Li A, Cho T, Pande A, Javle M. Infigratinib in patients with advanced cholangiocarcinoma with FGFR2 gene fusions/translocations: the PROOF 301 trial. Future Oncol. 2020 Oct;16(30):2375-2384. doi: 10.2217/fon-2020-0299. Epub 2020 Jun 25.