Phase 3 Study of BGJ398 (Oral Infigratinib) in First Line Cholangiocarcinoma With FGFR2 Gene Fusions/Translocations

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

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.

Study Overview

• Status: Terminated
• Conditions: FGFR2 Gene Mutation; Advanced Cholangiocarcinoma
• Intervention / Treatment: Drug: BGJ398; Drug: Gemcitabine; Drug: Cisplatin

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia
      • Chris O'Brien Lifehouse Hospital
    • Darlinghurst, New South Wales, Australia
      • Blacktown Hospital
  • South Australia
    • Adelaide, South Australia, Australia
      • Royal Adelaide Hospital
  • Victoria
    • Bentleigh East, Victoria, Australia
      • Monash Medical Centre
    • Frankston, Victoria, Australia
      • Peninsula & South Eastern Haematology and Oncology Group
  • Western Australia
    • Subiaco, Western Australia, Australia
      • St John of God Hospital Subiaco
• Belgium
  • Charleroi, Belgium, 6000
    • Grand Hôpital de Charleroi
  • Edegem, Belgium, 2650
    • Universitair Ziekenhuis Antwerpen
  • Brussels
    • Bruxelles, Brussels, Belgium, 1200
      • Cliniques Universitaires Saint-Luc
• Canada
  • Alberta
    • Edmonton, Alberta, Canada
      • Cross Cancer Institute
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • Ottawa Hospital
    • Toronto, Ontario, Canada
      • St. Josephs Health Centre
  • Quebec
    • Montréal, Quebec, Canada, H3T 1E2
      • Jewish General Hospital
• China
  • Beijing, China, 100142
    • Beijing Cancer Hospital
  • Beijing, China, 100191
    • Peking University Third Hospital
  • Beijing, China, 100033
    • Peking University People's Hospital
  • Changsha, China, 410006
    • Hunan Cancer Hospital
  • Guangzhou, China, 510080
    • Guangzhou First People's Hospital
  • Hubei, China, 430079
    • Hubei Cancer Hospital
  • Shenyang, China, 110042
    • Liaoning Cancer Hospital & Institute
  • Zhongshan, China, 510060
    • The First Affiliated Hospital, Sun Yat-sen University
• France
  • Dijon, France, 21079
    • Centre georges-François Leclerc
  • Dijon, France, 21000
    • CHRU Dijon
  • Lille, France, 59000
    • Hopital Claude Huriez Rue Michel Polonovski (CHRU) Lille
  • Lyon, France, 69437
    • Groupement Hospitalier Edouard Herriot
  • Montbéliard, France, 25200
    • Hôpital Nord Franche-Comté
  • Nice, France, 06202
    • Groupe Hospitalier Archet I Et II
  • Paris, France, 75014
    • Hopital Cochin
  • Paris, France, 75571
    • Hôpital Saint Antoine
  • Paris, France, 75674
    • L'Institut Mutualiste Montsouris
  • Val-de-Marne
    • Créteil, Val-de-Marne, France, 94000
      • Hopital Henri Mondor
• Germany
  • Dortmund, Germany, 44137
    • Klinikum Dortmund gGmbH
  • Heidelberg, Germany, 69120
    • University Clinic Heidelberg
  • Baden-Wurttemberg
    • Tübingen, Baden-Wurttemberg, Germany, 72076
      • Universitätsklinikum Tübingen
  • Bayern
    • München, Bayern, Germany, 81675
      • Klinikum rechts der Isar der Technischen Universität München
• Italy
  • Cremona, Italy, 26100
    • Azienda Socio Sanitaria Territoriale di Cremona (ASST)
  • Meldola, Italy, 47014
    • Istituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori IRST
  • Milano, Italy, 20122
    • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
  • Milano, Italy, 20162
    • Asst Grande Ospedale Metropolitano Niguarda
  • Padova, Italy, 35128
    • Istituto Oncologico Veneto - I.R.C.C.S.
  • Roma, Italy, 00128
    • Policlinico Universitario Campus Biomedico Di Roma
• Korea, Republic of
  • Pusan, Korea, Republic of
    • Pusan National University Hospital
  • Seongnam-si, Korea, Republic of
    • Seoul National University Bundang Hospital
  • Seoul, Korea, Republic of
    • Seoul National University Hospital
  • Seoul, Korea, Republic of
    • Samsung Medical Center
  • Seoul, Korea, Republic of, 07061
    • SMG - SNU Boramae Medical Center
  • Seoul, Korea, Republic of
    • The Catholic University of Korea, Seoul St. Mary's Hospital
  • Seoul, Korea, Republic of
    • Severance Hospital Yonsei University Health System
  • Suwon-si, Korea, Republic of
    • Ajou University Hospital
• Portugal
  • Almada, Portugal, 2801-951
    • Hospital Garcia de Orta
  • Coimbra, Portugal, 3000-075
    • Centro Hospitalar E Universitario de Coimbra EPE
  • Coimbra, Portugal, 3000-075
    • Instituto Português de Oncologia Francisco Gentil Centro Regional de Oncologia de Coimbra EPE
  • Lisboa, Portugal, 1998-018
    • Hospital CUF Descobertas
  • Lisboa, Portugal, 1649-035
    • Centro Hospitalar Lisboa Norte, E.P.E. - Hospital de Santa Maria
  • Lisbon, Portugal, 1099-023
    • Instituto Português de Oncologia de Lisboa Francisco Gentil, E.P.E.
  • Porto, Portugal, 4200-319
    • Centro Hospitalar de São João, E.P.E.
  • Porto, Portugal, 4200-072
    • Instituto Portugues de Oncologia Do Porto Francisco Gentil Epe - PPDS
  • Porto, Portugal, 4099-001
    • Centro Hospitalar do Porto - Hospital de Santo António
  • Lisboa
    • Loures, Lisboa, Portugal, 2674-514
      • Hospital Beatriz Ângelo
• Puerto Rico
  • Rio Piedras, Puerto Rico, 00935
    • Hospital Oncologico, Puerto Rico Medical Center
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron - PPDS
  • Madrid, Spain, 28034
    • Hospital Universitario Ramon y Cajal
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Marañón
  • Madrid, Spain, 28050
    • Hospital Universitario HM Sanchinarro - CIOCC
  • Valencia, Spain, 46026
    • Hospital Universitari i Politecnic La Fe de Valencia
  • Andalucia
    • Sevilla, Andalucia, Spain, 41009
      • Hospital Universitario Virgen Macarena
  • Aragon
    • Zaragoza, Aragon, Spain, 50009
      • Hospital Universitario Miguel Servet
  • Castilla Y Leon
    • Salamanca, Castilla Y Leon, Spain, 37007
      • Complejo Asistencial Universitario de Salamanca - Hospital Clínico
  • Cataluna
    • Badalona, Cataluna, Spain, 08916
      • Hospital Universitario Germans Trias i Pujol
    • Barcelona, Cataluna, Spain, 08907
      • Instituto Catalan de Oncologio ICO I'Hospitalet
• Taiwan
  • Huwei, Taiwan, 632
    • National Taiwan University Hospital - YunLin Branch
  • Kaohsiung, Taiwan, 833
    • Chang Gung Memorial Hospital - Kaohsiung
  • Taichung City, Taiwan, 40447
    • China Medical University Hospital
  • Tainan, Taiwan, 73657
    • Chi Mei Hospital, Liouying
  • Taipei, Taiwan
    • National Taiwan University Hospital
  • Taipei, Taiwan, 11217
    • Taipei Veterans General Hospital
  • Taoyuan City, Taiwan, 333
    • Chang Gung Memorial Hospital, Linkou
  • Tainan
    • Tainan City, Tainan, Taiwan, 704
      • National Cheng Kung University Hospital
• Thailand
  • Bangkok, Thailand, 10330
    • Chulalongkorn University
  • Bangkok, Thailand
    • Ramathibodi Hospital Mahidol University
  • Chiang Mai, Thailand, 50200
    • Maharaj Nakorn Chiang Mai Chiang Mai University
  • Khon Kaen, Thailand
    • Srinagarind Hospital
  • Phitsanulok, Thailand
    • Naresuan University
  • Songkla
    • Hat Yai, Songkla, Thailand, 90110
      • Songklanagarind Hospital, Prince of Songkla University
• United Kingdom
  • London, United Kingdom, SE1 9RT
    • Guys Hospital
  • Manchester, United Kingdom, M20 4BX
    • The Christie NHS Foundation Trust - PPDS
  • Nottinghamshire
    • Nottingham, Nottinghamshire, United Kingdom, NG5 1PB
      • Nottingham City Hospital
  • Surrey
    • Sutton, Surrey, United Kingdom, SM2 5PT
      • Royal Marsden Hospital
  • Wirral
    • Bebington, Wirral, United Kingdom, CH63 4JY
      • The Clatterbridge Cancer Centre NHS Foundation Trust
• United States
  • Arizona
    • Gilbert, Arizona, United States, 85234
      • Banner MD Anderson Cancer Center
    • Tucson, Arizona, United States, 85724
      • University of Arizona
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences
  • California
    • Fullerton, California, United States, 92835
      • St. Joseph Heritage Healthcare
    • Los Angeles, California, United States, 90095
      • University of California Los Angeles
    • Los Angeles, California, United States, 90033
      • USC Norris Cancer Center
  • Florida
    • Orlando, Florida, United States, 32806
      • UF Health Cancer Center at Orlando Health
    • Orlando, Florida, United States, 32804
      • Florida Hospital Medical Group
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern Memorial Hospital
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • University Medical Center - New Orleans
  • Maryland
    • Frederick, Maryland, United States, 21702
      • Frederick Regional Healthcare Systems/James M. Stockman Cancer Institute
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Barbara Ann Karmanos Cancer Institute - Lawrence and Idell Weisberg Cancer Treatment Center
    • Grand Rapids, Michigan, United States, 49503
      • Cancer and Hematology Centers of Western Michigan
    • Royal Oak, Michigan, United States, 48073
      • William Beaumont Hospital
  • New York
    • New York, New York, United States, 10021
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10016
      • NYU Langone Medical Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Levine Cancer Institute - Charlotte
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati Medical Center
    • Columbus, Ohio, United States, 43202
      • Ohio State University Comprehensive Cancer Center
  • South Carolina
    • Charleston, South Carolina, United States, 29414
      • Charleston Oncology
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
    • Dallas, Texas, United States, 75343
      • Parkland Health and Hospital System
    • Houston, Texas, United States, 77030
      • University of Texas MD Anderson Cancer Center
    • Houston, Texas, United States, 77096
      • Baylor College of Medicine

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Infigratinib (BGJ398) 125 mg; Infigratinib (BGJ398) 125 mg orally daily, 3 weeks on, 1 week off.	Drug: BGJ398; Infigratinib (BGJ398) 125 mg orally daily, 3 weeks on, 1 week off.; Other Names: Infigratinib
Active Comparator: Gemcitabine + Cisplatin; Participants who experience disease progression while receiving gemcitabine + cisplatin will be allowed to cross over and receive infigratinib if certain criteria are met.	Drug: Gemcitabine; Gemcitabine 1000 mg/m2 IV D1 and D8 for a 21-day cycle. Participants who experience disease progression while receiving gemcitabine + cisplatin will be allowed to cross over and receive infigratinib.; Drug: Cisplatin; Cisplatin 25 mg/m2 IV D1 and D8 for a 21-day cycle. Participants who experience disease progression while receiving gemcitabine + cisplatin will be allowed to cross over and receive infigratinib.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (Central Imaging Assessment)	Defined as the time from randomization until date of disease progression by blinded independent central imaging assessment (Response Evaluation Criteria in Solid Tumors [RECIST] v. 1.1) or death, whichever occurs first.	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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS) in Participants Treated With Infigratinib Versus Gemcitabine With Cisplatin	OS by investigator assessment, defined as time from date of randomization until death due to any cause	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.
Investigator Assessed Progression Free Survival in Participants Treated With Infigratinib Compared to Gemcitabine and Cisplatin	Defined as the time from randomization until date of disease progression by site investigator (RECIST v1.1) or death, whichever occurs first.	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.
Overall Response Rate (ORR) Determined by Blinded Independent Central (BICR) and Investigator Assessment	ORR is defined as the proportion of subjects with a best overall response (BOR) of either confirmed partial response (PR) or confirmed complete response (CR) as assessed by BICR and the investigator according to RECIST v1.1 among patients with measurable disease at baseline	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).
Best Overall Response (BOR) Determined by Blinded Independent Central Assessment and the Investigator.	BOR was defined as the best response a subject ever achieved after study treatment prior to crossover and any subsequent anticancer therapy, complete response (CR) and partial response (PR) were claimed only if the criteria for each were met at a subsequent time point at least 4 weeks apart. In the case of stable disease (SD), measurements must have met the SD criteria at least once post-baseline no less than 6 weeks from the randomization date.	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).
Duration of Response (DOR) Determined by Blinded Independent Central Assessment and the Investigator.	DOR is defined as the time from initiation of confirmed partial response (PR) or confirmed complete response (CR) to the time of confirmed progressive disease (PD) or death. If subjects do not reach PD or death before crossover, the DOR is censored at the last valid tumor assessment before crossover.	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).
Disease Control Rate (DCR=PR+CR+SD) Determined by Blinded Independent Central Assessment and the Investigator.	DCR is defined as the proportion of subjects with a best overall response (BOR) of either confirmed partial response (PR), confirmed complete response (CR) or stable disease (SD) or non-CR/non-PD before crossover.	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).
Number of Participants With Adverse Events (AEs)	Safety analyses were performed for subjects in the safety analysis population for each group. Unless otherwise specified, summaries were provided only for the on-treatment safety assessments, which are the assessments occurring or taken during the on-treatment period	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).
Number of Participants With Serious Adverse Events (SAEs)	Safety analyses were performed for subjects in the safety analysis population for each group. Unless otherwise specified, summaries were provided only for the on-treatment safety assessments, which are the assessments occurring or taken during the on-treatment period	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).

Collaborators and Investigators

• Sponsor: QED Therapeutics, Inc.
• Collaborators: Helsinn Healthcare SA
• Investigators: Study Director: Clinical Development, QED Therapeutics

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 27, 2019
• Primary Completion (Actual): March 2, 2023
• Study Completion (Actual): March 2, 2023

Study Registration Dates

• First Submitted: December 10, 2018
• First Submitted That Met QC Criteria: December 10, 2018
• First Posted (Actual): December 12, 2018

Study Record Updates

• Last Update Posted (Actual): May 8, 2024
• Last Update Submitted That Met QC Criteria: April 15, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: cholangiocarcinoma; FGFR2; fibroblast growth factor receptor inhibitor; BGJ398; unresectable cholangiocarcinoma; metastatic cholangiocarcinoma; FGFR2 gene fusions/translocations
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Cholangiocarcinoma; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Infigratinib; Gemcitabine
• Other Study ID Numbers: QBGJ398-301; 2018-004004-19 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No