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

Advanced Cholangiocarcinoma Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03773302
• Other study ID #: QBGJ398-301
• Secondary ID: 2018-004004-19
• Status: Terminated
• Phase: Phase 3
• Start date: December 27, 2019
• Est. completion date: March 2, 2023

Study information

• Verified date: April 2024
• Source: QED Therapeutics, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 48
• Est. completion date: March 2, 2023
• Est. primary completion date: March 2, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Advanced Cholangiocarcinoma
• Cholangiocarcinoma
• FGFR2 Gene Mutation

Intervention

Drug:
• BGJ398
Infigratinib (BGJ398) 125 mg orally daily, 3 weeks on, 1 week off.
• 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.
• 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.

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Monash Medical Centre	Bentleigh East	Victoria
Australia	Chris O'Brien Lifehouse Hospital	Camperdown	New South Wales
Australia	Blacktown Hospital	Darlinghurst	New South Wales
Australia	Peninsula & South Eastern Haematology and Oncology Group	Frankston	Victoria
Australia	St John of God Hospital Subiaco	Subiaco	Western Australia
Belgium	Cliniques Universitaires Saint-Luc	Bruxelles	Brussels
Belgium	Grand Hopital de Charleroi	Charleroi
Belgium	Universitair Ziekenhuis Antwerpen	Edegem
Canada	Cross Cancer Institute	Edmonton	Alberta
Canada	Jewish General Hospital	Montréal	Quebec
Canada	Ottawa Hospital	Ottawa	Ontario
Canada	St. Josephs Health Centre	Toronto	Ontario
China	Beijing Cancer Hospital	Beijing
China	Peking University People's Hospital	Beijing
China	Peking University Third Hospital	Beijing
China	Hunan Cancer Hospital	Changsha
China	Guangzhou First People's Hospital	Guangzhou
China	Hubei Cancer Hospital	Hubei
China	Liaoning Cancer Hospital & Institute	Shenyang
China	The First Affiliated Hospital, Sun Yat-sen University	Zhongshan
France	Hopital Henri Mondor	Créteil	Val-de-Marne
France	Centre Georges-Francois Leclerc	Dijon
France	CHRU Dijon	Dijon
France	Hopital Claude Huriez Rue Michel Polonovski (CHRU) Lille	Lille
France	Groupement Hospitalier Edouard Herriot	Lyon
France	Hopital Nord Franche-Comte	Montbéliard
France	Groupe Hospitalier Archet I Et II	Nice
France	Hopital Cochin	Paris
France	Hôpital Saint Antoine	Paris
France	L'Institut Mutualiste Montsouris	Paris
Germany	Klinikum Dortmund gGmbH	Dortmund
Germany	University Clinic Heidelberg	Heidelberg
Germany	Klinikum rechts der Isar der Technischen Universität München	München	Bayern
Germany	Universitätsklinikum Tübingen	Tübingen	Baden-Wurttemberg
Italy	Azienda Socio Sanitaria Territoriale di Cremona (ASST)	Cremona
Italy	Istituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori IRST	Meldola
Italy	ASST Grande Ospedale Metropolitano Niguarda	Milano
Italy	Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico	Milano
Italy	Istituto Oncologico Veneto - I.R.C.C.S.	Padova
Italy	Policlinico Universitario Campus Biomedico Di Roma	Roma
Korea, Republic of	Pusan National University Hospital	Pusan
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam-si
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	SMG - SNU Boramae Medical Center	Seoul
Korea, Republic of	The Catholic University of Korea, Seoul St. Mary's Hospital	Seoul
Korea, Republic of	Ajou University Hospital	Suwon-si
Portugal	Hospital Garcia de Orta	Almada
Portugal	Centro Hospitalar E Universitário de Coimbra EPE	Coimbra
Portugal	Instituto Português de Oncologia Francisco Gentil Centro Regional de Oncologia de Coimbra EPE	Coimbra
Portugal	Centro Hospitalar Lisboa Norte, E.P.E. - Hospital de Santa Maria	Lisboa
Portugal	Hospital CUF Descobertas	Lisboa
Portugal	Instituto Português de Oncologia de Lisboa Francisco Gentil, E.P.E.	Lisbon
Portugal	Hospital Beatriz Angelo	Loures	Lisboa
Portugal	Centro Hospitalar de São João, E.P.E.	Porto
Portugal	Centro Hospitalar do Porto - Hospital de Santo António	Porto
Portugal	Instituto Portugues de Oncologia Do Porto Francisco Gentil Epe - PPDS	Porto
Puerto Rico	Hospital Oncologico, Puerto Rico Medical Center	Rio Piedras
Spain	Hospital Universitario Germans Trias i Pujol	Badalona	Cataluna
Spain	Hospital Universitario Vall d'Hebrón - PPDS	Barcelona
Spain	Instituto Catalan de Oncologio ICO I'Hospitalet	Barcelona	Cataluna
Spain	Hospital General Universitario Gregorio Maranon	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario HM Sanchinarro - CIOCC	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Ramon y Cajal	Madrid
Spain	Complejo Asistencial Universitario de Salamanca - Hospital Clinico	Salamanca	Castilla Y Leon
Spain	Hospital Universitario Virgen Macarena	Sevilla	Andalucia
Spain	Hospital Universitari i Politecnic La Fe de Valencia	Valencia
Spain	Hospital Universitario Miguel Servet	Zaragoza	Aragon
Taiwan	National Taiwan University Hospital - YunLin Branch	Huwei
Taiwan	Chang Gung Memorial Hospital - Kaohsiung	Kaohsiung
Taiwan	China Medical University Hospital	Taichung City
Taiwan	Chi Mei Hospital, Liouying	Tainan
Taiwan	National Cheng Kung University Hospital	Tainan City	Tainan
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei
Taiwan	Chang Gung Memorial Hospital, Linkou	Taoyuan City
Thailand	Chulalongkorn University	Bangkok
Thailand	Ramathibodi Hospital Mahidol University	Bangkok
Thailand	Maharaj Nakorn Chiang Mai Chiang Mai University	Chiang Mai
Thailand	Songklanagarind Hospital, Prince of Songkla University	Hat Yai	Songkla
Thailand	Srinagarind Hospital	Khon Kaen
Thailand	Naresuan University	Phitsanulok
United Kingdom	The Clatterbridge Cancer Centre NHS Foundation Trust	Bebington	Wirral
United Kingdom	Guys Hospital	London
United Kingdom	The Christie NHS Foundation Trust - PPDS	Manchester
United Kingdom	Nottingham City Hospital	Nottingham	Nottinghamshire
United Kingdom	Royal Marsden Hospital	Sutton	Surrey
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Charleston Oncology	Charleston	South Carolina
United States	Levine Cancer Institute - Charlotte	Charlotte	North Carolina
United States	Northwestern Memorial Hospital	Chicago	Illinois
United States	University of Cincinnati Medical Center	Cincinnati	Ohio
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Parkland Health and Hospital System	Dallas	Texas
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Barbara Ann Karmanos Cancer Institute - Lawrence and Idell Weisberg Cancer Treatment Center	Detroit	Michigan
United States	Frederick Regional Healthcare Systems/James M. Stockman Cancer Institute	Frederick	Maryland
United States	St. Joseph Heritage Healthcare	Fullerton	California
United States	Banner MD Anderson Cancer Center	Gilbert	Arizona
United States	Cancer and Hematology Centers of Western Michigan	Grand Rapids	Michigan
United States	Baylor College of Medicine	Houston	Texas
United States	University of Texas MD Anderson Cancer Center	Houston	Texas
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	University of California Los Angeles	Los Angeles	California
United States	USC Norris Cancer Center	Los Angeles	California
United States	University Medical Center - New Orleans	New Orleans	Louisiana
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	NYU Langone Medical Center	New York	New York
United States	Florida Hospital Medical Group	Orlando	Florida
United States	UF Health Cancer Center at Orlando Health	Orlando	Florida
United States	William Beaumont Hospital	Royal Oak	Michigan
United States	University of Arizona	Tucson	Arizona

Sponsors (2)

Lead Sponsor	Collaborator
QED Therapeutics, Inc.	Helsinn Healthcare SA

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  China,  France,  Germany,  Italy,  Korea, Republic of,  Portugal,  Puerto Rico,  Spain,  Taiwan,  Thailand,  United Kingdom, 

Outcome

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