Oral Infigratinib for the Adjuvant Treatment of Subjects With Invasive Urothelial Carcinoma With Susceptible FGFR3 Genetic Alterations

NCT04197986 | Terminated Phase 3 Results DMC FDA Drug

• 2 other identifiers: QBGJ398-3022019-003248-63
• Study Type: interventional
• Target: 39
• Locations: 11 countries
• Sites: 143

Brief Summary

This is a Phase 3 multicenter, double-blind, randomized, placebo-controlled study to evaluate the efficacy of infigratinib (an oral targeted FGFR1-3 inhibitor) versus placebo, as adjuvant treatment following surgery in adult subjects with invasive urothelial carcinoma and susceptible FGFR3 genetic alterations (mutations, and gene fusions or rearrangements) who have disease that is considered at high risk for recurrence with surgery alone. The study enrolls subjects with either bladder cancer post radical cystectomy or upper tract urothelial cancer post distal ureterectomy and/or nephrectomy. Study treatment is randomized 1:1 between infigratinib or placebo with treatment up to 1 year or until invasive local, distal, or metastatic disease recurrence confirmed by independent imaging reviewer.

Conditions

Upper Tract Urothelial Carcinomas; Urothelial Bladder Cancer

Keywords

FGFR3 Genetic Alterations; Upper Tract Urothelial Carcinomas; UTUC; Muscle Invasive Urothelial Carcinoma; Fibroblast Growth Factor Receptor Inhibitor; BGJ398; FGFR3; Urothelial Bladder Cancer; UBC; Infigratinib Phosphate; Infigratinib; Adjuvant; Nephroureterectomy; Distal ureterectomy; Cystectomy

Outcome Measures

Primary Outcomes (1)

• Centrally Determined Disease-free Survival (DFS)

  DFS was defined as the number of months from date of randomization to local/regional invasive or metastatic recurrence or death due to any cause (referred as DFS event), whichever occurs earlier. Due to early termination of the study by the sponsor, results will focus primarily on the primary and key secondary endpoints of the study. Due to early termination of the study by the sponsor, data were censored for 85.0% to 89.5% of all subjects. Data cutoff 28 Feb 2023.

  The number of months from date of randomization to local/regional invasive or metastatic recurrence or death due to any cause.

Secondary Outcomes (6)

• Investigator-assessed DFS

  The number of months from date of randomization to local/regional invasive or metastatic recurrence or death due to any cause.

• Metastasis-free Survival (MFS)

  The time from randomization to any metastatic recurrence as determined by the investigator, or death due to any cause.

• Overall Survival (OS)

  The number of months from randomization to death.

• Investigator-reviewed DFS Including Intraluminal Low-Risk Recurrence

  The number of months from date of randomization to local/regional invasive or metastatic recurrence or death due to any cause.

• Number of Participants With Adverse Events (AEs)

  From first dose to last dose of study treatment +30 days (an average of 4 months for the infigratinib arm and 8 months for the placebo arm).

Study Arms (2)

Infigratinib 125 mg

EXPERIMENTAL

Participants will be randomly assigned (1:1) to receive oral infigratinib administered once daily for the first 3 weeks (21 days) of each 28-day cycle for a maximum of 52 weeks

Drug: Infigratinib

Placebo

PLACEBO COMPARATOR

Participants will be randomly assigned (1:1) to receive oral placebo administered once daily for the first 3 weeks (21 days) of each 28-day cycle for a maximum of 52 weeks

Drug: Placebo

Interventions

Infigratinib DRUG

Participants randomly assigned to infigratinib will receive hard gelatin capsules for oral administration of infigratinib 125 mg once a day (administered as one 100-mg capsule and one 25-mg capsule) using a 3 weeks on (Days 1-21) /1 week off (Days 22-28) dosing schedule.

Also known as: IP, Study drug

Infigratinib 125 mg

Placebo DRUG

Participants randomly assigned to placebo will receive placebo matching in appearance the investigational product (infigratinib), which will be provided as hard gelatin capsules for oral use and will be administered once daily on a 3 weeks on (Days 1-21) /1 week off (Days 22-28) dosing schedule.

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Are randomized within 120 days following nephroureterectomy, distal ureterectomy or cystectomy.
• Have histologically or cytologically confirmed, invasive urothelial carcinoma with susceptible FGFR3 alterations. Variant histology is allowed provided urothelial carcinoma is predominant (\>50%). Neuroendocrine (including small and large cell), sarcomatoid, and plasmacytoid variants are excluded (any component).
• Regarding samples and documentation of FGFR3
• i. FGFR3 mutation is confirmed if: FGFR3 gene is mutated in Exon 7 (R248C, S249C), Exon 10 (G370C, A391E, Y373C), or Exon 15 (K650M/T, K650E/Q)
• ii. FGFR3 gene fusion or FGFR3 rearrangement is confirmed based on the following genomic criteria if:
• Any fusion/rearrangement with a literature-derived known partner gene regardless of strand or frame.
• Fusion/rearrangements in the same strand that are in frame with a novel partner gene.
• Fusion/rearrangements with one breakpoint in the intron 17 - exon 18 hotspot region and the other breakpoint in an intergenic region or another gene. This rule excludes 3' duplications comprising only exon 18.
• iii. The amino acid numbers for the FGFR3 mutations refer to the functional FGFR3 isoform 1 (NP\_000133.1) that is the NCBI Refseq ID used to report genetic alterations in FGFR3 by the FoundationOne® CDx test (F1CDx, Foundation Medicine, USA).
• iv. FGFR3 alteration must be confirmed by Foundation Medicine for F1CDx testing:
• The tumor sample to be used should be from the definitive surgical resection (cystectomy, nephroureterectomy, or distal ureterectomy), or from an archival biopsy of confirmed invasive urothelial carcinoma (≥pT2).
• If status post neoadjuvant chemotherapy, pathologic stage at surgical resection must be Stage ≥ ypT2 and/or yN+. Prior neoadjuvant therapy is defined as at least 3 cycles of neoadjuvant cisplatin-based chemotherapy with a planned cisplatin dose of 70 mg/m2/cycle. Subjects who received less than this or non-cisplatin-based neoadjuvant treatment are not excluded.
• If not status post neoadjuvant chemotherapy, is ineligible to receive cisplatin-based adjuvant chemotherapy based on Galsky criteria:
• Subjects who refuse cisplatin-based chemotherapy or who are ineligible to receive cisplatin-based chemotherapy based on Galsky criteria must also meet the following criteria:
• Must have a centrally reviewed negative postoperative computed tomography (CT) (defined as lymph nodes with short axis \<1.0 cm and without growth and no distant metastases according to \[RECIST v1.1 criteria or negative biopsy within 28 days before randomization to confirm absence of disease at baseline.

You may not qualify if:

• Presence of positive invasive surgical margins following nephroureterectomy, distal ureterectomy, or cystectomy. In subjects not eligible for further surgery, radiotherapy, or other efficacious treatment, microscopic positive noninvasive margins (eg, carcinoma in situ) without gross residual disease are allowed.
• Have received Bacillus Calmette-Guerin (BCG) or other intravesical therapy for Non-Muscle Invasive Bladder Cancer (NMIBC) within the previous 30 days.
• Are currently receiving or are planning to receive during participation in this study, treatment with agents that are known moderate or strong inducers or inhibitors of CYP3A4 and medications which increase serum phosphorus and/or calcium concentration. Prior anticancer or other therapies are restricted as follows:
• Prior adjuvant treatment for urothelial cancer is not allowed.
• Prior biologic, immunotherapy, or investigational therapy should have been completed within a period that is ≥5 half-lives or 30 days, whichever is shorter, before the first dose of study drug.
• Have previously or currently is receiving treatment with a mitogen-activated protein kinase (MEK) or selective FGFR inhibitor.
• Have a history of primary malignancy within the past 3 years other than (1) invasive UBC or UTUC (ie, disease under study), (2) noninvasive urothelial carcinoma, (3) any adequately treated in situ carcinoma or non-melanoma carcinoma of the skin, (4) any other curatively treated malignancy that is not expected to require treatment for recurrence during participation in the study, or (5) an untreated cancer on active surveillance that may not affect the subject's survival status for ≥3 years based on clinician assessment/statement and with medical monitor approval.
• Have current evidence of corneal keratopathy or retinal disorder confirmed by ophthalmic examination. Subjects with asymptomatic ophthalmic conditions assessed by the investigator to pose minimal risk for study participation may be enrolled in the study.
• Have a history and/or current evidence of extensive tissue calcification
• Have impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral infigratinib
• Have current evidence of endocrine alterations of calcium/phosphate homeostasis (eg, parathyroid disorders, history of parathyroidectomy, tumor lysis, tumoral calcinosis), unless well controlled.
• Have consumed grapefruit, grapefruit juice, grapefruit hybrids, pomegranates, star fruits, pomelos, or Seville oranges or products containing juice of these fruits within 7 days before the first dose of study drug; 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 insufficient bone marrow function:
• Absolute neutrophil count (ANC) \<1,000/mm3 (1.0 × 109/L).
• Platelets \<75,000/mm3 (\<75 × 109/L).

Sponsors & Collaborators

• QED Therapeutics, a BridgeBio company: lead
• Helsinn Healthcare SA: collaborator

Study Sites (143)

Arizona Oncology Associates

Tucson, Arizona, 85711, United States

Location

City of Hope - Duarte

Duarte, California, 91010, United States

Location

City of Hope

Duarte, California, 91010, United States

Location

Loma Linda University Faculty Medical Clinics

Loma Linda, California, 92350, United States

Location

USC Norris Comprehensive Cancer Center

Los Angeles, California, 90033, United States

Location

University of Colorado Cancer Center

Aurora, Colorado, 80045, United States

Location

The Urology Center of Colorado

Denver, Colorado, 80211, United States

Location

Georgetown University Medical Center

Washington D.C., District of Columbia, 20007, United States

Location

Urological Research Network CORP

Hialeah, Florida, 33016, United States

Location

Mayo Clinic - Jacksonville

Jacksonville, Florida, 32224, United States

Location

Lakeland Regional Health Hollis Cancer Center

Lakeland, Florida, 33805, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

Winship Cancer Institute of Emory University

Atlanta, Georgia, 30322, United States

Location

Northwestern University Feinberg School of Medicine

Chicago, Illinois, 60611, United States

Location

UChicago Medicine Duchossois Center for Advanced Medicine (DCAM) - Hyde Park

Chicago, Illinois, 60637, United States

Location

DuPage Medical Group - Warrenville Road

Lisle, Illinois, 60532, United States

Location

Indiana University Melvin and Bren Simon Cancer Center

Indianapolis, Indiana, 46202, United States

Location

Tulane University/Southeastern Louisiana VA Health Care

New Orleans, Louisiana, 70112, United States

Location

Johns Hopkins Hospital

Baltimore, Maryland, 21287, United States

Location

Saint Louis University- SLUCare Academic Pavilion

St Louis, Missouri, 63110, United States

Location

University of Nebraska Medical Center

Omaha, Nebraska, 68198, United States

Location

Dartmouth-Hitchcock Medical Center

Lebanon, New Hampshire, 03766, United States

Location

John Theurer Cancer Center at Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

New Jersey Urology - Saddle Brook

Saddle Brook, New Jersey, 07663, United States

Location

New Jersey Urology

Voorhees Township, New Jersey, 08043, United States

Location

Albany Medical Center - Division of Urology

Albany, New York, 12208, United States

Location

Associated Medical Professionals - Syracuse

Syracuse, New York, 13210, United States

Location

Duke University Cancer Center

Durham, North Carolina, 27710, United States

Location

Accellacare-DuPage Medical Group

Raleigh, North Carolina, 27609, United States

Location

Wake Forest Baptist Health

Winston-Salem, North Carolina, 27157, United States

Location

University of Toledo

Arlington, Ohio, 43606, United States

Location

Oncology Hematology Care

Cincinnati, Ohio, 45242, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

The Ohio State University College of Medicine

Columbus, Ohio, 43210, United States

Location

The University of Toledo Medical Center

Toledo, Ohio, 43614, United States

Location

Stephenson Cancer Center

Oklahoma City, Oklahoma, 73104, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

Urology Associates

Nashville, Tennessee, 37209, United States

Location

Harold C. Simmons Comprehensive Cancer Center

Dallas, Texas, 75390, United States

Location

Bayor College of Medicine

Houston, Texas, 77030, United States

Location

Houston Methodist Hospital- Department of Urology

Houston, Texas, 77030, United States

Location

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

UT Southwestern

Richardson, Texas, 75080, United States

Location

Urology San Antonio

San Antonio, Texas, 78229, United States

Location

Huntsman Cancer Institute and Hospital

Salt Lake City, Utah, 84112, United States

Location

Seattle Cancer Care Alliance

Seattle, Washington, 98109, United States

Location

West Virginia University

Morgantown, West Virginia, 26506, United States

Location

CHU de Liège - Sart Tilman

Liège, Liège/Belgium, 4000, Belgium

Location

ZNA Middelheim

Antwerp, Belgium

Location

Cliniques Universitaires Saint-Luc

Brussels, 1200, Belgium

Location

Universitair Ziekenhuis Leuven

Leuven, Belgium

Location

University Multiprofile Hospital For Active Treatment Deva Maria

Burgas, 8001, Bulgaria

Location

University Multiprofile Hospital For Active Treatment Dr. Georgi Stranski EAD

Pleven, Bulgaria

Location

Multiprofile Hospital For Active Treatment "Sveta Sofia"

Sofia, Bulgaria

Location

Cross Cancer Institute

Edmonton, Alberta, T6G 1Z2, Canada

Location

BC Cancer- Vancouver

Vancouver, British Columbia, V5Z 4E6, Canada

Location

Princess Margaret Cancer Centre

Toronto, Ontario, M5G2M9, Canada

Location

McGill University Health Centre (MUHC)

Montreal, Quebec, H4A 3J1, Canada

Location

CHU de Québec Université Laval

Québec, G1R 2J6, Canada

Location

BC Cancer - Vancouver

Vancouver, Canada

Location

Centre de Lutte Contre le Cancer - Centre Léon Bérard

Lyon, Auvergne-Rhône-Alpes, 69008, France

Location

CHU de Nantes Hopital Hotel Dieu

Paris, Paris/France, 75018, France

Location

Institut de Cancerologie Strasbourg Europe

Strasbourg, Strasbourg/France, 67200, France

Location

Institut Claudius Regaud

Toulouse, Toulouse/France, 31059, France

Location

Gustave Roussy

Villejuif, Villejuif/France, 94805, France

Location

Hôpital Morvan

Brest, 29200, France

Location

CHU de Nantes Hopital Hotel Dieu

Nantes, France

Location

Hopital Bichat - Claude - Bernard

Paris, France

Location

Centre Eugène Marquis

Rennes, 35042, France

Location

Centre Hospitalier Privé Saint-Grégoire

Saint-Grégoire, 35760, France

Location

Institut De Cancerologie De L'ouest - Site Saint-Herblain

Saint-Herblain, France

Location

Clinique Mutualiste de l'Estuaire

Saint-Nazaire, 44600, France

Location

Gustave Roussy

Villejuif, France

Location

Hôpital Universitaire Pitié Salpêtrière

Paris, Île-de-France Region, 75013, France

Location

Hôpital Européen Georges-Pompidou

Paris, Île-de-France Region, 75015, France

Location

Charité - Universitatsmedizin Berlin

Berlin, Berlin/Germany, 10117, Germany

Location

Urologicum Duisburg

Duisburg, North Rhine-Westphalia, 47179, Germany

Location

Universitätsklinikum Düsseldorf

Düsseldorf, North Rhine-Westphalia, 40225, Germany

Location

Universitätsklinikum Essen

Essen, North Rhine-Westphalia, 45147, Germany

Location

Marien Hospital Herne - Universitätsklinikum der Ruhr-Universität Bochum

Herne, North Rhine-Westphalia, 44625, Germany

Location

Charite Universitaetsmedizin Berlin

Berlin, Germany

Location

Urologie

Berlin, Germany

Location

University Hospital Duesseldorf

Düsseldorf, Germany

Location

Universitätsklinikum des Saarlandes Klinik für Urologie & Kinderurologie

Homburg, Germany

Location

Universitatsklinikum des Saarlandes Klinik fur Urologie & Kinderurologie

Homburg/saar, Germany

Location

Universitatsklinikum Magdeburg

Magdeburg, Germany

Location

Caritas-Krankenhaus St. Josef Klinik für Urologie

Regensburg, 93053, Germany

Location

Universitätsklinikum Tübingen

Tübingen, Germany

Location

Henry Dunant Hospital Center

Athens, Attica, 11526, Greece

Location

Bioclinic Thessalonikis

Thessaloniki, Makedonia, 54622, Greece

Location

Anassa General Clinic

Volos, Greece

Location

Ospedale di Cremona

Cremona, Cremona/Italy, 26100, Italy

Location

Ospedale Policlinico San Martino

Genova, Genova/Italy, 16132, Italy

Location

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori

Meldola, Meldola/Italy, 47014, Italy

Location

Istituto Europeo di Oncologia

Milan, Milano/Italy, 20141, Italy

Location

Istituto Nazionale Tumori IRCCS Fondazione G. Pascale

Napoli, Naples, 80131, Italy

Location

Azienda Ospedaliero-Universitaria Pisana

Pisa, Pisa/italy, 56126, Italy

Location

IRCCS Centro di Riferimento Oncologico di Basilicata

Rionero in Vulture, Potenza, 85028, Italy

Location

Arcispedale Santa Maria Nuova

Reggio Emilia, Reggio Emilia/Italy, 42100, Italy

Location

Università Campus Bio-Medico di Roma

Roma, Roma/Italy, 00128, Italy

Location

Azienda Ospedaliero - Universitaria San Luigi Gonzaga

Orbassano, Torino, 10043, Italy

Location

Ospedale di Trento - Presidio Ospedaliero Santa Chiara

Trento, Trentino-Alto Adige, 38100, Italy

Location

Centro di Riferimento Oncologico

Aviano, Italy

Location

Azienda Universitaria Ospedaliera Consorziale - Policlinico di Bari

Bari, 70124, Italy

Location

A.O.U.C. Polclinico di Bari U.O. Oncologia Medica Universitaria

Bari, Italy

Location

ASST Cremona

Casalmaggiore, Italy

Location

Ospedale Policlinico San Martino Irccs

Genova, Italy

Location

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori

Meldola, Italy

Location

Fondazione IRCCS INT Milano

Milan, Italy

Location

Istituto Europeo di Oncologia

Milan, Italy

Location

Int Pascale Napoli

Napoli, Italy

Location

AOU San Luigi Gonzaga

Orbassano, Italy

Location

Azienda Ospedaliero-Universitaria Pisana

Pisa, Italy

Location

IRCCS di Reggio Emilia

Reggio Emilia, Italy

Location

Policlinico Universitario Campus Biomedico

Roma, Italy

Location

Citta Della Salute e Della Scienz - Torino

Torino, Italy

Location

Ospedale di Trento - Presidio Ospedaliero Santa Chiara

Trento, Italy

Location

IRCCS Centro di Riferimento Oncologico di Basilicata

Volterra, Italy

Location

Canisius-Wilhelmina Ziekenhuis

Nijmegen, Gelderland, 6532 SZ, Netherlands

Location

The Netherlands Cancer Institute

Amsterdam, Netherlands

Location

Zuyderland MC locatie Sittard

Geleen, Netherlands

Location

VHIO

Barcelona, Barcelona/Spain, 08003, Spain

Location

Sofia

Barcelona, Barcelona/Spain, 08041, Spain

Location

Institut Català d'Oncologia - Hospital Duran i Reynals (ICO L'Hospitalet)

Barcelona, Barcelona/Spain, 08908, Spain

Location

Institut Català d'Oncologia Badalona

Badalona, Barcelona, 08916, Spain

Location

Hospital Parc Taulí de Sabadell

Sabadell, Barcelona, 08208, Spain

Location

Hospital Universitario Reina Sofía

Córdoba, Córdoba/Spain, 14004, Spain

Location

Institut Català d'Oncologia Girona

Girona, Girona/Spain, 17007, Spain

Location

Hospital Universitario Puerta Hierro-Majadahonda

Majadahonda, Madrid, 28222, Spain

Location

MD Anderson Cancer Center Madrid

Madrid, Madrid/Spain, 28033, Spain

Location

Hospital Universitario Ramon y Cajal

Madrid, Madrid/Spain, 28034, Spain

Location

Hospital Clinico San Carlos

Madrid, Madrid/Spain, 28040, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, Madrid/Spain, 28041, Spain

Location

Hospital Universitario La Paz

Madrid, Madrid/Spain, 28046, Spain

Location

Hospital Universitario HM Sanchinarro

Madrid, Madrid/Spain, 28050, Spain

Location

Hospital Universitario Virgen del Rocio

Seville, Sevilla/Spain, 41013, Spain

Location

Hospital Virgen De La Salud

Toledo, Toledo/Spain, 45005, Spain

Location

Fundacion Instituto Valenciano de Oncologia

Valencia, València, 46009, Spain

Location

Hospital de la Santa Creu i Sant Pau

Barcelona, Spain

Location

Hospital del Mar

Barcelona, Spain

Location

Althaia Xarxa Assistencial Universitària de Manresa

Manresa, Spain

Location

Guy's and St Thomas' NHS Foundation Trust

London, United Kingdom

Location

Lister Hospital

Stevenage, United Kingdom

Location

Related Publications (2)

• Szymaniak J, Porten SP. Which Biomarkers are Useful in the Management of Muscle-invasive Bladder Cancer in 2022? Eur Urol Focus. 2022 Jul;8(4):901-903. doi: 10.1016/j.euf.2022.08.009. Epub 2022 Sep 2.

  PMID: 36058810 DERIVED

• Pal SK, Somford DM, Grivas P, Sridhar SS, Gupta S, Bellmunt J, Sonpavde G, Fleming MT, Lerner SP, Loriot Y, Hoffman-Censits J, Valderrama BP, Andresen C, Schnabel MJ, Cole S, Daneshmand S. Targeting FGFR3 alterations with adjuvant infigratinib in invasive urothelial carcinoma: the phase III PROOF 302 trial. Future Oncol. 2022 Jul;18(21):2599-2614. doi: 10.2217/fon-2021-1629. Epub 2022 May 24.

  PMID: 35608106 DERIVED

MeSH Terms

Interventions

infigratinib; Drug Evaluation

Intervention Hierarchy (Ancestors)

Drug Development; Investigative Techniques; Evaluation Studies as Topic

Results Point of Contact

• Title: Acting Chief Medical Officer
• Organization: QED Therapeutics, Inc.

Proof302.ct@qedtx.com

1-877-280-5655

Study Officials

• David van Veenhuyzen, M.B., Ch.B., M.Pharm.Med.

  QED Therapeutics, a BridgeBio company

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: As a double-blind study, participants, investigators, study monitor(s) and the clinical study team will be blinded to the treatment administered.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Participants will be randomly assigned (1:1) to receive oral infigratinib phosphate or placebo

Study Record Dates

• First Submitted: December 2, 2019
• First Posted: December 13, 2019
• Study Start: March 11, 2020
• Primary Completion: February 28, 2023
• Study Completion: February 28, 2023
• Last Updated: March 13, 2024
• Results First Posted: March 13, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

BE (4); CA (6); IT (27); ES (20); GR (3); US (47); NL (3); BU (3); GB (2); FR (15); DE (13)