Adjuvant Encorafenib and Binimetinib in High-risk Stage II Melanoma With a BRAF Mutation.
- Conditions
- Melanoma
- Interventions
- Drug: Placebo to match Encorafenib ; Placebo to match Binimetinib
- Registration Number
- NCT05270044
- Lead Sponsor
- Pierre Fabre Medicament
- Brief Summary
The purpose of the Columbus-AD study is to evaluate the efficacy and safety of 12 months of encorafenib in combination with binimetinib in adjuvant setting of BRAF V600E/K mutant stage IIB/C melanoma versus the current standard of care (surveillance).
- Detailed Description
This is a randomized triple-blind placebo-controlled international multicenter phase III superiority clinical trial.
Participants with completely resected cutaneous melanoma and documented BRAF V600E/K status by central assay will be randomized 1 to 1 to receive either treatment with encorafenib and binimetinib or their two placebos for 12 months. Patients will be stratified according to the stage of the disease according to AJCC version 8 between:
* stage IIB (i.e., pT3b or pT4a)
* stage IIC (i.e., pT4b).
The long-term evaluation of all endpoints (including information about the occurrence of new treatment-related adverse events, if any) will take place 10 years from the randomization of the last patient.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 815
Pre-Screening
- Male or female ≥ 18 years of age;
- Surgically resected, with tumour free margins, and histologically/pathologically confirmed new diagnosis of stage II (pT3b-pT4bN0) cutaneous melanomaa;
- Sentinel node (SN) biopsy within 14 weeks from initial diagnosis of melanoma.
- Sentinel node (SN) staged node negative (pN0);
- Available tumour sample for central determination of the BRAF V600E/K mutation.
Screening
-
Melanoma confirmed centrally to be BRAF V600E/K mutation-positive;
-
Participant still free of disease as evidenced by the required baseline imaging and physical/dermatological assessments performed respectively within 6 weeks and 2 weeks before randomization (Day 1);
-
No more than 12 weeks elapsed between full surgical resection (including SLNB) and randomization;
-
Recovered from definitive surgery (e.g., complete wound healing, no uncontrolled wound infections or indwelling drains);
-
ECOG performance status of 0 or 1;
-
Adequate haematological function as defined as Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L and Hemoglobin
≥ 9.0 g/dL;
-
Adequate renal function as defined as Serum creatinine ≤ 1.5 × ULN; or calculated creatinine clearance ≥ 50 mL/min;
-
Adequate electrolytes, defined as serum potassium and magnesium levels within institutional normal limits;
-
Adequate hepatic function as defined as Serum total bilirubin ≤ 1.5 x ULN and < 2 mg/dL, Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 2.5 x ULN;
-
Adequate cardiac function as defined as LVEF ≥ 50% as determined by MUGA scan or echocardiogram and Mean triplicate QTcF value ≤ 480 msec and no history of QT syndrome;
-
Adequate coagulation function, defined as INR ≤1.5× ULN unless the patient is receiving anticoagulant therapy as long as PT or aPTT is within the therapeutic range;
-
Negative serum β-HCG test (female patient of childbearing potential only) performed within 3 days prior to Day 1;
-
Female patients of child-bearing potential and male patients must agree to follow the protocol's contraception guidance during the treatment period and for ≥30 days after last administration.
Pre-screening
- Unknown ulceration status;
- Uveal and mucosal melanoma;
- Clinically apparent metastases (N+/M1);
- Microsatellites, satellites and/or in-transit metastases,
- Local (scar) recurrences.
Screening
- Breast feeding women;
- Pregnant women;
- History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO;
- History of thromboembolic or cerebrovascular events ≤ 12 weeks prior to randomization;
- History of previous or concurrent malignancy within preceding 3 years or any condition with a life expectancy of less than 5 years;
- Participants with a prior cancer associated with RAS mutation;
- Prior systemic anticancer therapy for melanoma or radiotherapy for melanoma;
- Hypersensitivity to the study drugs or to any of the excipients;
- Participants with severe lactose intolerance (e.g., Rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption);
- Impaired cardiovascular function or clinically significant cardiovascular diseases;
- Neuromuscular disorders that are associated with CK > ULN (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy);
- Non-infectious pneumonitis and Interstitial Lung Disease;
- Positive SARs-CoV-2 or variants of SARs-CoV2 RT-PCR test at screening or suspected to be infected with SARs-CoV2 or variants of SARsCoV2 with confirmation pending;
- Active bacterial, fungal, or viral infection, including, but not limited to HBV, HCV, and known HIV or AIDS-related illness, or an infection requiring systemic therapeutic treatment within 2 weeks prior to randomization.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm A Encorafenib and Binimetinib Encorafenib and Binimetinib Arm B Placebo to match Encorafenib ; Placebo to match Binimetinib Placebo to match Encorafenib Placebo to match Binimetinib
- Primary Outcome Measures
Name Time Method Recurrence-free survival (RFS) Approximately 4.4 years from the accrual of the first patient. RFS is defined as the time between the date of randomization and the date of 1) first recurrence (local, regional, or a distant metastasis), 2) new melanoma that is known to be either ulcerated, thick (Breslow thickness\>1 mm) or requiring a treatment other than surgery or 3) death (whatever the cause), whichever occurs first.
- Secondary Outcome Measures
Name Time Method Overall survival (OS) Approximately 10 years from first Patient In. OS is defined as time from randomization to the date of death whatever the cause.
Distant metastasis-free survival (DMFS) Approximately 6.0 years from first patient in DMFS is defined as the time between the date of randomization and the date of first distant metastasis or date of death (whatever the cause), whichever occurs first.
Safety and tolerability - Incidence of treatment-emergent adverse events (TEAEs) related to notable or abnormal changes in ophtalmic examination From the signing of the ICF up to 30 days after end of treatment-approximately up to 14.5 months Changes from baseline and worse value on ophthalmic examination over time will be reported.
a full ophthalmic examination by an ophthalmologist will be performed (at baseline an end of treatment) including best corrected visual acuity (BCVA), slit lamp examination, intraocular pressure (IOP), dilatedfundoscopy and optical coherence tomography (OCT). Retinal examination is required to identify findings associated with retinal pigment epithelial detachments (RPED), serous detachment of the retina and RVO (OCT and angiography).
the investigator will also monthly monitor visual assesment (general inspection of the eyes, examination of motility and alignment, visual disturbance including diminished central vision, blurred vision or loss of vision).Pharmacokinetic (PK) parameter of encorafenib and its metabolite (LHY746)-Cmax From randomization up to 11 months Maximum serum concentration (Cmax) will be calculated and reported.
Pharmacokinetic (PK) parameter of encorafenib and its metabolite (LHY746)_AUC From randomization up to 11 months Area under the curve (AUC) will be calculated and reported.
Safety -Incidence of Serious adverse events (SAEs) From the signing of the ICF to study completion- approximately 10 years from last patient in Incidence nature and severity of serious adverse events will be recorded and graded as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0
Safety and tolerability-Treatment emergent adverse events (TEAEs) leading to dose interruption, reduction and discontinuation. On treatment period - 12 months from randomization. Incidence of dose interruptions, dose modifications and discontinuation due to AEs and incidence of AEs requiring additional therapy
Performance status using the Eastern Co-operative Oncology Group (ECOG) performance status scale. From the signing of the ICF up to 30 days after end of treatment-approximately up to 14.5 months Changes from baseline and worse value on Eastern Cooperative Oncology Group (ECOG) Scale with a range from 0 to 5 with lower score mean a lower functional impairment, 5 corresponding to death .
Safety -Incidence, nature and severity of cutaneous malignancies by dermatological examination From the signing of ICF to study completion- approximately 10 years from last patient in This is to monitor for the possible development of keratoacanthoma and/or squamous cell carcinoma and new primary melanoma, as these have been reported to occur with selective BRAF inhibitor treatment. Incidence, nature and severity of new cutaneous malignancies (kerantoacanthoma, squamous cell carcinoma and new primary melanoma) will be recorded and graded as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0
Safety and tolerability - Incidence of treatment-emergent adverse events (TEAEs) related to notable or abnormal changes in physical examination From the signing of the ICF up to 30 days after end of treatment- approximately up to 14.5 months Standard physical examinations on cardiovascular, respiratory, gastrointestinal, dermatological, ophthalmological and neurological systems will be performed and will be evaluated based on normal/abnormal and clinical significance observations. Number of participants with TEAEs related to abnormal or clinical significance observations to the physical examinations after the start of study drug will be reported.
Safety and tolerability - Incidence of treatment-emergent adverse events (TEAEs) related to notable or abnormal changes in vital signs From the signing of the ICF up to 30 days after end of treatment- approximately up to 14.5 months Clinically notable elevated values: Systolic blood pressure (BP): ≥ 160 mmHg and an increase ≥ 20 mmHg from baseline; Diastolic BP: ≥ 100 mmHg and an increase ≥ 15 mmHg from baseline; Heart rate: ≥ 100 beats/min (bpm) with increase from baseline of ≥ 15 bpm; Body temperature \[°C\] ≥ 38°C). Clinically notable low values: Systolic BP: \<120 mmHg with decrease from baseline of ≥ 20 mmHg; Diastolic BP: \< 80 mmHg with decrease from baseline of ≥ 15 mmHg; Heart rate: \<50 bpm with decrease from baseline of ≥ 15 bpm; Body temperature \[°C\]: ≤ 35 °C
Safety and tolerability : Incidence of TEAEs related to notable changes in clinical safety laboratory parameters from baseline. From the signing of the ICF up to 30 days after end of treatment- approximately up to 14.5 months incidence of treatment-emergent adverse events (TEAEs) related to notable changes in clinical safety laboratory parameters from baseline.
Number of participants with clinically notable shift from baseline in laboratory parameter values based on national cancer institute common terminology criteria (NCI-CTCAE) grade, Version 5.0 will be graded from Grades 1 to 5. Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: Moderate; minimal, local or noninvasive intervention indicated. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death. Clinically notable shift is defined as a worsening from baseline by at least 2 grades, or to grade 3 or above.Pharmacokinetic (PK) parameter of encorafenib and its metabolite (LHY746)_Cmin From randomization up to 11 months Minimum serum concentration (Cmin) will be calculated and reported.
Safety - Incidence, nature, severity and seriousness of treatment emergent adverse events (TEAEs) From the signing of the ICF up to 30 days after end of treatment- approximately 14.5 months Incidence nature and severity of adverse events and SAEs graded as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0
Safety and tolerability -Incidence of treatment-emergent adverse events (TEAEs) related to notable or abnormal changes from baseline of 12-lead electrocardiograms (ECGs) From the signing of the ICF up to 30 days after end of treatment-approximately up to 14.5 months 12-lead ECGs will be obtained using an internationally recognized 12-lead cardiograph. Clinically notable ECG values: QT \[millisecond (ms)\] and QT interval (ms) corrected for heart rate using Fridericia's formula (QTcF) intervals (ms): increase from baseline \> 60 ms, new \> 450 ms, new \> 480 ms, new \> 500 ms.
Patient-reported health-related (HRQoL)-European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) . From the signing of the ICF up to 30 months. To determine if there is any change from baseline during the treatment and every 6 months thereafter up to 30 months in the European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) questionnaire scores.
EQ-5D-5L consists of the EQ-5D descriptive system and the EQ visual analogue scale (VAS). The descriptive system has five dimension (mobility, self-care, usual activities, pain/discomfort and anxiety/depression), each is rated according to a five-point verbal rating scale (VRS): 1. no problems, 2. slight problems, 3. moderate problems, 4. severe problems and 5. extreme problems) and translated into a five-digit number that describes the participant's health statePharmacokinetic (PK) parameter of binimetinib and its metabolite (AR00426032)-Cmax From randomization up to 11 months Maximum serum concentration (Cmax) will be calculated and reported.
Pharmacokinetic (PK) parameter of binimetinib and its metabolite (AR00426032)-AUC From randomization up to 11 months Area under the curve (AUC) will be calculated and reported.
Safety and tolerability - Incidence of treatment-emergent adverse events (TEAEs) related to notable or abnormal changes from baseline of echocardiogram or multigated acquisition (ECHO/MUGA) scans. From the signing of the ICF up to 30 days after end of treatment-approximately up to 14.5 months ECHO/MUGA scan assess Left Ventricular Ejection Fraction (LVEF). Changes from baseline of LVEF measurements over time will be reported
Patient-reported health-related (HRQoL)_European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer Patients (EORTC QLQ-C30) From the signing of the ICF up to 30 months. To determine if there is any change from baseline during the treatment and every 6 months thereafter up to 30 months in the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer Patients (EORTC QLQ-C30) questionnaire scores EORTC QLQ-C30 consists of fifteen multi-item scales: five functional scales (physical, role, cognitive, emotional and social); nine symptom/items scales (fatigue, pain, nausea, vomiting, dyspnea, insomnia, apetite loss, constipation, diarrhae and financial difficulties) and a global health and Quality of Life (QoL) scale. Each scale in the questionnaire will be scored (0 to 100). High scores represents a high health/quality of life
Pharmacokinetic (PK) parameter of binimetinib and its metabolite (AR00426032)-Cmin From randomization up to 11 months Minimum serum concentration (Cmin) will be calculated and reported
Trial Locations
- Locations (155)
Toronto Sunnybrook Hospital
🇨🇦Toronto, Ontario, Canada
Krankenhaus der Elisabethinen Linz
🇦🇹Linz, Austria
Debreceni Egyetem
🇭🇺Debrecen, Hungary
The Alfred Hospital
🇦🇺Prahran, Victoria, Australia
Institut Claudius Regaud - Oncopole
🇫🇷Toulouse, Haute Garonne, France
CRLCC Eugene Marquis
🇫🇷Rennes cedex, Ille Et Vilaine, France
Fakultni nemocnice Hradec Kralove
🇨🇿Hradec Králové, Czechia
Box Hill Hospital
🇦🇺Box Hill, Victoria, Australia
Universitaetsklinikum Carl Gustav Carus TU Dresden
🇩🇪Dresden, Sachsen, Germany
Fakultni nemocnice Kralovske Vinohrady
🇨🇿Praha 10, Czechia
Vseobecna fakultni nemocnice v Praze
🇨🇿Praha 2, Czechia
London Health Sciences Centre (LHSC) - Victoria Hospital
🇨🇦London, Ontario, Canada
Universitaetsklinikum Wuerzburg
🇩🇪Wuerzburg, Bayern, Germany
Instituto de Cancer de Londrina
🇧🇷Londrina, Paraná, Brazil
Hôpital Ambroise Paré
🇫🇷Boulogne-Billancourt, Hauts De Seine, France
Centre Hospitalier Lyon Sud
🇫🇷Pierre Bénite cedex, Rhone, France
Elbekliniken Buxtehude GmbH
🇩🇪Buxtehude, Niedersachsen, Germany
AMO - Assistência Multidisciplinar em Oncologia
🇧🇷Salvador, Bahia, Brazil
Vitaz
🇧🇪Sint-Niklaas, Belgium
Hôpital Saint-Louis
🇫🇷Paris Cedex 10, Paris, France
CHU de Dijon - Hôpital du Bocage
🇫🇷Dijon, Cote dÝOr, France
CHU de Grenoble - Hôpital André Michallon
🇫🇷La Tronche, Isere, France
Universitaetsklinikum Schleswig-Holstein
🇩🇪Kiel, Schleswig Holstein, Germany
Universitaetsklinikum Hamburg-Eppendorf
🇩🇪Hamburg, Germany
Princess Margaret Cancer Centre
🇨🇦Toronto, Ontario, Canada
Fakultni nemocnice Olomouc
🇨🇿Olomouc, Czechia
Anticancer Hospital of Thessaloniki " Theagenio"
🇬🇷Thessaloníki, Greece
Hospital Universitario Ramon y Cajal
🇪🇸Madrid, Spain
Ålesund Hospital
🇳🇴Ålesund, Norway
Azienda Ospedaliero Universitaria Pisana
🇮🇹Pisa, Italy
Orszagos Onkologiai Intezet
🇭🇺Budapest, Hungary
Petz Aladar Egyetemi Oktato Korhaz
🇭🇺Győr, Hungary
Antoni van Leeuwenhoek
🇳🇱Amsterdam, Netherlands
Maastricht University Medical Center
🇳🇱Maastricht, Netherlands
Johese Clinical Research: Midstream
🇿🇦Centurion, Gauteng, South Africa
Radboudumc
🇳🇱Nijmegen, Netherlands
Ospedale San Raffaele
🇮🇹Milano, Italy
Leids Universitair Medisch Centrum
🇳🇱Leiden, Netherlands
Hospital Regional Universitario de Malaga
🇪🇸Málaga, Spain
Karolinska University Hospital
🇸🇪Stockholm, Sweden
Hospital Clinico Universitario de Valencia
🇪🇸Valencia, Spain
Hospital Universitari Vall d'Hebron
🇪🇸Barcelona, Spain
Hospital Clinic de Barcelona
🇪🇸Barcelona, Spain
Norrlands Universitetssjukhus
🇸🇪Umeå, Sweden
Hospital General Universitario Gregorio Marañon
🇪🇸Madrid, Spain
Hospital Universitario 12 de Octubre
🇪🇸Madrid, Spain
Hospital Universitario Reina Sofia
🇪🇸Córdoba, Spain
Centro Oncologico Korben
🇦🇷Caba, Buenos Aires, Argentina
Centro de Investigaciones Medicas Mar del Plata
🇦🇷Mar Del Plata, Buenos Aires, Argentina
Sanatorio Britanico S.A.
🇦🇷Rosario, Santa Fe, Argentina
Instituto de Oncologia de Rosario
🇦🇷Rosario, Santa Fe, Argentina
Hospital Aleman
🇦🇷Ciudad Autonoma Buenos Aires, Argentina
Instituto Medico Especializado Alexander Fleming
🇦🇷Ciudad Autonoma Buenos Aires, Argentina
Clinica Adventista Belgrano
🇦🇷Ciudad Autonoma Buenos Aires, Argentina
Melanoma Institute Australia
🇦🇺Wollstonecraft, New South Wales, Australia
Adelaide Oncology & Haematolog, Calvary North Adelaide Hospital
🇦🇺North Adelaide, South Australia, Australia
Hollywood Private Hospital
🇦🇺Nedlands, Western Australia, Australia
CEPHO - Centro de Estudos e Pesquisas de Hematologia e Oncologia
🇧🇷Santo André, Sao Paulo, Brazil
Fakultni nemocnice Ostrava
🇨🇿Ostrava - Poruba, Czechia
CHU Tours - Hôpital Trousseau
🇫🇷Chambray-lès-Tours, Indre Et Loire, France
CHU Nantes - Hôtel Dieu
🇫🇷Nantes Cedex 1, Loire Atlantique, France
Universitaetsklinikum Heidelberg
🇩🇪Heidelberg, Baden Wuerttemberg, Germany
UMC Utrecht
🇳🇱Utrecht, Netherlands
Oncology Institute of Vojvodina
🇷🇸Sremska Kamenica, Serbia
Sandton Oncology Medical Group
🇿🇦Johannesburg, Gauteng, South Africa
ICO l'Hospitalet - Hospital Duran i Reynals
🇪🇸L'Hospitalet De Llobregat, Barcelona, Spain
Hospital General Universitario de Valencia
🇪🇸Valencia, Spain
Royal Preston Hospital
🇬🇧Preston, Lancashire, United Kingdom
Sir Charles Gairdner Hospital
🇦🇺Nedlands, Western Australia, Australia
Hospital de Clínicas de Porto Alegre
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
HGB - Hospital Giovanni Battista - Mãe de Deus Center
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
Hôpital de la Timone
🇫🇷Marseille cedex 5, Bouches-du-Rhône, France
Instituto de Oncologia Saint Gallen
🇧🇷Santa Cruz Do Sul, Rio Grande Do Sul, Brazil
IRCCS Istituto Scientifico Romagnolo Per Lo Studio e La Cura Dei Tumori "Dino Amadori" - IRST
🇮🇹Meldola, Forli - Cesena, Italy
Ospedale San Vincenzo
🇮🇹Taormina, Messina, Italy
Istituto Nazionale Tumori Regina Elena IRCCS
🇮🇹Roma, Italy
Istituto Nazionale Tumori Fondazione G. Pascale
🇮🇹Naples, Napoli, Italy
Istituto Tumori Giovanni Paolo II IRCCS Ospedale Oncologico Bari
🇮🇹Bari, Italy
Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII (Presidio Papa Giovanni XXIII)
🇮🇹Bergamo, Italy
Azienda Sanitaria Ospedaliera S.Croce e Carle
🇮🇹Cuneo, Italy
IRCCS Ospedale Policlinico San Martino
🇮🇹Genova, Italy
Fondazione IRCCS Istituto Nazionale dei Tumori
🇮🇹Milano, Italy
IEO Istituto Europeo di Oncologia
🇮🇹Milano, Italy
IOV - Istituto Oncologico Veneto IRCCS
🇮🇹Padova, Italy
Azienda Ospedaliero Universitaria Policlinico Paolo Giaccone
🇮🇹Palermo, Italy
Azienda Ospedaliera di Perugia Ospedale S. Maria della Misericordia
🇮🇹Perugia, Italy
Policlinico Universitario di Sassari
🇮🇹Sassari, Italy
A.O.U. Senese Policlinico Santa Maria alle Scotte
🇮🇹Siena, Italy
IDI-Istituto Dermopatico dell'Immacolata IRCCS
🇮🇹Roma, Italy
Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino
🇮🇹Torino, Italy
Azienda Sanitaria Universitaria Friuli Centrale
🇮🇹Udine, Italy
CHU Nice - Hopital de l Archet 2
🇫🇷Nice cedex 3, Alpes Maritimes, France
CAC Clermont-Ferrand Centre Jean Perrin
🇫🇷Clermont-Ferrand, Puy De Dome, France
Centre Hospitalier de Pau - Hôpital François Mitterrand
🇫🇷Pau cedex, Pyrenees Atlantiques, France
CHU de Rouen - Hôpital Charles Nicolle
🇫🇷Rouen, Seine Maritime, France
Institut Gustave Roussy
🇫🇷Villejuif cedex, Val De Marne, France
Northern Centre for Cancer Care
🇬🇧Newcastle Upon Tyne, Tyne & Wear, United Kingdom
Fundação Doutor Amaral Carvalho
🇧🇷Jaú, Sao Paulo, Brazil
A. C. Camargo Cancer Center
🇧🇷São Paulo, Sao Paulo, Brazil
Westmead Hospital
🇦🇺Sydney, New South Wales, Australia
National Hospital Oncology
🇿🇦Bloemfontein, Free State, South Africa
Princess Alexandra Hospital
🇦🇺Woolloongabba, Queensland, Australia
Centro Integral Oncologico Clara Campal
🇪🇸Madrid, Spain
Wielkopolskie Centrum Onkologii
🇵🇱Poznań, Poland
Dolnoslaskie Centrum Onkologii
🇵🇱Wrocław, Poland
S.C Medisprof S.R.L
🇷🇴Cluj-Napoca, Romania
Universitair Ziekenhuis Brussel
🇧🇪Brussel, Belgium
UZ Gent
🇧🇪Gent, Belgium
CHU UCL Namur
🇧🇪Yvoir, Belgium
CHU Saint Etienne - Hôpital Nord
🇫🇷Saint Etienne Cedex 2, Loire, France
Metropolitan Hospital
🇬🇷Néo Fáliro, Greece
Przychodnia Lekarska Komed
🇵🇱Konin, Poland
Centrum Onkologii-Instytut im. M. Sklodowskiej-Curie
🇵🇱Kraków, Poland
AKH - Medizinische Universität Wien
🇦🇹Vienna, Austria
Hopital Claude Huriez - CHU Lille
🇫🇷Lille cedex, Nord, France
CHU Poitiers - Hôpital la Milétrie
🇫🇷Poitiers, Vienne, France
Universitair Medisch Centrum Groningen (UMCG)
🇳🇱Groningen, Netherlands
Isala
🇳🇱Zwolle, Netherlands
S.C Centrul de Oncologie Sf. Nectarie S.R.L
🇷🇴Craiova, Romania
Clinical Center Nis
🇷🇸Niš, Serbia
Universitätsklinikum St.Pölten-Lilienfeld
🇦🇹St. Pölten, Austria
ZNA Middelheim
🇧🇪Antwerpen, Belgium
CIUSSS du Centre Ouest de l'lle de Montreal
🇨🇦Montréal, Quebec, Canada
General Hospital of Athens Laiko
🇬🇷Athens, Greece
Interbalkan Hospital of Thessaloniki
🇬🇷Thessaloníki, Greece
IRCCS Centro di Riferimento Oncologico
🇮🇹Aviano, Pordenone, Italy
Oslo University Hospital
🇳🇴Oslo, Norway
Instituto Português de Oncologia do Porto Francisco Gentil, EPE
🇵🇹Porto, Portugal
CEPON - Centro de Pesquisas Oncológicas de Santa Catarina
🇧🇷Florianópolis, Santa Catarina, Brazil
Semmelweis Egyetem
🇭🇺Budapest, Hungary
Centrum Medyczne Pratia Poznan
🇵🇱Skórzewo, Poland
Landeskrankenhaus - Universitaetsklinikum Graz
🇦🇹Graz, Austria
Bioclinic Thessaloniki
🇬🇷Thessaloníki, Greece
Erasmus MC
🇳🇱Rotterdam, Netherlands
Narodowy Instytut Onkologii im. M. Sklodowskiej-Curie - Panstwowy Instytut Badawczy
🇵🇱Gliwice, Poland
Institutul Regional de Oncologie Iasi
🇷🇴Iasi, Romania
Clinical Center Kragujevac
🇷🇸Kragujevac, Serbia
Universitaetsspital Zuerich
🇨🇭Zuerich, Switzerland
Hospital Erasto Gaertner - Liga Paranaense de Combate ao Câncer
🇧🇷Curitiba, Paraná, Brazil
Fundacion CIDEA
🇦🇷Ciudad Autonoma Bs As, Ciudad Autonoma Buenos Aires, Argentina
Institut Jules Bordet
🇧🇪Anderlecht, Belgium
Cliniques Universitaires Saint-Luc
🇧🇪Brussels, Belgium
ZNA
🇧🇪Merksem, Belgium
Pecsi Tudomanyegyetem
🇭🇺Pécs, Hungary
Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinikai Kozpont
🇭🇺Szeged, Hungary
Narodowy Instytut Onkologii im. Marii Skłodowskiej-Curie - Państwowy Instytut Badawczy
🇵🇱Warszawa, Poland
Instituto Português de Oncologia de Lisboa Francisco Gentil, EPE
🇵🇹Lisboa, Portugal
Centro Hospitalar de Lisboa Norte, E.P.E. - Hospital de Santa Maria
🇵🇹Lisboa, Portugal
Clinical Center "Bezanijska kosa"
🇷🇸Belgrade, Serbia
Institute of Oncology and Radiology of Serbia
🇷🇸Belgrade, Serbia
Austin Health
🇦🇺Heidelberg, Victoria, Australia
CHU de Bordeaux - Hôpital Saint André
🇫🇷Bordeaux, Gironde, France
ICO Badalona - Hospital Universitari Germans Trias i Pujol
🇪🇸Badalona, Barcelona, Spain
Military Medical Academy
🇷🇸Belgrade, Serbia
Hospital Universitario Virgen de la Arrixaca
🇪🇸El Palmar, Murcia, Spain