A Study of Efficacy and Safety of Fruquintinib (HMPL-013) in Participants With Metastatic Colorectal Cancer
- Conditions
- Metastatic Colorectal CancerMetastatic Colon Cancer
- Interventions
- Drug: Placebo
- Registration Number
- NCT04322539
- Lead Sponsor
- Hutchison Medipharma Limited
- Brief Summary
This is a global, randomized, double-blind, placebo-controlled, multicenter phase 3 clinical trial to compare the efficacy and safety of fruquintinib plus best supportive care (BSC) versus placebo plus BSC in participants with refractory metastatic colorectal cancer (mCRC). 691 participants were randomized to one of the following treatment arms in a 2:1 ratio, fruquintinib plus BSC or placebo plus BSC.
- Detailed Description
This is a global, randomized, double-blind, placebo-controlled, multicenter phase 3 clinical trial to compare the efficacy and safety of fruquintinib in combination with BSC versus placebo in combination with BSC in metastatic colorectal cancer participants who have progressed on, or were intolerant to, chemotherapy, anti-VEGF and anti-EGFR biologics, and TAS-102 or regorafenib. Participants with MSI-H/MMR deficient tumors must have also received an immune checkpoint inhibitor if approved and available and if deemed appropriate. Subjects with BRAF-mutant tumors must have been treated with a BRAF inhibitor if approved and available and if deemed appropriate.
Metastatic colorectal cancer cannot be cured by surgery. Therefore, treatment principals are primarily aimed at controlling disease progression and prolonging survival. Standard first- and second-line therapy includes cytotoxic drugs such as 5-fluorouracil, oxaliplatin, and irinotecan; anti-VEGF therapy; and, if RAS wild type, anti-EGFR therapy. After the first two lines of chemotherapy, standard third-line treatment is either TAS-102 or regorafenib. There are currently no effective treatments for patients who have progressed on standard, approved therapies, and treatment options include reuse of prior therapies, clinical trials or BSC. Consequently, there is an unmet medical need for additional safe and effective treatment.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 691
- Provide written informed consent;
- Age ≥18 years;
- Histologically and/or cytologically documented metastatic colorectal adenocarcinoma. RAS, BRAF, and microsatellite instability microsatellite instability (MSI)/mismatch repair (MMR) status for each patient must be documented, according to country level guidelines;
- Participants must have progressed on or been intolerant to treatment with either trifluridine/tipiracil (TAS-102) or regorafenib. Participants are considered intolerant to TAS-102 or regorafenib if they have received at least 1 dose of either agents and were discontinued from therapy for reasons other than disease progression. Participants who have been treated with both TAS-102 and regorafenib are permitted. Participants must also have been previously treated with standard approved therapies: fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and, if RAS wild-type, an anti-EGFR therapy;
- Participants with microsatellite-high (MSI-H) or mismatch repair deficient (dMMR) tumors must have been treated with immune checkpoint inhibitors if approved and available in the participant's country unless the patient is ineligible for treatment with a checkpoint inhibitor;
- Participants who received oxaliplatin in the adjuvant setting and developed metastatic disease during or within 6 months of completing adjuvant therapy are considered eligible without receiving oxaliplatin in the metastatic setting. Participants who developed metastatic disease more than 6 months after completion of oxaliplatin-containing adjuvant treatment must be treated with oxaliplatin-based therapy in the metastatic setting to be eligible;
- Body weight ≥40kg;
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1;
- Have measurable disease according to RECIST Version 1.1, assessed locally. Tumors that were treated with radiotherapy are not measurable per RECIST Version 1.1, unless there has been documented progression of those lesions;
- Expected survival >12 weeks.
- For female participants of childbearing potential and male participants with partners of childbearing potential, agreement to use a highly effective form(s) of contraception, that results in a low failure rate (<1% per year) when used consistently and correctly, starting during the screening period, continuing throughout the entire study period, and for 90 days after taking the last dose of study drug. Such methods include: oral hormonal contraception (combined estrogen/ progestogen, or progestogen-only) associated with inhibition of ovulation, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal ligation, vasectomized partner, or true sexual abstinence in line with the preferred and usual lifestyle of the participant. Highly effective contraception should always be combined with an additional barrier method (eg, diaphragm, with spermicide). The same criteria are applicable to male participants involved in this clinical trial if they have a partner of childbirth potential, and male participants must always use a condom.
- Participants with BRAF-mutant tumors must have been treated with a BRAF inhibitor if approved and available in the participant's home country unless the patient is ineligible for treatment with a BRAF inhibitor.
- Absolute neutrophil count (ANC) <1.5×109/L, platelet count <100×109/L, or hemoglobin <9.0 g/dL. Blood transfusion within 1 week prior to enrollment for the purpose of increasing the likelihood of eligibility is not allowed;
- Serum total bilirubin >1.5 × the upper limit of normal (ULN). Participants with Gilbert syndrome, bilirubin <2 X ULN, and normal AST/ALT are eligible;
- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 × ULN in participants without hepatic metastases; ALT or AST >5 × ULN in participants with hepatic metastases;
- Serum creatinine >1.5 × ULN or creatinine clearance <60 mL/min. Creatinine clearance can either be measured in a 24-hour urine collection or estimated by the Cockroft-Gault equation.
- Urine dipstick protein ≥2+ or 24-hour urine protein ≥1.0 g/24-h. Participants with greater than 2+ proteinuria by dipstick must undergo a 24-hour urine collection to assess urine protein level;
- Uncontrolled hypertension, defined as: systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg despite optimal medical management. Participants were required to have blood pressure values below both limits. Repeated assessments were permitted;
- International Normalized Ratio (INR) >1.5 x ULN or activated partial thromboplastin time (aPTT) >1.5 × ULN, unless the patient is currently receiving or intended to receive anticoagulants for prophylactic purposes;
- History of, or active gastric/duodenal ulcer or ulcerative colitis, active hemorrhage of an unresected gastrointestinal tumor, history of perforation or fistulas; or any other condition that could, in the investigator's judgment, result in gastrointestinal hemorrhage or perforation; within the 6 months prior to screening;
- History or presence of hemorrhage from any other site (eg, hemoptysis or hematemesis) within 2 months prior to screening;
- History of a thromboembolic event, including deep vein thrombosis (DVT), pulmonary embolism (PE), or arterial embolism within 6 months prior to screening.
- Stroke and/or transient ischemic attack within 12 months prior to screening;
- Clinically significant cardiovascular disease, including but not limited to acute myocardial infarction or coronary artery bypass surgery within 6 months prior to enrollment, severe or unstable angina pectoris, New York Heart Association Class III/IV congestive heart failure, ventricular arrhythmias requiring treatment, or left ventricular ejection fraction (LVEF) <50% by echocardiogram;
- Mean corrected QT interval using the Fridericia method (QTcF) >480 msec or any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in a first-degree relative.
- Concomitant medications with a known risk of causing QT prolongation and/or Torsades de Pointes.
- Systemic anti-neoplastic therapies (except for those described in Exclusion 18) or any investigational therapy within 4 weeks prior to the first dose of study drug, including chemotherapy, radical radiotherapy, hormonotherapy, biotherapy and immunotherapy;
- Systemic small molecule targeted therapies (eg, tyrosine kinase inhibitors) within 5 half-lives or 4 weeks (whichever is shorter) prior to the first dose of study drug;
- Palliative radiotherapy for bone metastasis/lesion within 2 weeks prior to the initiation of study drug;
- Brachytherapy (i.e., implantation of radioactive seeds) within 60 days prior to the first dose of study drug.
- Use of strong inducers or inhibitors of CYP3A4 within 2 weeks (or 5 half-lives, whichever is longer) before the first dose of study drug;
- Surgery or invasive procedure (i.e., a procedure that includes a biopsy; central venous catheter placement is allowed) within 60 days prior to the first dose of study drug or unhealed surgical incision;
- Any unresolved toxicities from a previous antitumor treatment greater than CTCAE v5.0 Grade 1 (except for alopecia or neurotoxicity grade≤2);
- Known human immunodeficiency virus (HIV) infection;
- Known history of active viral hepatitis. For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Participants with HCV infection who are currently on treatment are eligible if they have an undetectable HCV viral load.
- Clinically uncontrolled active infection requiring IV antibiotics;
- Tumor invasion of a large vascular structure, eg, pulmonary artery, superior or inferior vena cava;
- Women who are pregnant or lactating;
- Brain metastases and/or spinal cord compression untreated with surgery and/or radiotherapy, and without clinical imaging evidence of stable disease for 14 days or longer; participants requiring steroids within 4 weeks prior to start of study treatment are excluded;
- Other malignancy, except for non-melanoma skin cancer, in situ cervical ca or bladder ca (Tis and T1) that have been adequately treated during the 5 years prior to screening;
- Inability to take medication orally, dysphagia or an active gastric ulcer resulting from previous surgery (eg, gastric bypass) or a severe gastrointestinal disease, or any other condition that investigators believe may affect absorption of the investigational product;
- Other disease, metabolic disorder, physical examination anomaly, abnormal laboratory result, or any other condition (e.g., current alcohol or drug abuse) that investigators suspect may prohibit use of the investigational product, affect interpretation of study results, or put the patient at undue risk of harm based on the investigator's assessment;
- Known hypersensitivity to fruquintinib (or placebo) or any of its inactive ingredients including the azo dyes Tartrazine - FD&C Yellow 5 and Sunset yellow FCF - FD&C Yellow 6;
- Participants who have received prior fruquintinib;
- Live vaccine <28days before the first dose of study drug(s). Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and are not allowed.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Plus BSC Group Placebo Participants will be orally administered Placebo 5 mg in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break (with each cycle length of 28 days). Fruquintinib Plus Best Supportive Care (BSC) Group Fruquintinib Participants will be orally administered Fruquintinib 5 mg in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break (with each cycle length of 28 days).
- Primary Outcome Measures
Name Time Method Overall Survival (OS) From date of randomization to death from any cause (up to 22 months) OS was defined as the time (months) from date of randomization to death from any cause. OS was calculated as (date of death or last known alive - date of randomization + 1)/30.4375. Participants without report of death at the time of analysis will be censored at the date last known alive.
- Secondary Outcome Measures
Name Time Method Progression Free Survival (PFS), as Assessed by the Investigator Using Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 From randomization until the first documentation of objective progression or death, whichever comes first (up to 22 months) PFS was defined as the time (months) from randomization until the first radiographic documentation of objective progression as assessed by investigator using RECIST v1.1, or death from any cause, whichever comes first. More specifically, PFS was determined using all data until the last evaluable visit prior to or on the date of: (i) radiographic disease progression (PD) per RECIST v1.1; (ii) withdrawal of consent to obtain additional scans on study; or (iii) initiation of subsequent anticancer therapy other than the study drugs, whichever was earlier. PD was defined as: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; and the appearance of one or more new lesions.
Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) From randomization until the first documentation of best overall response (up to 22 months) ORR was defined as the percentage of participants who achieved a best overall response of confirmed complete response (CR) or partial response (PR), per RECIST v1.1, as determined by the investigator. PR: At least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<)10 millimeters (mm).
Observed Plasma Concentrations of Fruquintinib and Metabolite M11 Cycle 1 (Day 1 and 21): Pre-dose, 1, 2, 3 and 4 hours; Cycle 2 (Day 21): Predose and 2 hours, Cycle 3 (Day 1): Pre-dose, Cycle 3 (Day 21): Pre-dose and 2 hours, Cycle 5, 7, 9, 11, 13, 15 and 17 (Day 1): Pre-dose (Each cycle = 28 days) Plasma samples were collected from the participants at the defined time points. Plasma concentrations were measured using a validated, specific, and sensitive liquid chromatography tandem mass spectrometry method. M11 is the active metabolite for the study drug.
Disease Control Rate (DCR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) From randomization until the first documentation of best overall response (up to 22 months) DCR was defined as percentage of participants achieving a best overall response of confirmed CR, PR, or stable disease (SD) (for at least 7 weeks) per RECIST v1.1, as determined by the investigator. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum on study. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (nadir), including baseline.
Change From Baseline of Electrocardiogram (ECG) Results - QTcF Intervals Using Fridericia's Formula Baseline, Cycle 1 (Day 1 and 21): Pre-dose, 1, 2, 3 and 4 hours; Cycle 2 and 3 (Day 21): Pre-dose (Each cycle = 28 days) QT Interval: Ventricular depolarization plus ventricular repolarization Normal Range: 400 to 460 milliseconds (msec). QTc: QT interval corrected based on the patient's heart rate. QTcF: An electrocardiographic finding in which the QT interval corrected for heart rate using Fridericia's formula. QTc = QT/∛(RR) RR = Respiration rate.
Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) From first occurrence of PR or CR until the first documentation progression or death, whichever comes first (up to 22 months DOR was defined as the time (in months) from the first occurrence of PR or CR by RECIST Version 1.1, until the first date that progressive disease is documented by RECIST Version 1.1, or death, whichever comes first. Only those participants with confirmed responses of CR or PR were included in this analysis. DOR was calculated as (date of death or PD or last assessment - date of first occurrence of confirmed CR or PR + 1)/30.4375.
Correlation Between Fruquintinib Exposure (CminSS) and Efficacy Parameters (OS) Up to 22 months Model-predicted steady-state minimum plasma concentrations (CminSS) of fruquintinib based on the starting dose or adjusted for relative dose intensity \[RDI\] were used as the exposure measures in the efficacy exposure-response analyses. The correlation between OS and exposure was estimated using multivariable Cox proportional hazards modeling. OS was analyzed as time-to-event variable using a survival model. The efficacy exposure-response analyses included participants with mCRC and pooled the data from the fruquintinib group of current Study 2019-013-GLOB1 (N=328) and from Cohort B of Study 2015-013-00US1 (NCT03251378) (N=40) as per planned analysis. Here, the "unit of measure" i.e., '1/(nanogram per milliliter \[ng/mL\])', corresponds to the coefficient that describes the relationship between the probability of survival and CminSS value.
Correlation Between Fruquintinib Exposure (CmaxSS) and Safety Parameters (Any Grade [Gr] and Grade 3+ (Gr3+): Dermatological Toxicity, Proteinuria and Gr Hemorrhage) Up to 22 months Model-predicted steady-state maximum plasma concentration (CmaxSS) of fruquintinib based on the assigned dose of fruquintinib were investigated as fruquintinib exposure measure for the safety exposure-response analyses. The correlation between exposure and the probability of experiencing these AEs was evaluated using logistic regression analysis, with the slope serving as the estimate. The safety exposure-response analysis included participants with cancer, and the data of this outcome measure were pooled with data from the following studies as per the planned analysis: 2019-013-GLOB1 (NCT04322539) (N=334), 2009-013-00CH1 (NCT01645215) (N=40), 2012-013-00CH3 (NCT01975077) (N=40), and 2015-013-00US1 (NCT03251378) (N=101). Here, the "unit of measure" i.e., '1/(ng/mL)', corresponds to the coefficient that describes the relationship between the probability of occurrence of the safety parameter and CmaxSS value.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs From start of study drug administration up to approximately 40 months An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE was considered a TEAE if the onset date was on or after the start of study treatment or if the onset date was missing, or if the AE had an onset date before the start of study treatment but worsened in severity after the study treatment until 30 days after the last dose of study treatment or a new treatment of anti-tumor therapy, whichever was earlier. After this period, treatment-related SAEs were also considered as TEAEs. AEs with an unknown/not reported onset date were also included.
Change From Baseline of ECG Results -QTcB Intervals Using Bazzett's Formula Baseline, Cycle 1 (Day 1 and 21): Pre-dose, 1, 2, 3 and 4 hours; Cycle 2 and 3 (Day 21): Pre-dose (Each cycle = 28 days) QT Interval: Ventricular depolarization plus ventricular repolarization Normal Range: 400 to 460 msec. QTc: QT interval corrected based on the patient's heart rate. QTcB: An electrocardiographic finding in which the QT interval corrected for heart rate using Bazzett's formula.
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life (QOL) Questionnaire Core 30 (EORTC QLQ-C30) Global Health Status/Quality of Life Scale Score Baseline, Cycle 2, 3 and 4 (Each cycle=28 days) EORTC QLQ-C30 contains 30 items across 5 functional scales (physical, role, cognitive, emotional, and social), 9 symptom scales (fatigue, nausea and vomiting, pain, dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial difficulties) and global health status/QOL scale. EORTC QLQ-C30 contains 28 questions (4-point scale where 1=Not at all \[best\] to 4=Very Much \[worst\]) and 2 questions (7-point scale where 1=Very poor \[worst\] to 7= Excellent \[best\]). Raw scores are standardized and converted into scale scores ranging from 0 to 100. For global health status/QOL scale, higher scores represent better QOL. A negative change from baseline value indicates patient condition worsened. Change from baseline in the EORTC QLQ-C30 Global Health Status/Quality of Life Scale scores was performed by visit (i.e., cycle), using a restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach.
Change From Baseline in EuroQoL 5 Dimension 5 Level (EQ-5D-5L) Visual Analog Scale (VAS) Score Baseline, Cycle 2, 3 and 4 (Each cycle=28 days) The EQ-5D-5L is a self-reported health status questionnaire that consisted of six questions used to calculate a health utility score. There were two components to the EQ-5D-5L: a five-item health state profile that assessed mobility, self-care, usual activities, pain/discomfort, and anxiety/depression used to obtain an Index Utility Score and a general VAS score for health status. EQ-5D VAS was used to record participant's rating for his/her current health-related quality of life state on a vertical VAS with scores ranging from 0 to 100, where 0 = worst imaginable health state and 100 = best imaginable health state. The higher the score the better the health status. A negative change from baseline value represents patient condition worsened. Change from baseline in the EQ-5D-5L VAS scores was performed by visit (i.e. cycle), using a REML-based MMRM approach.
Change From Baseline in EuroQoL 5 Dimension 5 Level (EQ-5D-5L) Health Utility Index Scores Baseline, Cycle 2, 3 and 4 (Each cycle=28 days) EQ-5D-5L consisted of 2 components: health state profile and optional VAS. EQ-5D health state profile had 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression. Each dimension has 5 levels: 1= no problem, 2= slight problem, 3= moderate problem, 4= severe problem, and 5= extreme problem. The response levels collected from the EQ-5D-5L five dimensions as a health profile are converted into an EQ-5D-5L index (utility) scores to represent participants' utility value. The range of health utility index score is from -0.285 to 1, where higher value indicates perfect health and a negative value represents a state worse than dead. Change from baseline in EQ-5D-5L health utility index scores was performed by visit (i.e., cycle), using a REML-based MMRM approach.
Health Care Resource Utilization: Duration of Hospital Visits by Participants From start of study drug administration up to 22 months Duration of hospital visit was calculated as = stop date - start date + 1. Mean and standard deviation data for duration of hospital visits (in days) by participants was reported in this outcome measure.
Health Care Resource Utilization: Number of Participants With Any Concomitant Medications Prescribed From start of study drug administration up to 22 months Number of participants with any concomitant medications prescribed were reported.
Trial Locations
- Locations (153)
Sarah Cannon Research-E-WPB (Florida Cancer Specialists-FCS East)
🇺🇸West Palm Beach, Florida, United States
Sarah Cannon Research Institute-S-Ft. Myers (FCS South)
🇺🇸Fort Myers, Florida, United States
Illinois Cancer Specialists
🇺🇸Arlington Heights, Illinois, United States
Mount Sinai Medical Center
🇺🇸Miami Beach, Florida, United States
City of Hope Comprehensive Cancer Center
🇺🇸Los Angeles, California, United States
The George Washington University Medical Center
🇺🇸Washington, District of Columbia, United States
Emory Winship Cancer Institute
🇺🇸Atlanta, Georgia, United States
XCancer / Pontchartrain Cancer Center
🇺🇸Hammond, Louisiana, United States
Arizona Oncology Associates, PC-HOPE
🇺🇸Tucson, Arizona, United States
California Research Institute (CRI)
🇺🇸Los Angeles, California, United States
Rocky Mountain Cancer Center
🇺🇸Aurora, Colorado, United States
Affiliated Oncologists
🇺🇸Chicago Ridge, Illinois, United States
Mayo Clinic Florida
🇺🇸Jacksonville, Florida, United States
XCancer / Central Care Cancer Center
🇺🇸Garden City, Kansas, United States
Monash Health
🇦🇺Melbourne, Victoria, Australia
Sarah Cannon Research Institute-N-St Pete (FCS North)
🇺🇸Saint Petersburg, Florida, United States
Klinikum Steyr
🇦🇹Steyr, AUT, Austria
Mayo Clinic Rochester
🇺🇸Rochester, Minnesota, United States
HELIOS Klinikum Berlin-Buch Saarow
🇩🇪Berlin, DEU, Germany
ICM-Val d'Aurelle
🇫🇷Montpellier, FRA, France
Klinikum Neuperlach
🇩🇪Muenchen, DEU, Germany
The Queen Elizabeth Hospital
🇦🇺Adelaide, South Australia, Australia
Landesklinikum Wiener Neustadt
🇦🇹Wiener Neustadt, AUT, Austria
CHU Besancon
🇫🇷Besançon, Franche-Comte, France
UCL St-Luc
🇧🇪Brussels, BEL, Belgium
Institut Bergonie
🇫🇷Bordeaux, FRA, France
University Hospital Essen
🇩🇪Essen, DEU, Germany
Universitaeres Krebszentrum Leipzig
🇩🇪Leipzig, DEU, Germany
Universitaetsklinik Dresden
🇩🇪Dresden, DEU, Germany
Masaryk Memorial Cancer Institute, Hematoonkologie
🇨🇿Brno, Moravia, Czechia
Vseobecna Fakultni Nemocnice VFN, Onkologicka Klinika
🇨🇿Prague, Czechia
Unicancer
🇫🇷Caen, FRA, France
RKH Kliniken
🇩🇪Ludwigsburg, DEU, Germany
Zentrum für Hämatologie und Onkologie MVZ GmbH
🇩🇪Porta Westfalica, DEU, Germany
The Royal Marsden Hospital
🇬🇧London, GBR, United Kingdom
Istituto Nazionale Tumori IRCCS Fondazione G. Pascale
🇮🇹Naples, ITA, Italy
Hospital Universitario Virgen del Rocio
🇪🇸Sevilla, Spain
Hospital Clinico Universitario de Valencia
🇪🇸Valencia, Spain
Hospital Universitario Ramón y Cajal
🇪🇸Madrid, ESP, Spain
Hospital Universitario 12 de Octubre
🇪🇸Madrid, ESP, Spain
Hospital Universitario La Paz
🇪🇸Madrid, ESP, Spain
Hospital Universitario Puerta de Hierro
🇪🇸Majadahonda, ESP, Spain
Sarah Cannon Research Institute-Pan-Tallahassee (FCS Panhandle)
🇺🇸Tallahassee, Florida, United States
Cancer Care Centers of Brevard, Inc.
🇺🇸Palm Bay, Florida, United States
University of Louisville - James Brown Cancer Center
🇺🇸Louisville, Kentucky, United States
Norton Cancer Institute Audubon
🇺🇸Louisville, Kentucky, United States
Maryland Oncology Hematology, P.A.
🇺🇸Columbia, Maryland, United States
University of Michigan Health System
🇺🇸Ann Arbor, Michigan, United States
Center for Pharmaceutical Research
🇺🇸Kansas City, Missouri, United States
Texas Oncology - Austin
🇺🇸Austin, Texas, United States
Texas Oncology Baylor Sammons
🇺🇸Dallas, Texas, United States
Texas Oncology-El Paso
🇺🇸El Paso, Texas, United States
Texas Oncology-Tyler
🇺🇸Tyler, Texas, United States
Northwest Cancer Specialists, P.C.
🇺🇸Vancouver, Washington, United States
Virginia Oncology Associates
🇺🇸Norfolk, Virginia, United States
Providence Regional Cancer Partnership
🇺🇸Everett, Washington, United States
Integrated Clinical Oncology Network Pty Ltd (Icon)
🇦🇺Brisbane, Queensland, Australia
Flinders Medical Centre
🇦🇺Adelaide, South Australia, Australia
Western Health
🇦🇺Melbourne, Victoria, Australia
Austin Hopistal Medical Oncology Unit
🇦🇺Melbourne, Victoria, Australia
Schwerpunktkrankenhaus Feldkirch
🇦🇹Rankweil, AUT, Austria
Fakultni nemocnice Olomouc, Onkologicka klinika
🇨🇿Olomouc, Moravia, Czechia
East Tallinn Central Hospital Centre of Oncology
🇪🇪Tallinn, Harju, Estonia
CHU Poitiers
🇫🇷Poitiers, FRA, France
Centre Hospitalier Universitaire CHU de Rennes - Hopital de Pontchaillou
🇫🇷Rennes, FRA, France
Charite - Universitaetsmedizin Berlin
🇩🇪Berlin, DEU, Germany
Asklepios Tumorzentrum Hamburg AK Altona
🇩🇪Hamburg, DEU, Germany
Institut fr Klinisch Onkologische ForschungKrankenhaus Nordwest GmbH
🇩🇪Frankfurt Am Main, DEU, Germany
Universitaetsmedizin Mannheim- III. Medizinische Klinik
🇩🇪Mannheim, DEU, Germany
ASST Grande Ospedale Metropolitano Niguarda
🇮🇹Milano, ITA, Italy
Istituto Clinico Humanitas
🇮🇹Rozzano MI, Lombardy, Italy
Aichi Cancer Center
🇯🇵Nagoya, Aichi, Japan
Shikoku Cancer Center
🇯🇵Matsuyama City, Ehime, Japan
Kyushu Cancer Center
🇯🇵Fukuoka-shi, Fukuoka, Japan
Hospital Universitario Reina Sofa
🇪🇸Córdoba, ESP, Spain
Hospital Universitari Vall dHebron
🇪🇸Barcelona, ESP, Spain
Hospital General Universitario de Elche
🇪🇸Elche, ESP, Spain
Hospital Clinico San Carlos
🇪🇸Madrid, ESP, Spain
Hospital Universitario HM Sanchinarro
🇪🇸Madrid, ESP, Spain
Hospital Regional Universitario Carlos Haya
🇪🇸Malaga, ESP, Spain
Hospital Universitario Central de Asturias
🇪🇸Oviedo, ESP, Spain
Hospital Universitario Marques de Valdecilla
🇪🇸Santander, ESP, Spain
Hospital General Universitario Gregorio Maranon HGUGM
🇪🇸Madrid, Spain
University of Chicago Medical Center
🇺🇸Chicago, Illinois, United States
Texas Oncology-San Antonio
🇺🇸San Antonio, Texas, United States
Vanderbilt Ingram Cancer Center
🇺🇸Nashville, Tennessee, United States
Clinique CHC MontLegia
🇧🇪Liège, Wallonia, Belgium
CHU de Lige - Domaine Universitaire du Sart Tilman
🇧🇪Liège, Wallonia, Belgium
Minnesota Oncology
🇺🇸Minneapolis, Minnesota, United States
Fondazione Poliambulanza Hospital
🇮🇹Brescia, ITA, Italy
Policlinico San Martino di Genova
🇮🇹Genova, ITA, Italy
Fondazione IRCCS Istituto Nazionale dei Tumori
🇮🇹Milano, ITA, Italy
Istituto Oncologico Veneto Irccs
🇮🇹Padova, ITA, Italy
Azienda Ospedaliero Universitaria Pisana
🇮🇹Pisa, ITA, Italy
Azienda USL-IRCCS di Reggio Emilia
🇮🇹Reggio Emilia, ITA, Italy
AO Card G Panico
🇮🇹Tricase, ITA, Italy
Ospedale San Bortolo Azienda ULSS8 Berica - Distretto Est
🇮🇹Vicenza, ITA, Italy
Mayo Clinic Arizona
🇺🇸Phoenix, Arizona, United States
Barbara Ann Karmanos Cancer Institute
🇺🇸Detroit, Michigan, United States
Rutgers Cancer Institute of New Jersey
🇺🇸New Brunswick, New Jersey, United States
Wiener Gesundheitsverbund - Klinik Ottakring
🇦🇹Wien, AUT, Austria
UZ Antwerpen
🇧🇪Edegem, BEL, Belgium
Del-Pesti Centrumkorhaz Orszagos Hematologiai es Infektologiai Intezet, Szent Laszlo Korhaz
🇭🇺Budapest, HUN, Hungary
Magyar Honvedseg Egeszsegugyi Kozpont
🇭🇺Budapest, HUN, Hungary
Onze-Lieve-Vrouwziekenhuis OLV - Campus Aalst
🇧🇪Aalst, BEL, Belgium
AZ Delta Roeselare
🇧🇪Roeselare, BEL, Belgium
CHU Mont-Godinne
🇧🇪Yvoir, BEL, Belgium
Zala Megyei Szent Rafael Korhaz, Onkologiai Osztaly, F epulet 3. em.
🇭🇺Zalaegerszeg, Zala, Hungary
Universitaetsklinikum Erlangen
🇩🇪Erlangen, Bavaria, Germany
Hematology Oncology Clinic
🇺🇸Baton Rouge, Louisiana, United States
AZ Turnhout
🇧🇪Turnhout, BEL, Belgium
Tartu University Hospital Clinic of Haematology and Oncology
🇪🇪Tartu, Estonia
St. Marianna University School of Medicine Hospital
🇯🇵Kawasaki-shi, Kanagawa, Japan
Osaka University Hospital
🇯🇵Suita-shi, Osaka, Japan
Charleston Oncology
🇺🇸Charleston, South Carolina, United States
Ordensklinikum Linz Barmherzige Schwestern
🇦🇹Linz, AUT, Austria
Centres Hospitaliers Jolimont
🇧🇪Haine-Saint-Paul, BEL, Belgium
Comprehensive Cancer Centers of Nevada
🇺🇸Las Vegas, Nevada, United States
National Institute of Oncology
🇭🇺Budapest, HUN, Hungary
Institut Gustave Roussy
🇫🇷Villejuif, Paris, France
Sarah Cannon Tennessee Oncology
🇺🇸Nashville, Tennessee, United States
Klinikum Wels-Grieskirchen GmbH
🇦🇹Wels, AUT, Austria
Grand Hopital de Charleroi
🇧🇪Charleroi, BEL, Belgium
UZ Leuven
🇧🇪Leuven, BEL, Belgium
Sihtasutus Pohja-Eesti Regionaalhaigla (PERH) (North Estonia Medical Centre)
🇪🇪Tallinn, Harju, Estonia
Szabolcs-Szatmar-Bereg megyei Korhazak es Egyetemi Oktatokorhaz
🇭🇺Nyiregyhaza, HUN, Hungary
Bekes Megyei Kozponti Korhaz, Pandy Kalman Tagkorhaz, Megyei Onkologiai Kozpont
🇭🇺Gyula, Hungary
Hokkaido University Hospital
🇯🇵Sapporo-shi, Hokkaido, Japan
MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
National Cancer Center Hospital
🇯🇵Chuo-ku, Tokyo, Japan
Medical College of Wisconsin/ Froedtert Hospital
🇺🇸Milwaukee, Wisconsin, United States
Debreceni Egyetem Klinikai Kozpont
🇭🇺Debrecen, HUN, Hungary
Bacs- Kiskun Megyei Korhaz
🇭🇺Kecskemét, HUN, Hungary
Hetenyi G Korhaz, Onkologiai Kozpont
🇭🇺Szolnok, HUN, Hungary
Szent Borbala Korhaz
🇭🇺Tatabanya, HUN, Hungary
Somogy Megyei Kaposi Mor Oktato Korhaz, Klinikai Onkologiai Osztaly
🇭🇺Kaposvár, Somogy, Hungary
National Cancer Center Hospital East
🇯🇵Kashiwa-shi, Chiba, Japan
Kindai University Hospital
🇯🇵Osakasayama-shi, Osaka, Japan
Shizuoka Cancer Center
🇯🇵Shizuoka, Sunto-gun, Japan
M Sklodowska Curie Memorial Cancer Center, Klinika Gastroenterologii Onkologicznej
🇵🇱Warszawa, Masovia, Poland
Bialostockie Centrum Onkologii im. Marii Skodowskiej-Curie
🇵🇱Bialystok, Podlaskie, Poland
Hopital Pitie Salptriere
🇫🇷Paris, FRA, France
Centre Georges-Francois Leclerc
🇫🇷Dijon, FRA, France
Saint-Louis Hospital
🇫🇷Paris, FRA, France
Hopital St Antoine
🇫🇷Paris, FRA, France
Centre hospitalier Annecy Genevois
🇫🇷Pringy, FRA, France
Institut de cancerologie Strasbourg-Europe
🇫🇷Strasbourg, FRA, France
Aberdeen Royal Infirmary
🇬🇧Aberdeen, GBR, United Kingdom
Sarah Cannon Research Institute UK
🇬🇧London, Middlesex, United Kingdom
Haematologisch-Onkologische Praxis Hamburg Eppendorf
🇩🇪Hamburg, DEU, Germany
Hospital ClÃ-nico Universitario de Santiago-CHUS
🇪🇸Santiago De Compostela, ESP, Spain
XCancer / New Mexico Oncology & Hematology Consultants
🇺🇸Albuquerque, New Mexico, United States
Texas Oncology-McAllen
🇺🇸McAllen, Texas, United States