Study of Dexamethasone Plus IXAZOMIB (MLN9708) or Physicians Choice of Treatment in Relapsed or Refractory Systemic Light Chain (AL) Amyloidosis
- Conditions
- Relapsed or Refractory Systemic Light Chain Amyloidosis
- Interventions
- Registration Number
- NCT01659658
- Lead Sponsor
- Millennium Pharmaceuticals, Inc.
- Brief Summary
The purpose of this study is to provide continued access of ixazomib and/or other study medications and to continue collecting relevant safety data to monitor participant's safety, determine whether dexamethasone plus IXAZOMIB improves hematologic response, 2-year vital organ (that is, heart or kidney) deterioration and mortality rate versus a physician's choice of a chemotherapy regimen in participants diagnosed with relapsed or refractory systemic light chain (AL) amyloidosis.
- Detailed Description
The drug being tested in this study is called IXAZOMIB. IXAZOMIB was being tested to treat people who have relapsed or Refractory Systemic Light Chain (AL) Amyloidosis.
The study will enroll approximately 177 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups:
* IXAZOMIB 4 mg plus Dexamethasone 20 mg
* Physician's choice: Participants will receive one of the following treatment options as selected by the physician:
1. Dexamethasone 20 mg
2. Dexamethasone 20 mg + Melphalan 0.22 mg/kg
3. Dexamethasone 20 mg + Cyclophosphamide 500 mg
4. Dexamethasone 20 mg + Thalidomide 200 mg
5. Dexamethasone 20 mg + Lenalidomide 15 mg
6. All participants will be asked to take oral formulation of the drugs. In both treatment arms, each participant will continue to receive sequential cycles of therapy until disease progression, unacceptable toxicity, or until the study is terminated, whichever occurs first. Participants in Arm B receiving melphalan and dexamethasone will be treated to best response plus 2 additional cycles.
This multi-center trial will be conducted worldwide. The overall time to participate in this study is 120 months (10 years), including 84 months of enrollment and 36 months of follow-up after the last participant is enrolled.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 177
-
Male or female participants 18 years or older.
-
Biopsy-proven diagnosis of primary systemic light chain amyloidosis (AL amyloidosis) according to the following standard criteria:
- Histochemical diagnosis of amyloidosis, as based on tissue specimens with Congo red staining with exhibition of an apple-green birefringence
- If clinical and laboratory parameters insufficient to establish AL amyloidosis or in cases of doubt, amyloid typing may be necessary.
-
Measurable disease as defined by serum differential free light chain concentration (dFLC, difference between amyloid forming [involved] and nonamyloid forming [uninvolved] free light chain [FLC]) ≥ 50 mg/L.
-
Objective, measurable major (cardiac or renal) organ amyloid involvement as defined as follows (amyloid involvement of at least 1 required):
- Cardiac involvement is defined as the presence of a mean left ventricular wall thickness on echocardiogram greater than 12 mm in the absence of other potential causes of left ventricular hypertrophy (controlled hypertension is allowed) with a noncardiac biopsy showing amyloid, or a positive cardiac biopsy in the presence of clinical or laboratory evidence of involvement. If there is isolated cardiac involvement, then typing of amyloid deposits is recommended.
- Renal involvement is defined as proteinuria (predominantly albumin) >0.5 g/day in a 24-hour urine collection.
Note: Amyloid involvement of other organ systems is allowed, but not required.
-
Must be relapsed or refractory after 1 or 2 prior therapies. For this protocol, relapsed is defined as progressive disease (PD) documented more than 60 days after last dose; refractory is defined as documented absence of hematologic response or hematologic progression on or within 60 days after last dose of prior therapy.
- Participant must not have been previously treated with proteasome inhibitors. (The sponsor reserves the right to open the study to proteasome inhibitor-exposed participants in the future, at some time point after the first interim analysis (IA). In that case, the participant may not be refractory to proteasome inhibitor therapy.)
- Given that the physician may select from an offered list of regimens to treat a specific participant, the participant may be refractory to an agent/s listed within the list of offered treatment choices
- Must have recovered (ie, ≤ Grade 1 toxicity or participant's baseline status) from the reversible effects of prior therapy
- If a participant has received a transplant as his/her first-line therapy, he/she must be at least 3 months post transplantation and recovered from the side effects of the stem cell transplant.
-
Must meet criteria for 1 of the following AL Amyloidosis Risk Stages (as defined by N-terminal proBNP [NT-proBNP] cut-off of < 332 pg/mL and troponin T cut-off of 0.035 ng/mL as thresholds):
- Stage 1: both NT-proBNP and troponin T under threshold
- Stage 2: either NT-proBNP or troponin T (but not both) over threshold;
- Stage 3: both NT-proBNP and troponin T over threshold (but NT-proBNP < 8000 pg/mL)
-
Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2.
-
Clinical laboratory values:
- Absolute neutrophil count ≥ 1000/µL
- Platelet count ≥ 75,000/µL
- Total bilirubin ≤ 1.5 upper limit of normal (ULN), except for participants with Gilbert's syndrome as defined by > 80% unconjugated bilirubin and total bilirubin ≤ 6 mg/dL
- Alkaline phosphatase ≤ 5 x ULN
- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3 x ULN
- Calculated creatinine clearance ≥ 30 mL/min
-
Female participants who:
- If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 90 days after the last dose of study treatment, AND
- Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
- Agree to practice true abstinence when this is line with the preferred and usual lifestyle of the participant. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.).
Male participants, even if surgically sterilized (ie, status post vasectomy), who:
- Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, AND
- Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
- Agree to practice true abstinence when this is line with the preferred and usual lifestyle of the participant. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)
-
Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.
-
Amyloidosis due to mutations of the transthyretin gene or presence of other non-AL amyloidosis.
-
Female participants who are lactating, breast feeding, or pregnant.
-
Medically documented cardiac syncope, uncompensated New York Heart Association (NYHA) Class 3 or 4 congestive heart failure, myocardial infarction within the previous 6 months, unstable angina pectoris, clinically significant repetitive ventricular arrhythmias despite antiarrhythmic treatment, or severe orthostatic hypotension or clinically important autonomic disease.
-
Clinically overt multiple myeloma, according to the International Myeloma Working Group (IMWG) criteria with at least 1 of the following:
- Bone lesions
- Hypercalcemia, defined as a calcium of > 11 mg/dL
-
Inability to swallow oral medication, inability or unwillingness to comply with the drug administration requirements, or gastrointestinal (GI) procedure that could interfere with the oral absorption or tolerance of treatment.
-
Requirement for other concomitant chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered to be investigational or which would be considered as a treatment of AL amyloidosis. However, participants may be on chronic steroids (maximum dose 20 mg/day prednisone or equivalent) if they are being given for disorders other than amyloidosis (eg, adrenal insufficiency, rheumatoid arthritis, etc.).
-
Comorbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the participant inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
-
Ongoing or active infection, known human immunodeficiency virus (HIV) positive, active hepatitis B or C infection.
-
Psychiatric illness/social situations that would limit compliance with study requirements.
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Known allergy to boron, MLN9708, any of the study treatments, their analogues, or excipients.
-
Systemic treatment with strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort within 14 days before the first dose of study treatment.
-
Diagnosed or treated for another malignancy within 3 years (or 5 years for participants in France) before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm A: Ixazomib + Dexamethasone Dexamethasone Ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15 and dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15, and 22 of each 28-day cycle for up to a maximum of 95.2 months. Dexamethasone was increased up to 40 mg/day after 4 weeks, if tolerated. Arm A: Ixazomib + Dexamethasone IXAZOMIB Ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15 and dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15, and 22 of each 28-day cycle for up to a maximum of 95.2 months. Dexamethasone was increased up to 40 mg/day after 4 weeks, if tolerated. Arm B: Dexamethasone + Melphalan Dexamethasone Participants received dexamethasone 20 mg, orally, and melphalan 0.22 mg/kg, orally once on Days 1 through 4 of each 28-day cycle, for up to a maximum of 72.4 months. Arm B: Dexamethasone + Cyclophosphamide Dexamethasone Participants received dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15, and 22, and cyclophosphamide 500 mg, orally, on Days 1, 8 and 15 of each 28-day cycle for up to a maximum of 72.4 months. Arm B: Dexamethasone + Melphalan Melphalan Participants received dexamethasone 20 mg, orally, and melphalan 0.22 mg/kg, orally once on Days 1 through 4 of each 28-day cycle, for up to a maximum of 72.4 months. Arm B: Dexamethasone + Cyclophosphamide Cyclophosphamide Participants received dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15, and 22, and cyclophosphamide 500 mg, orally, on Days 1, 8 and 15 of each 28-day cycle for up to a maximum of 72.4 months. Arm B: Dexamethasone + Lenalidomide Lenalidomide Participants received dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15 and 22 of each 28-day cycle and lenalidomide 15 mg, orally, once on Days 1 through 21 every 28 days for up to a maximum of 72.4 months. Arm B: Dexamethasone + Thalidomide Dexamethasone Participants received dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15 and 22 of each 28-day cycle, and thalidomide daily at a starting dose of 50 mg and increased, as tolerated, to a maximum of 200 mg, orally for up to a maximum of 72.4 months. Arm B: Dexamethasone + Thalidomide Thalidomide Participants received dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15 and 22 of each 28-day cycle, and thalidomide daily at a starting dose of 50 mg and increased, as tolerated, to a maximum of 200 mg, orally for up to a maximum of 72.4 months. Arm B: Dexamethasone + Lenalidomide Dexamethasone Participants received dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15 and 22 of each 28-day cycle and lenalidomide 15 mg, orally, once on Days 1 through 21 every 28 days for up to a maximum of 72.4 months.
- Primary Outcome Measures
Name Time Method Percentage of Participants With Overall Hematologic Response From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months) Overall hematologic response was defined as the percentage of participants with complete response (CR), very good partial response (VGPR) and partial response (PR) based on central laboratory results and the 2010 International Society of Amyloidosis (ISA) Consensus Criteria as assessed by an adjudication committee. CR: Complete disappearance of M-protein from serum and urine on immunofixation, and normalization of free light chain (FLC) ratio. VGPR: differential free light chain (difference between involved and uninvolved FLC levels; dFLC) \< 40 mg/L. PR: ≥50% reduction in dFLC. Percentages were rounded off to the nearest decimal.
2-Year Vital Organ (Heart or Kidney) Deterioration and Mortality Rate Up to 2 years Cardiac (Heart) deterioration was defined as the need for hospitalization for heart failure. Kidney deterioration was defined as progression to end-stage renal disease (ESRD) with the need for maintenance dialysis or renal transplantation. Vital organ deterioration was evaluated by an adjudication committee. Percentages were rounded off to the nearest decimal. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
- Secondary Outcome Measures
Name Time Method Percentage of Participants With Complete Hematologic Response From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months) Complete hematologic response was defined as the percentage of participants with CR based on central laboratory results and the 2010 ISA Consensus Criteria as assessed by the investigator. CR: Complete disappearance of M-protein from serum and urine on immunofixation, and normalization of FLC ratio. Percentages were rounded off to the nearest decimal. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Overall Survival From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months) Overall survival was defined as the time from the date of randomization to the date of death. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Progression Free Survival (PFS) From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months) PFS was defined as the time from the date of randomization to the date of first documentation of hematologic disease progression, or organ (cardiac or renal) progression, or death due to any cause, whichever occurred first according to central laboratory results and ISA criteria as evaluated by the investigator. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Hematologic Disease Progression Free Survival From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months) Hematologic disease PFS was defined as the time from the date of randomization to the date of first documentation of hematologic PD according to central laboratory results and ISA criteria as evaluated by an adjudication committee, or death due to any cause, whichever occurred first. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Time to Vital Organ (Heart or Kidney) Deterioration and Mortality Rate From randomization to time of vital organ deterioration or death (up to 115 months) Time to vital organ deterioration or death was assessed by the investigator and defined as the time from randomization to vital organ (heart or kidney) deterioration or death, whichever occurs first. Cardiac deterioration is defined as the need for hospitalization for heart failure. Kidney deterioration is defined as progression to ESRD with the need for maintenance dialysis or renal transplantation. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Percentage of Participants With Best Vital Organ (Cardiac and/or Kidney) Response From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months) Vital organ (heart and kidney) response rate was defined as the percentage of participants who achieved vital organ response according to central laboratory results and ISA criteria as evaluated by an adjudication committee. A vital organ response was defined as response of 1 or 2 of the involved vital organs with no change from Baseline in the rest of involved vital organs. Percentages were rounded off to the nearest decimal. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Vital Organ Progression Free Survival From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months) Vital organ PFS is defined as the time from the date of randomization to the date of first documentation of progression of vital organ (heart or kidney) according to central laboratory results and ISA criteria as evaluated by an adjudication committee, or death due to any cause, whichever occurs first. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Duration of Hematologic Response From time of first documented response to disease progression (up to 115 months) Duration of hematologic response (DOR) was defined as the time from the date of first documentation of a hematologic response to the date of first documented hematologic disease progression as determined by the investigator. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Number of Participants With Serious Adverse Events (SAEs) From first dose of study drug through 30 days after administration of the last dose of study drug (up to 115 months) A SAE was defined as any untoward medical occurrence that at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of an existing hospitalization, resulted in persistent or significant disability or incapacity, was a congenital anomaly/birth defect or medically important event.
EuroQol 5-Dimension 3-Level (EQ-5D-3L) Visual Analogue Scale Score At Week 28 of the OS follow-up The EQ visual analogue scale (VAS) records the participant's self-rated health on a 20 centimeter vertical VAS that ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). Baseline is defined as the value collected at the time closest to, but prior to, the start of study drug administration. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Time To Treatment Failure (TTF) From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months) TTF was defined as the time from randomization to the date of first documented treatment failure. Treatment failure was defined as: 1) death due to any cause; 2) hematologic progression or major organ progression according to central laboratory results and ISA criteria as evaluated by the investigator; 3) clinically morbid organ disease requiring additional therapy; or 4) withdrawn for any reason. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Time To Subsequent Anticancer Treatment From first dose of study drug until subsequent anticancer treatment (up to 115 months) Time to subsequent anticancer therapy was defined as the time from randomization to the first date of subsequent anticancer therapy. Participants without subsequent anticancer therapy were censored at the date of death or last known to be alive. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Change From Baseline in 36-item Short Form General Health Survey (SF-36) Mental Component Summary Score at Week 28 of the PFS Follow-up Baseline, Week 28 of the PFS Follow-up SF-36 Version 2 is a multipurpose, participant completed, short-form health survey with 36 questions that consists of an 8-scale profile of functional health and well-being scores as well as psychometrically-based physical and mental health summary measures. Physical component summary (PCS) is mostly contributed by physical function (PF), role physical (RP), bodily pain (BP), and general health (GH). Mental component summary (MCS) is mostly contributed by mental health (MH), role emotional (RE), social function (SF), and vitality (VT). Each component on the SF-36 item health survey is scored from 0 (best) to 100 (worst). Total score ranges from 0-100, where higher scores are associated with less disability and better quality of life. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Change From Baseline in SF-36 Physical Component Summary Score at Week 28 of the PFS Follow-up Baseline, Week 28 of the PFS Follow-up SF-36 Version 2 is a multipurpose, participant completed, short-form health survey with 36 questions that consists of an 8-scale profile of functional health and well-being scores as well as psychometrically-based physical and mental health summary measures. Physical component summary (PCS) is mostly contributed by physical function (PF), role physical (RP), bodily pain (BP), and general health (GH). Mental component summary (MCS) is mostly contributed by mental health (MH), role emotional (RE), social function (SF), and vitality (VT). Each component on the SF-36 item health survey is scored from 0 (best) to 100 (worst). Total score ranges from 0-100, where higher scores are associated with less disability and better quality of life. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Change From Baseline in Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) Score at Week 28 of the PFS Follow-up Baseline, Week 28 of the PFS Follow-up The FACT/GOG-Ntx is a participant completed questionnaire that comprises 11 individual items evaluating symptoms of neurotoxicity on a 5-point scale where: 0=not at all (best) to 4=very much for a total possible score of 0 to 44. Symptom scores are inverted so that higher scores of FACT/GOG-Ntx indicate higher quality of life or functioning. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Change From Baseline in Amyloidosis Symptom Scale Total Score at Week 28 of the PFS Follow-up Baseline, Week 28 of the PFS Follow-up The amyloidosis symptom scale questionnaire is a participant completed questionnaire that evaluates symptom severity of 3 symptoms: Swelling, Shortness of Breath and Dizziness, each rated on an 11-point scale where: 0=no symptoms to 10=very severe symptoms. Higher scores indicate worsening of symptoms. Total Score is the sum of all responses from the amyloidosis symptom scale ranging from 0 to 30. Higher scores represent higher levels of symptomatology or problems and a negative change from baseline indicates improvement. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Number of Participants in Each Category of the EuroQol 5-Dimensional (EQ-5D) Questionnaire Score At Week 28 of the OS follow-up The European Quality of Life (EuroQOL) 5-Dimensional (EQ-5D) is a patient completed questionnaire consisting of 2 pages: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The descriptive system comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression). Each dimension has 3 possible choices: no problems to extreme problems. Higher scores=worsening of the quality of life. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Plasma Concentration of Ixazomib Cycle 1, Day 1: 1, 4 hours postdose, Day 14: 144 hours postdose; Cycle 2, Day 1: predose, Day 14: 144 hours postdose; Cycles 3 to 10, Day 1: predose (cycle length=28 days) As prespecified in the protocol, data for this outcome measure was planned to be collected for ixazomib arm group only.
Number of Hospitalizations From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months) A hospitalization was defined as at least one overnight stay in an intensive care unit and/or non-intensive care unit. If a single hospitalization included both an intensive care unit stay and a non-intensive care unit stay, the hospitalization was counted only once (as an intensive care unit stay). The mean number of hospitalizations is reported in this outcome measure. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Trial Locations
- Locations (66)
Indiana University School of Medicine
🇺🇸Indianapolis, Indiana, United States
University of Cincinnati
🇺🇸Cincinnati, Ohio, United States
Tufts Medical Center
🇺🇸Boston, Massachusetts, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
Westmead Hospital
🇦🇺Westmead, New South Wales, Australia
Centro de Pesquisas Oncologicas
🇧🇷Florianopolis, Santa Catarina, Brazil
Vancouver General Hospital
🇨🇦Vancouver, British Columbia, Canada
Princess Alexandra Hospital
🇦🇺Woolloongabba, Queensland, Australia
Irmandade Da Santa Casa de Misericordia de Sao Paulo
🇧🇷Sao Paulo, Brazil
Vseobecna fakultni nemocnice v Praze
🇨🇿Praha, Praha, Hlavni Mesto, Czechia
Hospital Israelita Albert Einstein
🇧🇷Sao Paulo, Brazil
Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo
🇧🇷Sao Paulo, Brazil
Hopital de Rangueil
🇫🇷Toulouse, France
University of Texas Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Hospital Universitario Clementino Fraga Filho (UFRJ)
🇧🇷Rio de Janeiro, Brazil
Columbia University Medical Center
🇺🇸New York, New York, United States
Tom Baker Cancer Centre
🇨🇦Calgary, Alberta, Canada
Hopital Saint Louis
🇫🇷Paris, France
Fakultni nemocnice Ostrava
🇨🇿Ostrava, Moravskoslezsk Kraj, Czechia
Severance Hospital at Yonsei University Health System - PPDS
🇰🇷Seoul, Korea, Republic of
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Gachon University Gil Medical Center
🇰🇷Incheon, Korea, Republic of
Karmanos Cancer Institute
🇺🇸Detroit, Michigan, United States
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
Froedtert and The Medical College of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
Box Hill Hospital
🇦🇺Box Hill, Victoria, Australia
University General Hospital of Patras
🇬🇷Patras, Achaia, Greece
Maastricht University Medical Center
🇳🇱AZ Maastricht, Netherlands
Institute of Hematology "Seragnoli" University of Bologna
🇮🇹Bologna, Italy
Fondazione IRCCS Policlinico San Matteo di Pavia
🇮🇹Pavia, Italy
Samsung Medical Center - PPDS
🇰🇷Seoul, Korea, Republic of
Charite - Universitatsmedizin Berlin
🇩🇪Berlin, Germany
Hospital Universitario de Salamanca
🇪🇸Salamanca, Spain
Chaim Sheba Medical Center
🇮🇱Ramat-Gan, Israel
Alexandra Hospital
🇬🇷Athens, Greece
VU Medisch Centrum
🇳🇱Amsterdam, Noord-Holland, Netherlands
Hospital Universitario de La Princesa
🇪🇸Madrid, Spain
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
Universitair Medisch Centrum Utrecht
🇳🇱Utrecht, Netherlands
Universitatsklinikum Hamburg Eppendorf
🇩🇪Hamburg, Germany
Rabin Medical Center - PPDS
🇮🇱Petach Tikva, Israel
Meir Medical Center
🇮🇱Kfar Saba, Israel
Rambam Health Corporation
🇮🇱Haifa, Israel
Hospital Universitario Puerta de Hierro - Majadahonda
🇪🇸Majadahonda, Spain
Sir Charles Gairdner Hospital
🇦🇺Nedlands, Western Australia, Australia
Hotel Dieu
🇫🇷Nantes, Loire-Atlantique, France
Cedars Sinai Medical Center
🇺🇸Los Angeles, California, United States
Vanderbilt University Medical Center
🇺🇸Nashville, Tennessee, United States
Rigshospitalet
🇩🇰Copenhagen, Denmark
Arhus Universitetshospital Arhus Sygehus
🇩🇰Aahus, Denmark
Hopital Claude Huriez
🇫🇷Lille, France
Centre Hospitalier et Universitaire de Limoges
🇫🇷Limoges, France
Boston Medical Center
🇺🇸Boston, Massachusetts, United States
University of Chicago
🇺🇸Chicago, Illinois, United States
Washington University
🇺🇸Saint Louis, Missouri, United States
Princess Margaret Hospital
🇨🇦Toronto, Ontario, Canada
Cross Cancer Institute
🇨🇦Edmonton, Alberta, Canada
Universitat Heidelberg
🇩🇪Heidelberg, Germany
Hadasit Medical Research Services and Development Ltd
🇮🇱Jerusalem, Israel
The Catholic University of Korea, Seoul St Mary's Hospital
🇰🇷Seoul, Korea, Republic of
Clinica Universidad de Navarra
🇪🇸Pamplona, Navarra, Spain
Queen Elizabeth Hospital
🇬🇧Birmingham, United Kingdom
Hospital Clinic de Barcelona
🇪🇸Barcelona, Spain
Royal Free and University College Medical School
🇬🇧London, United Kingdom
Manchester Royal Infirmary
🇬🇧Manchester, United Kingdom
Oxford University Hospitals NHS Trust
🇬🇧Oxford, United Kingdom