A Study to Evaluate Subcutaneous Daratumumab in Combination With Standard Multiple Myeloma Treatment Regimens
- Conditions
- Multiple Myeloma
- Interventions
- Registration Number
- NCT03412565
- Lead Sponsor
- Janssen Research & Development, LLC
- Brief Summary
The purpose of this study is to evaluate the clinical benefit of subcutaneous (SC) daratumumab administered in combination with standard multiple myeloma (MM) regimens in participants with MM as measured by overall response rate (ORR) or very good partial response (VGPR) or better rate.
- Detailed Description
The hypothesis is that the addition of daratumumab administered SC to standard MM regimens will improve responses compared to response data observed in completed phase 3 studies without daratumumab. Disease evaluations will include measurements of myeloma proteins, bone marrow examinations, skeletal surveys, assessment of extramedullary plasmacytomas, and measurements of serum calcium corrected for albumin. Safety will be measured by adverse events, laboratory test results, electrocardiogram (ECGs), vital sign measurements, physical examination findings, SC injection-site assessments, and assessment of Eastern Cooperative Oncology Group (ECOG) performance status score. Study will consist of 3 phases (screening, treatment and follow-up) and duration of study is approximately 3 years.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 265
-
Multiple myeloma diagnosed according to the International Myeloma Working Group (IMWG) diagnostic criteria
-
Measurable, secretory disease as defined by any of the following:
- Serum monoclonal paraprotein (M-protein) level greater than or equal to (>=) 1.0 gram per deciliter (g/dL); or
- Urine M-protein level >= 200 milligram per 24 hours (mg/24 hours); or
- Light chain multiple myeloma (MM), for participants without measurable disease in the serum or urine: serum Immunoglobulin (Ig) free light chain (FLC) >= 10 mg/dL and abnormal FLC ratio
-
Meets one of the sets of the following criteria:
- For Daratumumab + bortezomib + lenalidomide + dexamethasone (D-VRd) and Daratumumab + bortezomib + melphalan + prednisone + dexamethasone (D-VMP) regimen: newly diagnosed myeloma
- For Daratumumab + lenalidomide + dexamethasone (D-Rd) and Daratumumab + Carfilzomib + Dexamethasone (D-Kd) regimen: relapsed or refractory disease
- D-Kd cohort: Participants must have received only 1 prior line of therapy for MM which included at least 2 consecutive cycles of lenalidomide therapy
-
Eastern Cooperative Oncology Group (ECOG) Performance Status grade of 0, 1, or 2
-
During the study, during dose interruptions, and for 3 months after receiving the last dose of any component of the study treatment, a female participant must agree not to donate eggs (ova, oocytes) and male participants of reproductive potential must not donate semen or sperm during the study, during dose interruptions, or for 3 months after the last dose of any study drug
- History of malignancy (other than MM) unless all treatment of that malignancy was completed at least 2 years before consent and the participant has no evidence of disease further exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or breast, or other non-invasive lesion, that in the opinion of the investigator, with concurrence with the sponsor's medical monitor, is considered cured with minimal risk of recurrence within 3 years
- Exhibits clinical signs of meningeal involvement of MM
- Either of the following: a) Chronic obstructive pulmonary disease with a forced expiratory volume in 1 second (FEV1) is less than (<) 50 percentage (%) of predicted normal b) Moderate or severe persistent asthma, or a history of asthma within the last 2 years, or currently has uncontrolled asthma of any classification c) For D-Kd cohort: Known infiltrative pulmonary disease or known pulmonary hypertension
- Any of the following: a) Known to be seropositive for human immunodeficiency virus; b) Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Participants with resolved infection (participants who are HBsAg negative but positive for antibodies to hepatitis B core antigen [Anti-HBc] and/or antibodies to hepatitis B surface antigen [Anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are polymerase chain reaction (PCR) positive will be excluded
- Known to be seropositive for hepatitis C (Anti-HCV antibody positive or HCV-RNA quantitation positive) except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy
- For D-Kd cohort only: Transthoracic echocardiogram showing left ventricular ejection fraction (LVEF) <40%; uncontrolled hypertension, defined as an average systolic blood pressure greater than (>)159 millimeters of mercury (mmHg) or diastolic >99 mmHg despite optimal treatment
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Daratumumab(D)+Bortezomib+Lenalidomide+Dexamethasone (D-VRd) Bortezomib Participants will receive daratumumab 1800 milligram (mg) by subcutaneous (SC) injection on Days 1, 8 and 15 of Cycles 1 to 3 (each cycle of 21 days) and on Day 1 of Cycle 4; bortezomib 1.3 milligram per square meter (mg/m\^2) SC injection on Days 1, 4, 8 and 11 of Cycles 1 to 4; lenalidomide 25 mg orally on Day 1 through Day 14 of Cycles 1 to 4 and dexamethasone 20 mg orally or intravenously on Days 1, 2 ,8, 9, 15 and 16 of Cycle 1 to 4. Daratumumab(D)+Bortezomib+Lenalidomide+Dexamethasone (D-VRd) Daratumumab Participants will receive daratumumab 1800 milligram (mg) by subcutaneous (SC) injection on Days 1, 8 and 15 of Cycles 1 to 3 (each cycle of 21 days) and on Day 1 of Cycle 4; bortezomib 1.3 milligram per square meter (mg/m\^2) SC injection on Days 1, 4, 8 and 11 of Cycles 1 to 4; lenalidomide 25 mg orally on Day 1 through Day 14 of Cycles 1 to 4 and dexamethasone 20 mg orally or intravenously on Days 1, 2 ,8, 9, 15 and 16 of Cycle 1 to 4. Daratumumab(D)+Bortezomib+Lenalidomide+Dexamethasone (D-VRd) Lenalidomide Participants will receive daratumumab 1800 milligram (mg) by subcutaneous (SC) injection on Days 1, 8 and 15 of Cycles 1 to 3 (each cycle of 21 days) and on Day 1 of Cycle 4; bortezomib 1.3 milligram per square meter (mg/m\^2) SC injection on Days 1, 4, 8 and 11 of Cycles 1 to 4; lenalidomide 25 mg orally on Day 1 through Day 14 of Cycles 1 to 4 and dexamethasone 20 mg orally or intravenously on Days 1, 2 ,8, 9, 15 and 16 of Cycle 1 to 4. Daratumumab(D)+Bortezomib+Lenalidomide+Dexamethasone (D-VRd) Dexamethasone Participants will receive daratumumab 1800 milligram (mg) by subcutaneous (SC) injection on Days 1, 8 and 15 of Cycles 1 to 3 (each cycle of 21 days) and on Day 1 of Cycle 4; bortezomib 1.3 milligram per square meter (mg/m\^2) SC injection on Days 1, 4, 8 and 11 of Cycles 1 to 4; lenalidomide 25 mg orally on Day 1 through Day 14 of Cycles 1 to 4 and dexamethasone 20 mg orally or intravenously on Days 1, 2 ,8, 9, 15 and 16 of Cycle 1 to 4. D + Bortezomib + Melphalan + Prednisone (D-VMP) Daratumumab Participants will receive daratumumab 1800 mg by SC injection on Days 1, 8, 15, 22, 29 and 36 of Cycle 1 then on Days 1 and 22 in Cycles 2 to 9 and Day 1 of Cycle 10 and thereafter until documented progression of disease, unacceptable toxicity, or end of study; bortezomib 1.3 mg/m\^2 SC injection on Day 1, 4, 8, 11, 22, 25, 29 and 32 of Cycle 1 and on Days 1, 8, 22 and 29 of Cycles 2 to 9; melphalan 9 mg/m\^2 orally on Day 1 through Day 4 of Cycles 1 to 9; prednisone 60 mg/m\^2 orally on Days 1 to 4 of cycles 1 to 9. D + Bortezomib + Melphalan + Prednisone (D-VMP) Bortezomib Participants will receive daratumumab 1800 mg by SC injection on Days 1, 8, 15, 22, 29 and 36 of Cycle 1 then on Days 1 and 22 in Cycles 2 to 9 and Day 1 of Cycle 10 and thereafter until documented progression of disease, unacceptable toxicity, or end of study; bortezomib 1.3 mg/m\^2 SC injection on Day 1, 4, 8, 11, 22, 25, 29 and 32 of Cycle 1 and on Days 1, 8, 22 and 29 of Cycles 2 to 9; melphalan 9 mg/m\^2 orally on Day 1 through Day 4 of Cycles 1 to 9; prednisone 60 mg/m\^2 orally on Days 1 to 4 of cycles 1 to 9. D + Bortezomib + Melphalan + Prednisone (D-VMP) Prednisone Participants will receive daratumumab 1800 mg by SC injection on Days 1, 8, 15, 22, 29 and 36 of Cycle 1 then on Days 1 and 22 in Cycles 2 to 9 and Day 1 of Cycle 10 and thereafter until documented progression of disease, unacceptable toxicity, or end of study; bortezomib 1.3 mg/m\^2 SC injection on Day 1, 4, 8, 11, 22, 25, 29 and 32 of Cycle 1 and on Days 1, 8, 22 and 29 of Cycles 2 to 9; melphalan 9 mg/m\^2 orally on Day 1 through Day 4 of Cycles 1 to 9; prednisone 60 mg/m\^2 orally on Days 1 to 4 of cycles 1 to 9. D + Bortezomib + Melphalan + Prednisone (D-VMP) Melphalan Participants will receive daratumumab 1800 mg by SC injection on Days 1, 8, 15, 22, 29 and 36 of Cycle 1 then on Days 1 and 22 in Cycles 2 to 9 and Day 1 of Cycle 10 and thereafter until documented progression of disease, unacceptable toxicity, or end of study; bortezomib 1.3 mg/m\^2 SC injection on Day 1, 4, 8, 11, 22, 25, 29 and 32 of Cycle 1 and on Days 1, 8, 22 and 29 of Cycles 2 to 9; melphalan 9 mg/m\^2 orally on Day 1 through Day 4 of Cycles 1 to 9; prednisone 60 mg/m\^2 orally on Days 1 to 4 of cycles 1 to 9. Daratumumab + Lenalidomide + Dexamethasone (D-Rd) Daratumumab Participants will receive daratumumab 1800 mg by SC injection on Days 1, 8, 15 and 22 of Cycles 1 and 2 then on Day 1 and 15 of Cycles 3 to 6 and on Day 1 of Cycle 7 and thereafter until documented progression of disease, unacceptable toxicity, or end of study; lenalidomide 25 mg orally on Day 1 through Day 21 of each cycle until documented progression of disease, unacceptable toxicity, or end of study and dexamethasone 40 mg orally or intravenously weekly until documented progression of disease, unacceptable toxicity, or end of study. Daratumumab + Lenalidomide + Dexamethasone (D-Rd) Lenalidomide Participants will receive daratumumab 1800 mg by SC injection on Days 1, 8, 15 and 22 of Cycles 1 and 2 then on Day 1 and 15 of Cycles 3 to 6 and on Day 1 of Cycle 7 and thereafter until documented progression of disease, unacceptable toxicity, or end of study; lenalidomide 25 mg orally on Day 1 through Day 21 of each cycle until documented progression of disease, unacceptable toxicity, or end of study and dexamethasone 40 mg orally or intravenously weekly until documented progression of disease, unacceptable toxicity, or end of study. Daratumumab + Lenalidomide + Dexamethasone (D-Rd) Dexamethasone Participants will receive daratumumab 1800 mg by SC injection on Days 1, 8, 15 and 22 of Cycles 1 and 2 then on Day 1 and 15 of Cycles 3 to 6 and on Day 1 of Cycle 7 and thereafter until documented progression of disease, unacceptable toxicity, or end of study; lenalidomide 25 mg orally on Day 1 through Day 21 of each cycle until documented progression of disease, unacceptable toxicity, or end of study and dexamethasone 40 mg orally or intravenously weekly until documented progression of disease, unacceptable toxicity, or end of study. Daratumumab + Carfilzomib + Dexamethasone (D-Kd) Daratumumab Participants will receive daratumumab 1800 mg by SC injection on Days 1, 8, 15 and 22 of Cycles 1 and 2 (each cycle is of 28 days) then on Day 1 and 15 of Cycles 3 to 6 and on Day 1 of Cycle 7 and thereafter until documented progression of disease, unacceptable toxicity, or end of study; Carfilzomib 20 mg/m\^2 intravenously (IV) on Day 1 of Cycle 1 only then 70 mg/m\^2 IV on Days 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2 and thereafter until documented progression of disease, unacceptable toxicity, or end of study and dexamethasone 40 mg orally or IV weekly for Cycles 1-9 then on Days 1, 8, 15 of each cycle for Cycles 10 and thereafter until documented progression of disease, unacceptable toxicity, or end of study. Daratumumab + Carfilzomib + Dexamethasone (D-Kd) Dexamethasone Participants will receive daratumumab 1800 mg by SC injection on Days 1, 8, 15 and 22 of Cycles 1 and 2 (each cycle is of 28 days) then on Day 1 and 15 of Cycles 3 to 6 and on Day 1 of Cycle 7 and thereafter until documented progression of disease, unacceptable toxicity, or end of study; Carfilzomib 20 mg/m\^2 intravenously (IV) on Day 1 of Cycle 1 only then 70 mg/m\^2 IV on Days 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2 and thereafter until documented progression of disease, unacceptable toxicity, or end of study and dexamethasone 40 mg orally or IV weekly for Cycles 1-9 then on Days 1, 8, 15 of each cycle for Cycles 10 and thereafter until documented progression of disease, unacceptable toxicity, or end of study. Daratumumab + Carfilzomib + Dexamethasone (D-Kd) Carfilzomib Participants will receive daratumumab 1800 mg by SC injection on Days 1, 8, 15 and 22 of Cycles 1 and 2 (each cycle is of 28 days) then on Day 1 and 15 of Cycles 3 to 6 and on Day 1 of Cycle 7 and thereafter until documented progression of disease, unacceptable toxicity, or end of study; Carfilzomib 20 mg/m\^2 intravenously (IV) on Day 1 of Cycle 1 only then 70 mg/m\^2 IV on Days 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2 and thereafter until documented progression of disease, unacceptable toxicity, or end of study and dexamethasone 40 mg orally or IV weekly for Cycles 1-9 then on Days 1, 8, 15 of each cycle for Cycles 10 and thereafter until documented progression of disease, unacceptable toxicity, or end of study.
- Primary Outcome Measures
Name Time Method D-VMP, D-Rd, and D-Kd Cohorts: Overall Response Rate (ORR) Up to 2 years 3 months ORR was defined as the percentage of participants who achieved partial response (PR) or better according to international myeloma working group (IMWG) criteria. IMWG criteria for PR: greater than or equal to (\>=) 50 percent (%) reduction of serum M-protein and reduction in 24-hour urinary M-protein by \>=90% or to less than (\<) 200 milligrams (mg) per 24 hours, If the serum and urine M-protein are not measurable, a decrease of \>=50% in the difference between involved and uninvolved free light chain (FLC) levels is required in place of the M-protein criteria, If serum and urine M-protein are not measurable, and serum free light assay is also not measurable, \>=50% reduction in bone marrow plasma cells (PCs) is required in place of M-protein, provided baseline bone marrow plasma cell percentage was \>=30%. In addition to the above criteria, if present at baseline, a \>=50% reduction in the size of soft tissue plasmacytomas is also required.
D-VRd Cohort: Percentage of Participants With Very Good Partial Response (VGPR) or Better Response Up to 2 years and 3 months VGPR or better rate was defined as the percentage of participants who achieved VGPR or complete response (CR) (including stringent complete response \[sCR\]) according to the IMWG criteria during or after the study treatment. VGPR: Serum and urine component detectable by immunofixation but not on electrophoresis, or \>= 90% reduction in serum M-protein plus urine M-protein level \<100 mg/24 hour; CR: negative immunofixation on the serum and urine, Disappearance of any soft tissue plasmacytomas and \<5% PCs in bone marrow; sCR: CR in addition to having a normal FLC ratio and an absence of clonal cells in bone marrow by immunohistochemistry, immunofluorescence, 2-4 color flow cytometry.
- Secondary Outcome Measures
Name Time Method D-VMP, D-Rd, and D-Kd Cohorts: Percentage of Participants With VGPR or Better Response From baseline up to 2 years 7 months VGPR or better rate was defined as the percentage of participants who achieved VGPR or CR (including sCR) according to the IMWG criteria during or after the study treatment. VGPR: Serum and urine component detectable by immunofixation but not on electrophoresis, or \>= 90% reduction in serum M-protein plus urine M-protein level \<100 mg per 24 hour; CR: negative immunofixation on the serum and urine, Disappearance of any soft tissue plasmacytomas and \<5% PCs in bone marrow; sCR: CR in addition to having a normal FLC ratio and an absence of clonal cells in bone marrow by immunohistochemistry, immunofluorescence, 2-4 color flow cytometry.
Maximum Observed Serum Concentration (Cmax) of Daratumumab D-VRd: Day 4 of Cycles 1 and 4 and post treatment at Week 8; D-VMP: Day 4 of Cycles 1 and 2 and post treatment at Week 8; D-Rd and D-Kd: Day 4 of Cycles 1 and 3 and post treatment at Week 8 Cmax was defined as maximum serum concentration observed following daratumumab administration. Each cycle for: D-VRd cohort is of 21 days, D-VMP cohort is of 42 days and D-Rd and D-Kd cohorts is of 28 days. Each cohort have a treatment period of 84 days.
Percentage of Participants With Infusion-Related Reactions (IRRs) For D-VRD Arm: Baseline up to 2 years 3 months; For D-VMP, D-Rd and D-Kd Arms: Baseline up to 2 years 7 months Percentage of Participants with IRRs were reported. The administration-related systemic reactions are referred to as IRRs.
D-VRd Cohort: Overall Response Rate (ORR) Up to 2 years and 3 months ORR was defined as the percentage of participants who achieved a PR or better, IMWG criteria, during the study or during follow up. IMWG criteria for PR \>= 50% reduction of serum M-protein and reduction in 24 hour urinary M-protein by \>=90% or to \<200 mg/24 hours, if the serum and urine M-protein are not measurable, a decrease of \>=50% in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria, If serum and urine M-protein are not measurable, and serum free light assay is also not measurable, \>=50% reduction in bone marrow PCs is required in place of M-protein, provided baseline bone marrow plasma cell percentage was \>=30%, in addition to the above criteria, if present at baseline, a \>=50% reduction in the size of soft tissue plasmacytomas is also required.
Percentage of Participants With CR or Better Response For D-VRD Arm: Baseline up to 2 years 3 months; For D-VMP, D-Rd and D-Kd Arms: Baseline up to 2 years 7 months CR or better rate was defined as the percentage of participants with a CR or better response (that is, CR and sCR) as per IMWG criteria. CR: as negative immunofixation on the serum and urine and disappearance of soft tissue plasmacytomas and less than (\<) 5 percent plasma cells in bone marrow; sCR: CR plus normal FLC ratio and absence of clonal PCs by immunohistochemistry, immunofluorescence or 2- to 4-color flow cytometry.
D-VMP, D-Rd and D-Kd Cohorts: Duration of Response (DOR) From baseline up to 2 years 7 months DOR was defined as the time from the date of initial documented response (PR or better response) to the date of first documented evidence of progressive disease (PD) or death due to PD. PD is defined as an increase of 25% from the lowest response value in one of the following: serum and urine M-component (absolute increase must be \>=0.5 gram per deciliter \[g/dL\] and \>=200 mg/24 hours respectively); only in participants without measurable serum and urine M-protein levels the difference between involved and uninvolved FLC levels (absolute increase must be \>10 mg/dL); definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; development of hypercalcemia (corrected serum calcium \>11.5 mg/dL) that can be attributed solely to PC proliferative disorder.
Percentage of Participants With Anti-Daratumumab Antibodies For D-VRD Arm: Baseline up to 2 years 3 months; For D-VMP, D-Rd and D-Kd Arms: Baseline up to 2 years 7 months Percentage of participants with antibodies to daratumumab were reported.
Percentage of Participants With Anti-rHuPH20 Antibodies For D-VRD Arm: Baseline up to 2 years 3 months; For D-VMP, D-Rd and D-Kd Arms: Baseline up to 2 years 7 months Percentage of participants with antibodies to rHuPH20 were reported.
D-VMP, D-Rd, and D-Kd Cohorts: Percentage of Participants With Minimal Residual Disease (MRD) Negative Rate Up to 2 years and 3 months MRD negativity rate was defined as the percentage of participants who were considered MRD negative after MRD testing at any timepoint after the first dose by bone marrow aspirate. MRD negativity rate was assessed by next-generation sequencing at a threshold of \<10\^5.
Trial Locations
- Locations (63)
Cancer Center of Central Connecticut - Southington
🇺🇸Southington, Connecticut, United States
Mayo Clinic in Florida
🇺🇸Jacksonville, Florida, United States
Avera Medical Group - Oncology & Hematology
🇺🇸Sioux Falls, South Dakota, United States
Universitaetsklinikum Hamburg Eppendorf
🇩🇪Hamburg, Germany
Asklepios Klinik Altona
🇩🇪Hamburg, Germany
Nebraska Hematology and Oncology
🇺🇸Lincoln, Nebraska, United States
San Juan Oncology Associates
🇺🇸Farmington, New Mexico, United States
NYU Winthrop
🇺🇸Mineola, New York, United States
Ministerio da Saude - Instituto Nacional do Cancer
🇧🇷Rio de Janeiro, Brazil
Associacao Hospitalar Beneficente Sao Vicente de Paulo - Hospital Sao Vicente de Paulo
🇧🇷Passo Fundo, Brazil
Clinica Sao Germano
🇧🇷São Paulo, Brazil
Fakultni nemocnice Brno
🇨🇿Brno, Czechia
SPDM - Associacao Paulista para o Desenvolvimento da Medicina - Hospital Sao Paulo
🇧🇷Sao Paulo, Brazil
Wake Forest University Baptist Medical Center (WFUBMC) - Comprehensive Cancer Center
🇺🇸Winston-Salem, North Carolina, United States
Utah Cancer Specialists
🇺🇸Salt Lake City, Utah, United States
CHU de Nantes hotel Dieu
🇫🇷Nantes Cedex 1, France
Centre hospitalier Lyon-Sud
🇫🇷Pierre-Bénite, France
Klinikum Chemnitz gGmbH
🇩🇪Chemnitz, Germany
Southeast Nebraska Cancer Center
🇺🇸Lincoln, Nebraska, United States
UF Health Cancer Center at Orlando Health
🇺🇸Orlando, Florida, United States
Inst. Cat. Doncologia-H Duran I Reynals
🇪🇸Barcelona, Spain
Karmonos Cancer Institute
🇺🇸Detroit, Michigan, United States
Kent and Canterbury Hospital
🇬🇧Canterbury, United Kingdom
Fakultni nemocnice Ostrava
🇨🇿Ostrava, Czechia
Nagoya City University Hospital
🇯🇵Nagoya, Japan
Vseobecna fakultni nemocnice v Praze - I. interni klinika - klinika hematologie
🇨🇿Praha 2, Czechia
CHU de Bordeaux - Hospital Haut-Leveque
🇫🇷Pessac cedex, France
University of Virginia Cancer Center - Emily Couric Clinical Cancer Center - Women's Oncology Clinic
🇺🇸Charlottesville, Virginia, United States
Mt. Sinai School of Medicine
🇺🇸New York, New York, United States
Fakultni nemocnice Hradec Kralove
🇨🇿Hradec Kralove, Czechia
Hadassah Medical Center
🇮🇱Jerusalem, Israel
Hosp. Univ. Dr. Peset
🇪🇸Valencia, Spain
Inst. Cat. D'Oncologia-Badalona
🇪🇸Badalona, Spain
CHU Bretonneau
🇫🇷Tours Cedex 9, France
Rambam Medical Center
🇮🇱Haifa, Israel
Hosp. Univ. Ramon Y Cajal
🇪🇸Madrid, Spain
Heart of England NHS Foundation Trust
🇬🇧Birmingham, United Kingdom
Hosp. Clinico Univ. de Salamanca
🇪🇸Salamanca, Spain
Hosp. Univ. 12 de Octubre
🇪🇸Madrid, Spain
Matsuyama Red Cross Hospital
🇯🇵Matsuyama, Japan
Galilee Medical Center
🇮🇱Nahariya, Israel
Clinica Univ. de Navarra
🇪🇸Pamplona, Spain
Hosp. Gral. Univ. Gregorio Maranon
🇪🇸Madrid, Spain
Carmel Medical Center
🇮🇱Haifa, Israel
Hosp. Univ. Vall D Hebron
🇪🇸Barcelona, Spain
Derriford Hospital
🇬🇧Plymouth, United Kingdom
Manchester Royal Infirmary
🇬🇧Manchester, United Kingdom
Royal Stoke University Hospital
🇬🇧Stoke on Trent, United Kingdom
Royal Bournemouth Hospital
🇬🇧Bournemouth, United Kingdom
Instituto de Assistencia Medica ao Servidor Publico Estadual IAMSPE
🇧🇷Sao Paulo, Brazil
Japanese Red Cross Medical Center
🇯🇵Shibuya, Japan
Tel-Aviv Sourasky Medical Center
🇮🇱Tel-Aviv, Israel
Hosp. Clinic de Barcelona
🇪🇸Barcelona, Spain
Liga Norte Riograndense Contra O Cancer
🇧🇷Natal, Brazil
Universitaetsklinikum Tuebingen der Eberhard-Karls-Universitaet, Abteilung fuer Innere Medizin II,
🇩🇪Tübingen, Germany
Kanazawa University Hospital
🇯🇵Kanazawa, Japan
Hosp. Son Llatzer
🇪🇸Mallorca, Spain
Universitaetsklinikum Heidelberg
🇩🇪Heidelberg, Germany
Sheba Medical Center
🇮🇱Ramat Gan, Israel
CHU Nancy Brabois
🇫🇷Vandoeuvre Les Nancy, France
Billings Clinic
🇺🇸Billings, Montana, United States
Providence Cancer Center
🇺🇸Southfield, Michigan, United States
Nebraska Cancer Specialists
🇺🇸Omaha, Nebraska, United States