Study to Evaluate Imetelstat (GRN163L) in Participants With International Prognostic Scoring System (IPSS) Low or Intermediate-1 Risk Myelodysplastic Syndrome (MDS)
- Conditions
- Myelodysplastic Syndromes
- Interventions
- Drug: Placebo
- Registration Number
- NCT02598661
- Lead Sponsor
- Geron Corporation
- Brief Summary
The purpose of this study is to evaluate the efficacy and safety of imetelstat sodium in transfusion-dependent participants with low or intermediate-1 risk myelodysplastic syndrome (MDS) that is relapsed/refractory to erythropoiesis-stimulating agent (ESA) treatment in Phase 2 study and to compare the efficacy, in terms of red blood cell (RBC) transfusion independence (TI), of imetelstat sodium to placebo in transfusion-dependent participants with low or intermediate-1 risk MDS that is relapsed/refractory to ESA treatment in Phase 3 study.
A separate Ventricular Repolarization Substudy (QTc Substudy) will evaluate the effect of imetelstat sodium on ventricular repolarization.
An Extension Phase has been included to allow continued treatment for those participants who are benefitting from imetelstat sodium and to continue to evaluate the long-term safety, overall survival (OS), and disease progression, including progression to acute myeloid leukemia (AML) in transfusion-dependent participants with low or immediate-1 risk MDS that is relapsed/refractory to ESA treatment.
- Detailed Description
This is a Phase 2/3, multicenter study of imetelstat sodium in which 289 participants were enrolled.
* Phase 2 is an open-label, single-arm design to assess the efficacy and safety of imetelstat sodium. A total of 57 participants were enrolled in Phase 2, including the expansion cohort.
* Phase 3 is a double-blind, randomized design to compare the efficacy of imetelstat sodium with placebo. In the Phase 3 study, 178 participants were enrolled and randomized in a 2:1 ratio to receive either imetelstat sodium or placebo, respectively.
* In a separate Ventricular Repolarization (VR) Substudy (QTc Substudy), 54 participants were enrolled and randomized 2:1 to receive either imetelstat sodium or placebo. If after a minimum of 2 treatment cycles in the VR substudy, a participant has no significant change to packed red blood cell (pRBC) transfusion burden or evidence of clinical benefit per Investigator, after discussion with the Sponsor the participant may be unblinded. If the participant was on placebo treatment, he/she may be permitted to start treatment with imetelstat sodium.
The Extension Phase was initiated at the end of the Phase 3 study (24 months after the last participant was randomized in the Phase 3) and will continue until participants who entered Phase 3 study participated in the study for up to 5 years from the first dose of imetelstat sodium (including treatment and follow-up), or 3 years of post-treatment follow-up from the last dose of study treatment, whichever occurs later, or until death, withdrawal of consent, study termination, or until a participant is lost to follow-up. Participants ongoing on imetelstat sodium and considered to be benefiting from treatment per Investigator in the Phase 3 Study or Ventricular Repolarization Substudy, have the option to continue receiving imetelstat sodium in the Extension Phase. Participants in the follow-up phase for the Phase 3 study or Ventricular Repolarization Substudy have the option to continue the follow-up in the Extension Phase.
The Phase 2, Phase 3, and VR Substudy all consist of 3 phases: a Screening phase (up to 28 days); a treatment phase; and a post-treatment follow-up phase which will continue until death, lost to follow-up, withdrawal of consent, or the End of the Study (whichever occurs first). The Extension Phase of the study will consist of an extended treatment phase and an extended follow-up phase which will continue until death, lost to follow-up, withdrawal of consent, or the End of the Study (whichever occurs first).
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 289
- Man or woman greater than or equal to (≥) 18 years of age
- Diagnosis of myelodysplastic syndrome (MDS) according to World Health Organization (WHO) criteria confirmed by bone marrow aspirate and biopsy within 12 weeks prior to Cycle 1 Day 1 (C1D1) (Phase 2) or randomization (Phase 3). In Ventricular Repolarization Substudy, diagnosis of MDS or myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) according to WHO criteria confirmed by bone marrow aspirate and biopsy within 12 weeks prior to C1D1
- International Prognostic Scoring System (IPSS) low Risk or intermediate-1 risk MDS
- Red blood cell (RBC) transfusion dependent, defined as requiring at least 4 RBC units transfused over an 8-week period during the 16 weeks prior to Study Entry; pre-transfusion hemoglobin (Hb) should be less than or equal to (≤) 9.0 gram per deciliter (g/dL) to count towards the 4 units total
- Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2
- Participant has known allergies, hypersensitivity, or intolerance to imetelstat sodium or its excipients
- Participant has received an investigational drug or used an invasive investigational medical device within 30 days prior to Study Entry or is currently enrolled in an investigational study
- Prior treatment with imetelstat sodium
- Have received corticosteroids greater than (>) 30 milligram per day (mg/day) prednisone or equivalent, or growth factor treatment within 4 weeks prior to study entry
- Has received an erythropoiesis-stimulating agent (ESA) or any chemotherapy, immunomodulatory, or immunosuppressive therapy within 4 weeks prior to study entry (8 weeks for long-acting ESAs)
- Phase 3: a) Prior treatment with a hypomethylating agent (example [eg], azacitidine, decitabine); b) Prior treatment with lenalidomide
Additional Exclusion Criteria for the Ventricular Repolarization Substudy:
-
Concurrent therapy with medications known to prolong the QT interval and have been associated with Torsade de pointes arrhythmia (TdP)
-
Cardiac function abnormalities on screening ECG as follows:
- Resting heart rate outside of 50 to 100 beats per minute
- QT interval by Fridericia's correction method (QTcF) >470 millisecond (msec) (or QTcF >490 msec in the presence of a right bundle branch block or ventricular conduction delay [QRS >119 msec]), determined by central assessment based on the average value of a triplicate set of ECGs
- Diagnosed or suspected congenital long QT syndrome
- Family history of sudden unexpected death from cardiac-related causes if indicative of a pathogenic mutation of cardiac ion channels
- Family history of congenital long QT syndrome
- History of Mobitz II second degree or third degree heart block
- Implantable pacemaker or automatic implantable cardioverter defibrillator
- Complete left bundle branch block
- Chronic or persistent atrial arrhythmia including atrial fibrillation and atrial flutter
- History or presence of clinically relevant heart rhythm disturbances including atrial, junctional, re-entry, and ventricular tachycardia
- Unusual T-wave morphology (i.e., bifid T-wave) likely to interfere with QT measurements
-
History or evidence for any of the following: severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (example, pulmonary embolism, cerebrovascular accident including transient ischemic attacks) within 12 months prior to Cycle 1 Day 1, New York Heart Association (NYHA) Class II to IV heart disease
-
Presence of uncontrolled hypertension (persistent systolic blood pressure [BP] ≥160 mmHg or diastolic BP ≥100 mmHg). Participants with a history of hypertension are permitted, provided that BP is controlled to within these limits by anti-hypertensive treatment
-
Any skin condition likely to interfere with electrocardiographic electrode placement or adhesion
-
History of thoracic surgery likely to cause abnormality of the electrical conduction through thoracic tissues
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Phase 2: Imetelstat Sodium Imetelstat Sodium Imetelstat sodium administered intravenously (IV), at a starting dose of 7.5 milligrams per kilogram (mg/kg), every 4 weeks (on a 28-day cycle) until death, lost to follow-up, withdrawal of consent, or study termination whichever occurs first. Dose escalation to 9.4 mg/kg was allowed before Protocol Amendment 2. Phase 3: Imetelstat Sodium Imetelstat Sodium Imetelstat sodium administered IV, at a starting dose of 7.5 mg/kg, every 4 weeks (on a 28-day cycle) until death, lost to follow-up, withdrawal of consent, or study termination whichever occurs first. Phase 3: Placebo Placebo Imetelstat sodium-matching placebo administered IV, every 4 weeks (on a 28-day cycle), until death, lost to follow-up, withdrawal of consent, or study termination whichever occurs first. QTc Substudy: Imetelstat Sodium Imetelstat Sodium Imetelstat sodium administered IV, at a starting dose of 7.5 mg/kg, every 4 weeks (on a 28-day cycle) until death, lost to follow-up, withdrawal of consent, or study termination whichever occurs first. QTc Substudy: Placebo Placebo Imetelstat sodium-matching placebo administered IV, every 4 weeks (on a 28-day cycle), until death, lost to follow-up, withdrawal of consent, or study termination whichever occurs first. If after a minimum of 2 treatment cycles a participant has no significant change to pRBC transfusion burden or evidence of clinical benefit per Investigator, after discussion with the Sponsor the participant, he/she may be permitted to start treatment with imetelstat sodium. Extension Phase: Imetelstat Sodium Imetelstat Sodium Participants randomized to the imetelstat sodium arm in the Phase 3 and the VR QTc Substudy, based on the response will continue to receive imetelstat sodium IV, at the dose they were receiving in the Phase 3 or VR QTc Substudy, every 4 weeks (on a 28-day cycle) until death, lost to follow-up, withdrawal of consent, study termination, or up to 3 years whichever occurs first. Extension Phase: Extended Follow-up Placebo Participants randomized to the placebo arm in the Phase 3 study will enter the Extended Follow-up part of the Extension Phase and continue in follow up until death, lost to follow-up, withdrawal of consent, study termination, or whichever occurs first up to approximately 3 years.
- Primary Outcome Measures
Name Time Method Phase 2: Percentage of Participants Without Any Red Blood Cell (RBC) Transfusion During Any Consecutive 8-Weeks Period (All Participants) Up to 5 years in Phase 2 Percentage of participants without any RBC transfusion during any consecutive 8 weeks (56 days) starting from Study Day 1 until subsequent anti-cancer therapy if any were reported. Study Day 1 is defined as the day of the first dose for participants enrolled in Phase 2. The 95% confidence interval (CI) was calculated using Clopper-Pearson method. Percentages were rounded off to the nearest single decimal place.
Phase 2: Percentage of Participants Without Any RBC Transfusion During Any Consecutive 8-Weeks Period in Target Population Up to 5 years in Phase 2 Percentage of participants without any RBC transfusion during any consecutive 8 weeks (56 days) starting from Study Day 1 until subsequent anti-cancer therapy if any were reported. Study Day 1 is defined as the day of the first dose for participants enrolled in Phase 2. The 95% confidence interval (CI) was calculated using Clopper-Pearson method. Percentages were rounded off to the nearest single decimal place.
Phase 3: Percentage of Participants Without Any RBC Transfusion During Any Consecutive 8-Weeks Period Up to 3.7 years in Phase 3 Percentage of participants without any RBC transfusion during any consecutive 8 weeks (56 days) starting from Study Day 1 until subsequent anti-cancer therapy if any were reported. Study Day 1 is defined as the day of the first dose for participants enrolled in Phase 2. The 95% CI was calculated using Clopper-Pearson method. Percentages were rounded off to the nearest single decimal place.
- Secondary Outcome Measures
Name Time Method Phase 2 and Phase 3: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Deaths Adverse events: Up to 5 years in Phase 2 and up to 3.7 years in Phase 3; Deaths: Up to 6.6 years in Phase 2 and up to 4 years in Phase 3 TEAEs were defined as those events that 1) occurred after the first dose of study drug, through the treatment phase, and for 30 days following the last dose of study drug or until subsequent anti-cancer therapy if earlier; 2) any event that was considered study drug-related regardless of the start date of the event; or 3) any event that was presented at baseline but worsened in severity or was subsequently considered drug-related by the investigator. Serious TEAEs are any TEAEs that result in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is a suspected transmission of any infectious agent via a medicinal product, is medically important. Any clinically significant vital sign measurements, clinical laboratory values, and electrocardiogram (ECG) findings were reported as TEAEs. TEAEs included both serious and non-serious TEAEs.
Phase 2 and Phase 3: Percentage of Participants Without Any RBC Transfusion During Any Consecutive 24-Weeks Period Up to 5 years in Phase 2 and up to 3.7 years in Phase 3 Percentage of participants without any RBC transfusion during any consecutive 24 weeks (168 days) starting from Study Day 1 until subsequent anti-cancer therapy if any were reported. Study Day 1 is defined as the day of the first dose for participants enrolled in Phase 2 and the day of randomization for participants enrolled in Phase 3. The 95% CI was calculated using Clopper-Pearson method. Percentages were rounded off to the nearest single decimal place.
Phase 2 and Phase 3: Time to the 8-Weeks RBC Transfusion Independence (TI) Up to 5 years in Phase 2 and up to 3.7 years in Phase 3 Time to 8-week RBC TI was defined as the interval from Study Day 1 to the first day of the first 8-week RBC TI period.
Phase 2 and Phase 3: Time to the 24-Weeks RBC TI Up to 5 years in Phase 2 and up to 3.7 years in Phase 3 Time to 24-week RBC TI was defined as the interval from Study Day 1 to the first day of the first 24-weeks RBC TI period.
Phase 2 and Phase 3: Duration of RBC TI Up to 5 years in Phase 2 and up to 3.7 years in Phase 3 Duration of RBC TI was defined as the first day of the longest RBC TI period to the date of the first RBC transfusion after the TI period started. The 95% CI was based on Kaplan-Meier product limit estimates.
Phase 2 and Phase 3: Percentage of Participants With Hematologic Improvement Including Erythroid Response (HI-E) as Per International Working Group (IWG) Response Criteria 2006 Up to 5 years in Phase 2 and up to 3.7 years in Phase 3 As per IWG Response Criteria 2006: HI-E was defined as a hemoglobin (Hb) increase by greater than or equal to (≥)1.5 grams per deciliter (g/dL) relevant reduction of units of RBC transfusions by an absolute number of at least 4 RBC transfusion units/8 weeks compared with the pretreatment transfusion number in the previous 8 weeks. Only RBC transfusions given for a Hb of less than or equal to (≤)9 g/dL pretreatment were counted in the RBC transfusion response evaluation. The 95% CI was calculated using Clopper-Pearson method. Percentages were rounded off to the nearest single decimal place.
Phase 2: Percentage of Participants With Complete Remission (CR), Partial Remission (PR), or Marrow Complete Remission (mCR) as Per International Working Group (IWG) Response Criteria 2006 as Assessed by the Investigator Up to 5 years in Phase 2 As per the IWG Response Criteria 2006, CR was defined as Bone marrow: ≤5% myeloblasts with normal maturation of all cell lines; Peripheral blood (PB): Hb ≥11 g/dL; platelets ≥100 x 10\^9/dL; neutrophils ≥1.0 x 10\^9/liter; blasts: 0%. PR was defined as Bone marrow: ≤5% myeloblasts and decrease by ≥50% over pretreatment; cellularity and morphology not relevant. mCR was defined as Bone marrow: ≤5% myeloblasts and decreased by ≥50% over pre-treatment PB. Percentages were rounded off to the nearest single decimal place. All participants in Phase 2 were evaluated by the Investigator for CR/PR/mCR regardless of bone marrow blasts at baseline.
Phase 3: Percentage of Participants With CR, PR, or mCR as Per IWG Response Criteria 2006 as Assessed by the Independent Review Committee (IRC) Up to 3.7 years in Phase 3 As per the IWG Response Criteria 2006, CR was defined as Bone marrow: ≤5% myeloblasts with normal maturation of all cell lines; PB: Hb ≥11 g/dL; platelets ≥100 x 10\^9/dL; neutrophils ≥1.0 x 10\^9/liter; blasts: 0%. PR was defined as Bone marrow: ≤5% myeloblasts and decrease by ≥50% over pretreatment; cellularity and morphology not relevant. mCR was defined as Bone marrow: ≤5% myeloblasts and decreased by ≥50% over pre-treatment PB. CR, PR and mCR were assessed by IRC in Phase 3 and participants were required to fit at least one of the following criteria (participants with \>5% baseline blasts per central pathology reviewer assessment; participants with CR, PR, mCR, or cytogenetic response as assessed by the investigator) and have at least one post-baseline assessment.
Phase 2 and Phase 3: Overall Survival (OS) Up to 6.6 years in Phase 2 and up to 4 years in Phase 3 OS was defined as the interval from Study Day 1 to death from any cause. Survival time of living participants was censored on the last date a participant is known to be alive or lost to follow-up. The Kaplan-Meier method was used to estimate overall survival.
Phase 2 and Phase 3: Progression Free Survival (PFS) Up to 6.6 years in Phase 2 and up to 4 years in Phase 3 Progression free survival was defined as the time interval from study Day 1 to the first date of disease progression or death from any cause, whichever occurs first. Disease progression as per IWG criteria was defined as: at least one of the following: at least 50 % decrement from maximum response levels in granulocytes or platelets; reduction in hemoglobin by ≥1.5 g/dL; transfusion dependence.
Phase 2 and Phase 3: Time to Progression to Acute Myeloid Leukemia (AML) Up to 6.6 years in Phase 2 and up to 4 years in Phase 3 Time to progression to AML was defined as the interval from Study Day 1 to the date of AML diagnosis. Participants who did not progress to AML and were still alive at the cutoff date for the analysis or who withdrew from the study (withdrawal of consent or lost to follow-up), data was censored at the date of the last disease evaluation.
Phase 2 and Phase 3: Amount of RBC Transfusions in the Best 8-week Interval Up to 5 years in Phase 2 and up to 3.7 years in Phase 3 Amount of RBC transfusions for 8-week interval was defined as the total number of RBC transfusion units in a given 8-week interval during study. The best 8-week interval is a post-baseline 8-week interval where the participant had the fewest post-Study Day 1 RBC transfusion units. A valid 8-week period must start before the date of last dose of study drug + 30 days or end of treatment (EOT) visit whichever occurs first and ends before the first transfusion in post-treatment follow-up or the first day of subsequent anti-cancer therapy whichever occurs first.
Phase 2 and Phase 3: Percent Change in RBC Transfusions Relative to Prior Transfusion Burden Up to 5 years in Phase 2 and up to 3.7 years in Phase 3 Relative percent change in RBC transfusions per 8-week = (amount of RBC transfusions per 8-week - prior RBC transfusion burden) / prior RBC transfusion burden multiplied by 100%. Prior RBC transfusion burden was defined as the maximum number of RBC units transfused over any consecutive 8 weeks prior to study entry.
Phase 2 and Phase 3: Percentage of Participants Who Received Any Myeloid Growth Factors Up to 5 years in Phase 2 and up to 3.7 years in Phase 3 Percentage of participants who received any myeloid growth factors starting from Study Day 1 were reported. Percentages were rounded off to the nearest single decimal place.
Phase 2 and Phase 3: Duration of Myeloid Growth Factors Administration Up to 5 years in Phase 2 and up to 3.7 years in Phase 3 Duration of myeloid growth factor administered starting from Study Day 1 was reported.
Phase 2 and Phase 3: Maximum Observed Plasma Concentration (Cmax) Pre-dose on Cycle 1 Day 1 and pre-dose on Day 1 of every 3 cycles from Cycle 4 up to Cycle 66 in Phase 2 and Cycle 34 in Phase 3 (each cycle length= 28 days) As pre-specified in the statistical analysis plan (SAP), participants in the imetelstat sodium arm group of Phase 2 and Phase 3 were pooled for pharmacokinetic (PK) data collection and analyses in this outcome measure. PK parameters were determined by population PK model.
Phase 2 and Phase 3: Area Under the Drug Concentration-Plasma Time Curve From Time Zero to Time 28 Days (AUC0-28d) Cycle 1 (Days 1 to 28) (Cycle duration= 28 days) As pre-specified in the statistical analysis plan (SAP), participants in the imetelstat sodium arm group of Phase 2 and Phase 3 were pooled for PK data collection and analyses in this outcome measure. PK parameters were determined by population PK model.
Phase 2 and Phase 3: Percentage of Participants With Anti-drug Antibodies (ADA) to Imetelstat Sodium Pre-dose on Cycle 1 Day 1 and pre-dose on Day 1 of every 3 cycles from Cycle 4 up to Cycle 66 in Phase 2 and Cycle 34 in Phase 3 (each cycle length= 28 days) As pre-specified in the SAP, participants in the imetelstat sodium arm group of Phase 2 and Phase 3 were pooled for immunogenicity data collection and analyses in this outcome measure. Percentages were rounded off to the nearest single decimal place.
Phase 3: Medical Resource Utilization Assessed Based on Percentage of Participants With Outpatient Medical Encounters Up to 3.7 years in Phase 3 Outpatient medical encounters included various sites of care: a) emergency room (ER) visits, b) hospital outpatient visits, c) home care visit, d) visit to lab, e) visit to doctor's office, f) other visits. Percentages were rounded off to the nearest single decimal place.
Phase 3: Medical Resource Utilization Assessed Based on Duration of Hospitalization Up to 3.7 years in Phase 3 Hospitalization included any medical encounter defined as hospice, hospital inpatient department, and intensive care unit (ICU). Hospitalizations without end dates were not counted in the calculation of length of stay. If any participant had multiple readmissions, duration was calculated as the sum of all hospital stays.
QTc Substudy: Change From Baseline in QT Interval by Fridericia's Correction Method (ΔQTcF) Baseline, Cycle 1, Day 1: 0.5, 1, 2, 4, 6, and 8 hours post-dose (cycle length= 28 days) Baseline was defined as the mean of the measured ECG intervals collected at 3 time points (-1 hour, -0.5 hour, and 0 hour) prior to treatment administration on Cycle 1 Day 1 (Cycle length= 28 days)
Trial Locations
- Locations (126)
Ege Universitesi Tip Fakultesi - Hematology
🇹🇷İzmir, Turkey
Meander Medisch Centrum
🇳🇱Amersfoort, Netherlands
VU Medisch Centrum
🇳🇱Amsterdam, Netherlands
Universitair Medisch Centrum Groningen
🇳🇱Groningen, Netherlands
Uniwersytecki Szpital Kliniczny im. J. Mikulicza-Radeckiego
🇵🇱Wrocław, Dolnoslaskie, Poland
Centrum Medyczne Pratia Poznan
🇵🇱Skorzewo, Kościerzyna, Poland
Wojewódzki Szpital Specjalistyczny sp.z o.o.
🇵🇱Słupsk, Pomorskie, Poland
Hosp. Univ. Germans Trias I Pujol
🇪🇸Badalona, Spain
Hosp. Univ. Vall D Hebron
🇪🇸Barcelona, Spain
Hosp. Gral. Univ. Gregorio Maranon
🇪🇸Madrid, Spain
Hosp. Univ. La Paz
🇪🇸Madrid, Spain
Hosp. Clinico Univ. de Salamanca
🇪🇸Salamanca, Spain
Hospital Universitario Nuestra Señora de Valme
🇪🇸Sevilla, Spain
Hospital Universitario Doctor
🇪🇸Valencia, Spain
Hospital Universitari i Politecnic La Fe
🇪🇸Valencia, Spain
Universitaetsspital Zuerich
🇨🇭Zuerich, Switzerland
Ankara University Medical Faculty - Hematology
🇹🇷Ankara, Anatolia, Turkey
Cukurova University Medical Faculty
🇹🇷Adana, Turkey
KZ "Miska bahatoprofilna klinichna likarnia No4", hematolohi
🇺🇦Dnipropetrovs'k, Dnipropetrovs'ka Oblast', Ukraine
Instytut patolohii krovi ta transfusiynoi medytsyny NAMN Ukr
🇺🇦Lviv, L'vivs'ka Oblast', Ukraine
UZ Leuven - Campus Gasthuisberg
🇧🇪Leuven, Belgium
Tom Baker Cancer Centre
🇨🇦Calgary, Alberta, Canada
University of Alberta Hospital - Hematology Research
🇨🇦Edmonton, Alberta, Canada
The Ottawa Hospital
🇨🇦Ottawa, Ontario, Canada
Sunnybrook Health Sciences Centre
🇨🇦Toronto, Ontario, Canada
Princess Margaret Hospital
🇨🇦Toronto, Ontario, Canada
Jewish General Hospital
🇨🇦Montréal, Quebec, Canada
Fakultni nemocnice Brno
🇨🇿Brno, Brno-město, Czechia
FN Hradec Kralove
🇨🇿Hradec Králové, Czechia
FN Kralovske Vinohrady
🇨🇿Praha 10, Czechia
Vseobecna fakultni nemocnice v Praze
🇨🇿Praha 2, Czechia
Hopital de l'Archet
🇫🇷Nice, Alpes-Maritimes, France
CHU Tours
🇫🇷Tours, Centre, France
Johannes Gutenberg Universität
🇩🇪Mainz, Germany
Kaplan Medical Center
🇮🇱Reẖovot, Hagalil Saint, Israel
The Edith Wolfson Medical Center
🇮🇱H̱olon, HaMerkaz, Israel
Meir Medical Center
🇮🇱Kfar Saba, HaMerkaz, Israel
Ha'Emek Medical Center
🇮🇱Afula, HaZafon, Israel
Carmel MC
🇮🇱Haifa, Israel
Ospedale di Circolo, PO Varese
🇮🇹Varese, Italy
FGU-Russian Research Institut
🇷🇺Saint Petersburg, Russian Federation
Oncologic Dispensary No.2
🇷🇺Sochi, Russian Federation
UAB Comprehensive Cancer Center
🇺🇸Birmingham, Alabama, United States
Acrc/Arizona Clinical Research, Inc.
🇺🇸Tucson, Arizona, United States
CBCC Global Research, Inc.
🇺🇸Bakersfield, California, United States
UCLA Ronald Regan Medical Center
🇺🇸Los Angeles, California, United States
Yale-New Haven Hospital (YNHH) - Smilow Cancer Hospital
🇺🇸New Haven, Connecticut, United States
BRCR Medical Center
🇺🇸Plantation, Florida, United States
University of South Florida (USF) - H. Lee Moffitt Cancer Center
🇺🇸Tampa, Florida, United States
Franciscan Health
🇺🇸Indianapolis, Indiana, United States
St. Agnes Healthcare, Inc
🇺🇸Baltimore, Maryland, United States
Center for Cancer and Blood Disorders
🇺🇸Bethesda, Maryland, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
University of New Mexico Cancer Center
🇺🇸Albuquerque, New Mexico, United States
Icahn School of Medicine at Mount Sinai Program for the Protection of Human Subjects
🇺🇸New York, New York, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
Weill Cornell Medical College-New York Presbyterian Hospital
🇺🇸New York, New York, United States
Cleveland Clinic Taussig Cancer
🇺🇸Cleveland, Ohio, United States
The Ohio State Comprehensive Cancer Center
🇺🇸Columbus, Ohio, United States
Prairie lakes Healthcare system, Inc
🇺🇸Watertown, South Dakota, United States
H.U.Pta.del Mar
🇪🇸Cadiz, Cádiz, Spain
Vanderbilt University Medical - Hematology-Oncology
🇺🇸Nashville, Tennessee, United States
Texas Oncology/Methodist Charlton Cancer Center
🇺🇸Dallas, Texas, United States
Simmons Comprehensive Cancer Center
🇺🇸Dallas, Texas, United States
Fred Hutchinson Cancer Research Center (FHCRC)
🇺🇸Seattle, Washington, United States
GZA Ziekenhuizen - Campus Sint
🇧🇪Wilrijk, Antwerpen, Belgium
AZ Sint-Jan Burgge-Oostende
🇧🇪Brugge, West-Vlaanderen, Belgium
Az Groeninge
🇧🇪Kortrijk, West-Vlaanderen, Belgium
ZNA Middelheim
🇧🇪Antwerpen, Belgium
ZNA Cadix
🇧🇪Antwerpen, Belgium
AZ Klina
🇧🇪Brasschaat, Belgium
Universitair Ziekenhuis Gent
🇧🇪Gent, Belgium
CHU de Limoges, Hopital Dupuytren
🇫🇷Limoges, Haute-Vienne, France
CHU de Grenoble - Hôpital Albe
🇫🇷La Tronche, Isère, France
CHRU Nancy Brabois
🇫🇷Vandœuvre-lès-Nancy, Meurthe-et-Moselle, France
CH Le Mans - HAEMATOLOGY
🇫🇷Le Mans, Sarthe, France
CHU de Poitiers
🇫🇷Poitiers, Vienne, France
Centre Hospitalier Universitai
🇫🇷Angers, France
CHRU de Lille - Hopital Claude Huriez - Maladies du Sang
🇫🇷Lille, France
CHU - Hôpital Saint Louis - H
🇫🇷Paris, Île-de-France, France
University Hospital Freiburg
🇩🇪Freiburg, Baden-Württemberg, Germany
Fachärztliche Gemeinschaftspraxis mit Schwerpunkt
🇩🇪Dresden, Sachsen, Germany
University Hospital Leipzig
🇩🇪Leipzig, Sachsen, Germany
Studienzentrum für Hämatologie, Onkologie,Diabetologie, Endoskopie und Fußambulanz
🇩🇪Aschaffenburg, Germany
University Hospital Bonn
🇩🇪Bonn, Germany
Universitatsklinikum Carl Gustav Carcus Dresden
🇩🇪Dresden, Germany
Universitätsklinikum Düsseldorf
🇩🇪Duesseldorf, Germany
Tel Aviv Sourasky Medical Center
🇮🇱Tel Aviv, Tel-Aviv, Israel
The Chaim Sheba Medical Center
🇮🇱Tel HaShomer, Tel-Aviv, Israel
Hadassah Medical Organization
🇮🇱Jerusalem, Israel
Rabin Medical Center, Beilinson Hospital
🇮🇱Petah Tikva, Israel
A.O. Ospedale Niguarda Ca' Granda
🇮🇹Milano, Lombardia, Italy
Istituto Clinico Humanitas Rozzano, IRCCS
🇮🇹Rozzano, Milano, Italy
Irccs Crob
🇮🇹Rionero In Vulture, Potenza, Italy
AOU Ospedali Riuniti Umberto I G.M. Lancisi G. Salesi
🇮🇹Ancona, Italy
AOU di Bologna Policlinico S. Orsola Malpighi
🇮🇹Bologna, Italy
Azienda Ospedaliera Universitaria Careggi di Firenze
🇮🇹Firenze, Italy
Grande Ospedale Metropolitano 'Bianchi-Melacrino-Morelli' Reggio Calabria
🇮🇹Reggio Calabria, Italy
A.O. Universitaria Policlinico Tor Vergata
🇮🇹Roma, Italy
AO S. Andrea, Università degli Studi di Roma La Sapienza
🇮🇹Roma, Italy
Gachon University Gil Medical Center - oncology
🇰🇷Incheon, Incheon Gwang'yeogsi, Korea, Republic of
Pusan National University Hospital - Hematology and Oncology
🇰🇷Seogu, Incheon, Korea, Republic of
Seoul National University Hospital
🇰🇷Seoul, Seoul Teugbyeolsi, Korea, Republic of
Chonnam National University Hwasun Hospital
🇰🇷Hwasun, South Jeolla, Korea, Republic of
Asan Medical Center
🇰🇷Seoul, Korea, Republic of
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of
The Catholic University of Korea Seoul St. Mary's Hospital
🇰🇷Seoul, Korea, Republic of
Severance Hospital, Yonsei Uni
🇰🇷Seoul, Korea, Republic of
Radboud Umcn
🇳🇱Nijmegen, Gelderland, Netherlands
SPZOZ MSWiA z Warminsko - Mazurskim Centrum Onkologii
🇵🇱Olsztyn, Warminsko-mazurskie, Poland
Ars Medical sp. z o.o.
🇵🇱Piła, Wielkopolskie Województwo, Poland
Clinics of Samarskiy GMU
🇷🇺Samara, Volga, Russian Federation
Emergency Hospital of Dzerzhinsk
🇷🇺Dzerzhinsk, Russian Federation
City Clinical Hospital
🇷🇺Moscow, Russian Federation
Nizhniy Novgorod Region Clinical Hospital
🇷🇺Nizhny Novgorod, Russian Federation
Ryazan Regional Clinical Hospital
🇷🇺Ryazan, Russian Federation
Hospital Universitario Puerta de Hierro Majadahonda
🇪🇸Majadahonda, Madrid, Spain
Hospital de Cruces
🇪🇸Baracaldo, Vizcaya, Spain
University Hospital in Basel
🇨🇭Basel, Basel-Stadt (de), Switzerland
Kantonsspital St. Gallen - Onkologie/Hämatologie
🇨🇭Saint Gallen, Sankt Gallen, Switzerland
Inselspital - Universitätsspital Bern
🇨🇭Bern, Switzerland
KNP "Cherkaskyi oblasnyi onkolohichnyi dyspanser Cherkaskoi
🇺🇦Cherkasy, Ukraine
Nottingham City Hospital - Clinical Haematology
🇬🇧Nottingham, Nottinghamshire, United Kingdom
Aberdeen Royal Infirmary
🇬🇧Aberdeen, United Kingdom
The Leeds Teaching Hospitals NHS Trust
🇬🇧Leeds, United Kingdom
Southampton University Hospital
🇬🇧Southampton, United Kingdom