Ponatinib in Participants With Resistant Chronic Phase Chronic Myeloid Leukemia (CP-CML) to Characterize the Efficacy and Safety of a Range of Doses

Phase 2

Active, not recruiting

Conditions: Myeloid Leukemia, Chronic, Chronic Phase

Interventions: Drug: Ponatinib

Registration Number: NCT02467270

Lead Sponsor: Takeda

Brief Summary: The purpose of this study is to characterize the efficacy of ponatinib administered in 3 starting doses (45 mg, 30 mg, and 15 mg daily) in participants with CP-CML who are resistant to prior tyrosine-kinase inhibitor (TKI) therapy or have T315I mutation, as measured by \<=1 % Breakpoint Cluster Region-Abelson Transcript Level using International Scale (BCR-ABL1IS) at 12 months.

Detailed Description: The drug being tested in this study is ponatinib. This study will characterize the safety and efficacy of ponatinib over a range of 3 starting doses.

The study will enroll 276 participants in 3 cohorts and each cohort will have 92 participants. All the participants will be randomized to receive once-daily oral administration of 1 of 3 starting doses of ponatinib:

* Cohort A: 45 mg ponatinib tablet

* Cohort B: 30 mg ponatinib tablet

* Cohort C: 15 mg ponatinib tablet

The study is designed to consist of 2 periods: 24-cycle Main treatment period and optional treatment continuation period. Participants will be treated with their randomized dose of study drug in the Main Treatment Period until the occurrence of at least one of the following: absence of CHR by 3 months, absence of MCyR at 12 months, absence of \<=1% BCR-ABL1IS at 12 months, loss of \<=1% BCR-ABL1IS development of intolerance, or completion of all 24 cycles of treatment (whichever occurs first). Following completion of approximately 5 years or following early withdrawal, participants may enter into an optional treatment continuation period.

This multi-center trial will be conducted in the United States, United Kingdom, Republic of Korea, Spain, France, Taiwan, Australia, Canada, Italy, Chile, Japan, Germany, Argentina, Poland, Czech Republic, Denmark, Hong Kong, Portugal, Russia, Singapore, Switzerland, and Sweden. The overall time to participate in this study is approximately 96 months. Participants will make a final visit to the clinic approximately 30 days after the last dose of study treatment.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 283

Inclusion Criteria

Have chronic phase-chronic myelogenous leukemia/chronic myeloid leukemia (CP-CML) and have received at least two prior tyrosine kinase inhibitor (TKI) therapies and have demonstrated resistance to treatment OR have documented history of presence of T315I mutation after receiving any number of prior TKI.

o] The diagnosis of chronic myeloid leukemia (CML) will be made using standard hematopathologic and cytogenetic criteria; CP-CML will be defined by all of the following: i <15% blasts in bone marrow ii <30% blasts plus promyelocytes in bone marrow iii <20% basophils in peripheral blood. iv >= 100*10^9/liter (L) platelets (>=100,000/mm^3). v No evidence of extramedullary disease except hepatosplenomegaly vi No prior diagnosis of AP-CML, and BP-CML o] Cytogenetic assessment at screening must demonstrate the BCR-ABL1 fusion by presence of the t(9;22) Philadelphia chromosome.

i Variant translocations are only allowed provided they meet inclusion criterion 1d.

o] Resistance to prior TKI therapy is defined as follows (participants must meet at least 1 criterion): i Three months after the initiation of prior TKI therapy: No cytogenetic response (>95% Ph+) or failure to achieve CHR or new mutation ii Six months after the initiation of prior TKI therapy: BCR-ABL1IS >10% and/or Ph+ >65% or new mutation iii Twelve months after the initiation of prior TKI therapy: BCR ABL1IS >10% and/or Ph+ >35% or new mutation iv At any time after the initiation of prior TKI therapy, the development of a new BCR-ABL1 kinase domain mutation(s) v At any time after the initiation of prior TKI therapy, the development of new clonal evolution vi At any time after the initiation of prior TKI therapy, the loss of CHR, or CCyR, or the confirmed loss of MMR in 2 consecutive tests, one of which has a BCR-ABL1IS transcript level of >=1% or new mutation o] >1% of BCR-ABL1IS as shown by real-time polymerase chain reaction
Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
Have adequate renal function as defined by the following criterion:

o] Serum creatinine <=1.5*ULN for institution o] Estimated creatinine clearance >=30 milliliter per minute (mL/min) (Cockcroft-Gault formula)
Have adequate hepatic function as defined by the following criteria:

o] Total serum bilirubin <=1.5*ULN, unless due to Gilbert's syndrome o] Alanine transaminase (ALT) <=2.5*ULN, or <=5*ULN if leukemic infiltration of the liver is present o] Aspartate transaminase (AST) <=2.5*ULN, or <=5*ULN if leukemic infiltration of the liver is present
Have normal pancreatic status as defined by the following criterion:

o] Serum lipase and amylase <=1.5*ULN
Have normal QT interval corrected (Frederica) (QTcF) interval on screening electrocardiogram (ECG) evaluation, defined as QTcF of <=450 milliseconds (ms) in males or <=470 ms in females.
Have a negative pregnancy test documented prior to enrollment (for females of childbearing potential).
Agree to use a highly effective form of contraception with sexual partners from randomization through at least 4 months after the end of treatment (for female and male participants who are fertile).
Provide written informed consent.
Be willing and able to comply with scheduled visits and study procedures.
Have recovered from toxicities related to prior anticancer therapy to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 4.0 grade <=1.

Exclusion Criteria

Have used any approved TKIs or investigational agents within 2 weeks or 6 half-lives of the agent, whichever is longer, prior to receiving study drug.
Received interferon, cytarabine, or immunotherapy within 14 days, or any other cytotoxic chemotherapy, radiotherapy, or investigational therapy within 28 days prior to receiving the first dose of ponatinib, or have not recovered (>grade 1 by NCI CTCAE, version 4.0) from AEs (except alopecia), due to agents previously administered.
Have undergone autologous or allogeneic stem cell transplant <60 days prior to receiving the first dose of ponatinib; have any evidence of ongoing graft-versus-host disease (GVHD) or GVHD requiring immunosuppressive therapy.
Are being considered for hematopoietic stem cell transplant (HSCT) within 6-12 months of enrollment (note: ponatinib is not to be used as a bridge to HSCT in this trial).
Are taking medications with a known risk of Torsades de Pointes.
Have previously been treated with ponatinib.
Have active CNS disease as evidenced by cytology or pathology; in the absence of clinical CNS disease, lumbar puncture is not required. History itself of CNS involvement is not exclusionary if CNS has been cleared with a documented negative lumbar puncture.
Have clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:

o] Any history of myocardial infarction (MI), unstable angina, cerebrovascular accident, or Transient Ischemic Attack (TIA) o] Any history of peripheral vascular infarction, including visceral infarction o] Any revascularization procedure, including the placement of a stent o] Congestive heart failure (CHF) (New York Heart Association [NYHA] class III or IV) within 6 months prior to enrollment, or left ventricular ejection fraction (LVEF) less than lower limit of normal, per local institutional standards, within 6 months prior to enrollment o] History of clinically significant (as determined by the treating physician) atrial arrhythmia or any history of ventricular arrhythmia o] Venous thromboembolism, including deep venous thrombosis or pulmonary embolism, within 6 months prior to enrollment
Have uncontrolled hypertension (that is, >150 and >90 for systolic blood pressure (SBP) and diastolic blood pressure (DBP) respectively). Participants with hypertension should be under treatment at study entry to ensure blood pressure control. Those requiring 3 or more antihypertensive medications should be discussed with the medical monitor.
Have poorly controlled diabetes defined as HbA1c values of >7.5%. Participants with preexisting, well-controlled diabetes are not excluded.
Have a significant bleeding disorder unrelated to CML.
Have a history of alcohol abuse.
Have a history of either acute pancreatitis within 1 year of study enrollment or of chronic pancreatitis.
Have malabsorption syndrome or other gastrointestinal illness that could affect oral absorption of study drug.
Have a history of another malignancy, other than cervical cancer in situ or basal cell or squamous cell carcinoma of the skin; the exception is if participants have been disease-free for at least 5 years, and are deemed by the investigator to be at low risk for recurrence of that malignancy.
Are pregnant or lactating.
Have undergone major surgery (with the exception of minor surgical procedures, such as catheter placement or BM biopsy) within 14 days prior to first dose of ponatinib.
Have an active infection which requires intravenous antibiotics.
Have a known history of human immunodeficiency virus infection; testing is not required in the absence of prior documentation or known history.
Have any condition or illness that, in the opinion of the investigator, would compromise participant safety or interfere with the evaluation of the drug.
Have hypersensitivity to the ponatinib active substance or to any of its inactive ingredients.

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort A: Ponatinib 45 mg	Ponatinib	Ponatinib 45 mg orally once daily in each 28-day cycle until achievement of ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.
Cohort B: Ponatinib 30 mg	Ponatinib	Ponatinib 30 mg orally once daily in each 28 day Cycle until achievement of ≤1% BCR-ABL1IS. Once ≤1% BCR-ABL1IS up to data cut-off: 31 May 2020. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily.
Cohort C: Ponatinib 15 mg	Ponatinib	Participants received ponatinib 15 mg orally once daily up to data cut-off: 31 May 2020 in each 28 day Cycle.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Molecular Response (MR2: <=1% Breakpoint Cluster Region-Abelson Transcript Level) as Measured by the International Scale (BCR-ABL1IS) at Month 12	12 months after the first dose of study treatment	MR2 is defined as a ratio of reverse transcribed transcript of BCR-ABL to ABL \<=1% Breakpoint Cluster Region-Abelson Transcript Level as Measured by the International Scale (BCR-ABL1IS), equivalent to a 2-log reduction in transcript.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Major Molecular Response (MMR/MR3)	12 months after the first dose of study treatment	MMR/MR3 is defined as a ratio of reverse transcribed transcript of BCR-ABL to ABL ≤0.1% on the international scale (equivalent to a 3-log reduction in transcript).
Percentage of Participants With Adjusted Incidence Rates for Treatment Emergent Arterial Occlusive Events (AOEs), Venous Thrombotic Events (VTEs), Adverse Events (AEs), and Serious AEs (SAEs)	From first dose up to 30 days after last dose of the study drug up to data cut-off date: 31 May 2020 (Up to approximately 5 years)	Percentage of participants with adjusted incidence rates who developed AOEs and VTEs were categorized according to arterial occlusive events and venous thrombotic events. AE is any untoward medical occurrence in participant administered medicinal investigational drug. Untoward medical occurrence does not necessarily have to have causal relationship with treatment. SAE is any untoward medical occurrence that results in death; is life-threatening; requires inpatient hospitalization or prolongation of present hospitalization; results in persistent or significant disability/incapacity; is congenital anomaly/birth defect/is medically important event that may not be immediately life-threatening/result in death or hospitalization, but may jeopardize participant/may require intervention to prevent one of other outcomes listed in definition above, or involves suspected transmission via a medicinal product of an infectious agent.
Percentage of Participants With Treatment Emergent AEs Leading to Treatment Discontinuation, Dose Reduction and Dose Interruption	Up to data cut-off: 31 May 2020 (Approximately 5 years)	An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.
Percentage of Participants With Molecular Response 4 (MR4) and Molecular Response (MR4.5)	Up to approximately 8 years	MR4 is defined as \<=0.01% BCR-ABL1IS. MR 4.5 is defined as \<=0.0032% BCR-ALB1IS.
Duration of Response in Responders	Baseline up to data cut-off: 31 May 2020 (Approximately 5 years)	Duration of response in "responders" is defined as any participants who achieved ≤1% BCR-ABL1IS at any time during the study. Responders are defined as those participants who meet all of the following: are randomized and treated, respond at 12 months after the initiation of study treatment, and undergo baseline polymerase chain reaction (PCR) assessment.
Percentage of Participants With Major Cytogenetic Response (MCyR)	12 months after the first dose of study treatment	MCyR is defined as percentage of participants with complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). Cytogenetic response is the percentage of Philadelphia chromosome positive (Ph+) metaphases in bone marrow (BM). Response is further defined as MCyR: CCyR or PCyR, where CCyR: 0% Ph + metaphases; PCyR: \>0 to 35% Ph + metaphases.
Duration of Major Molecular Response (MMR/MR3)	Baseline up to approximately 8 years	Duration of MMR/MR3 is defined as the interval between the first assessment at which the criteria for \<=0.1% MMR are met until the earliest date at which loss of \<=0.1% MMR occurs, or the criteria for progression are met. Progression to accelerated phase (AP) is defined as: \>= 15% and \<30% blasts in peripheral blood or bone marrow or \>=20% basophils in peripheral blood or bone marrow or \>=30% blasts + promyelocytes in peripheral blood or bone marrow (but \<30% blasts) or \<100\*109 platelets per liter (/L) in peripheral blood unrelated to therapy or cytogenetic, genetic evidence of clonal evolution, and no extramedullary disease. Progression to blast Phase (BP) is defined as: \>=30% blasts in peripheral blood or bone marrow or extramedullary disease other than hepatosplenomegaly.
Percentage of Participants With Molecular Response 1 (MR1)	3 months after the first dose of study treatment	MR1 is defined as percentage of participants achieving a ratio of \<=10% Breakpoint Cluster Region-abelson (BCR-ABL1) transcripts on the international scale. MR1 is molecular response with 1-log reduction in transcript.
Percentage of Participants With Complete Cytogenetic Response (CCyR)	Month 12	Cytogenetic response is defined as the percentage of Ph+ metaphases in bone marrow (peripheral blood may not be used), with a review of a minimum of 20 metaphases. CCyR is defined as 0% Ph+ metaphases.
Percentage of Participants With Complete Hematologic Response (CHR)	3 months after the first dose of study treatment	CHR is defined as achieving all of the following measurements: white blood cells (WBC) \<= institutional upper limit of normal (ULN), platelets \<450,000 per cubic millimeter (/mm\^3), no blasts or promyelocytes in peripheral blood, \<5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood \<5%, and no extramedullary involvement (including no hepatomegaly or splenomegaly).
Kaplan-Meier Estimate of Duration of Response (DOR) of Major Molecular Response (MMR/MR3)	12 and 24 months after the first dose of study treatment	Duration of MMR/MR3 is defined as interval between first assessment at which criteria for MMR are met until earliest date at which loss of MMR occurs, or criteria for progression (progression to AP or BP of CML) are met. Participants remaining in MMR will be censored at last date at which criteria for MMR are met. Loss of MMR is an increase to \>0.1% of BCR-ABL1IS. Progression to AP: \>= 15% and \<30% blasts in peripheral blood or bone marrow or \>=20% basophils in peripheral blood or bone marrow or \>=30% blasts+promyelocytes in peripheral blood or bone marrow (but \<30% blasts) or \<100\*109 platelets/L in peripheral blood unrelated to therapy or cytogenetic, genetic evidence of clonal evolution, and no extramedullary disease. Progression to BP: \>=30% blasts in peripheral blood or bone marrow or extramedullary disease other than hepatosplenomegaly. Kaplan-Meier method was used for analysis of percentage of participants who achieved DOR of 12 and 24 months.
Progression-free Survival (PFS)	Up to data cut-off: 31 May 2020 (Up to approximately 5 years)	PFS is defined as the interval between the first dose date of study treatment and the first date at which the criteria for progression are met (progression to the AP or BP of CML), or death due to any cause, censored at the last response assessment. Progression to AP is defined as: \>=15% and \<30% blasts in peripheral blood or bone marrow or \>=20% basophils in peripheral blood or bone marrow or \>=30% blasts + promyelocytes in peripheral blood or bone marrow (but \<30% blasts) or \<100\*109 platelets/L in peripheral blood unrelated to therapy or cytogenetic, genetic evidence of clonal evolution, and no extramedullary disease. Progression to BP is defined as: \>=30% blasts in peripheral blood or bone marrow or extramedullary disease other than hepatosplenomegaly.
Kaplan-Meier Estimate of Duration of Response (DOR) of <=1% BCR-ABL1 IS (MR2) at Months 12 and 24	12 and 24 months after the first dose of study treatment	DOR (≤1% BCR-ABL1IS) is defined as interval between first assessment at which criteria for ≤1% BCR-ABL1IS are met until earliest date at which loss of ≤1% BCR-ABL1IS occurs, or criteria for progression accelerated phase (AP) or blast Phase (BP) of chronic myeloid leukemia (CML) are met. Loss of ≤1% BCR-ABL1IS is an increase to \>1% of BCR-ABL1IS. Progression to AP: ≥15% and \<30% blasts in peripheral blood or bone marrow or ≥20% basophils in peripheral blood or bone marrow or ≥30% blasts + promyelocytes in peripheral blood or bone marrow (but \<30% blasts) or \<100\*109 platelets per liter in peripheral blood unrelated to therapy or cytogenetic, genetic evidence of clonal evolution, and no extramedullary disease. Progression to BP: ≥30% blasts in peripheral blood or bone marrow or extramedullary disease other than hepatosplenomegaly. Kaplan-Meier method was used for analysis of percentage of participants who achieved DOR of 12 and 24 months.
Time to Response	Baseline up to data cut-off: 31 May 2020 (Approximately 5 years)	Time to response was defined as the time interval from the date of the first dose of the study drug until the initial observation of CR or PR for participants with confirmed CR/PR. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to \<10 mm in short axis. CR for non-target lesion: Disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (\<10mm short axis) and norrmalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the Baseline sum diameters.
Percentage of Participants With Progression to Accelerated Phase (AP)-Chronic Myeloid Leukemia (CML) or Blast Phase (BP)-CML	From first dose date of study treatment up to data cut-off: 31 May 2020 (Approximately 5 years)	Progression to AP is defined as: \>=15% and \<30% blasts in peripheral blood or bone marrow or \>=20% basophils in peripheral blood or bone marrow or \>=30% blasts + promyelocytes in peripheral blood or bone marrow (but \<30% blasts) or \<100\*109 platelets/L in peripheral blood unrelated to therapy or cytogenetic, genetic evidence of clonal evolution, and no extramedullary disease. Progression to BP is defined as: \>=30% blasts in peripheral blood or bone marrow or extramedullary disease other than hepatosplenomegaly.
Overall Survival (OS)	Up to data cut-off: 31 May 2020 (Up to approximately 5 years)	OS is defined as the interval between the first does of study treatment and death due to any cause, censored at the last contact date when the participant was alive.

Trial Locations

Locations (86): Royal Adelaide Hospital
🇦🇺
Adelaide, South Australia, Australia
Saskatchewan Cancer Agency
🇨🇦
Regina, Saskatchewan, Canada
Imperial College Healthcare NHS Trust
🇬🇧
London, England, United Kingdom
MD Anderson Cancer Center
🇺🇸
Houston, Texas, United States
Indiana Blood & Marrow Transplantation
🇺🇸
Indianapolis, Indiana, United States
Duke University Medical Center
🇺🇸
Durham, North Carolina, United States
Institut Universitaire du Cancer de Toulouse Oncopole
🇫🇷
Toulouse Cedex 9, Midi-pyrenees, France
University of Utah Huntsman Cancer Institute
🇺🇸
Salt Lake City, Utah, United States
University of Minnesota Medical School
🇺🇸
Minneapolis, Minnesota, United States
Universitatsklinikum Hamburg-Eppendorf
🇩🇪
Hamburg, Germany
Fundaleu
🇦🇷
Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina
Hackensack University Medical Center
🇺🇸
Hackensack, New Jersey, United States
Russian Academy of Medical Science
🇷🇺
Moscow, Russian Federation
Hospital Italiano La Plata
🇦🇷
La Plata, Buenos Aires, Argentina
Hospital del Salvador
🇨🇱
Providencia, Santiago, Chile
Singapore General Hospital
🇸🇬
Singapore, Singapore
Universitaetsklinikum Heidelberg
🇩🇪
Mannheim, Baden-wuerttemberg, Germany
GBUZ Moscow Clinical Scientific Center DZM
🇷🇺
Moscow, Russian Federation
Centro de Investigaciones Clinicas Vina del Mar
🇨🇱
Vina del Mar, Valparaiso, Chile
Centre Hospitalier Universitaire de Nantes Hotel Dieu
🇫🇷
Nantes Cedex 1, PAYS DE LA Loire, France
Centre Hospitalier Universitaire de Nice Hopital l'Archet
🇫🇷
Nice Cedex 3, Provence Alpes COTE D'azur, France
AOUI - Ospedale Policlinico "Giambattista Rossi" di Borgo Roma
🇮🇹
Verona, Italy
University of Maryland Medical Center
🇺🇸
Baltimore, Maryland, United States
The Catholic University of Korea, Seoul St. Mary's Hospital
🇰🇷
Seoul, Korea, Republic of
Hospital General de Agudo Jose Maria Ramos Mejia
🇦🇷
Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina
Centre Hospitalier Regional Universitaire de Lille
🇫🇷
Lille cedex, NORD Pas-de-calais, France
Uniklinik RWTH Aachen
🇩🇪
Aachen, Nordrhein-westfalen, Germany
Universitaetsklinikum Essen
🇩🇪
Essen, Nordrhein-westfalen, Germany
Universitatsmedizin Rostock
🇩🇪
Rostock, Mecklenburg-vorpommern, Germany
Centre Hospitalier Universitaire de Poitiers
🇫🇷
Poitiers Cedex, Poitou-charentes, France
Azienda Ospedaliero - Universitaria Policlinico - Vittorio Emanuele
🇮🇹
Catania, Italy
Wielospecjalistyczne Centrum Onkologii i Traumatologii im. M. Kopernika w Lodzi
🇵🇱
Lodz, Lodzkie, Poland
Instituto Portugues de Oncologia de Lisboa Francisco Gentil
🇵🇹
Lisboa, Portugal
Centro Hospitalar Sao Joao
🇵🇹
Porto, Portugal
FGU Russian Scientific Research Institute of Hematology and Transfusiology
🇷🇺
Saint Petersburg, Russian Federation
Universitatsklinikum Ulm
🇩🇪
Ulm, Baden-wuerttemberg, Germany
King's College Hospital NHS Foundation Trust
🇬🇧
London, England, United Kingdom
Malopolskie Centrum Medyczne
🇵🇱
Krakow, Malopolskie, Poland
Instytut Hematologii i Transfuzjologii
🇵🇱
Warszawa, Mazowieckie, Poland
Hospital Universitario de Gran Canaria Doctor Nergrin
🇪🇸
Las Palmas de Gran Canaria, LAS Palmas, Spain
Oregon Health and Science University
🇺🇸
Portland, Oregon, United States
Rostov State Medical University
🇷🇺
Rostov-na-Donu, Rostov, Russian Federation
Chelyabinsk Regional Clinical Hospital
🇷🇺
Chelyabinsk, Russian Federation
Hospital Regional Universitario Carlos Haya
🇪🇸
Malaga, Andalucia, Spain
Akademiska Sjukhuset
🇸🇪
Uppsala, Sweden
National Taiwan University Hospital
🇨🇳
Taipei, Taiwan
Royal Liverpool University Hospital NHS Trust
🇬🇧
Liverpool, England, United Kingdom
University of Nebraska Medical Center
🇺🇸
Omaha, Nebraska, United States
Emory University Winship Cancer Institute
🇺🇸
Atlanta, Georgia, United States
Michigan Medicine
🇺🇸
Ann Arbor, Michigan, United States
Barbara Ann Karmanos Cancer Institute
🇺🇸
Detroit, Michigan, United States
Memorial Sloan-Kettering Cancer Center - New York
🇺🇸
New York, New York, United States
NewYork-Presbyterian Weill Cornell Medical Center
🇺🇸
New York, New York, United States
Cleveland Clinic Taussig Cancer Institute Main Campus
🇺🇸
Cleveland, Ohio, United States
Abramson Cancer Center
🇺🇸
Philadelphia, Pennsylvania, United States
Royal North Shore Hospital
🇦🇺
Saint Leonards, New South Wales, Australia
Princess Margaret Hospital - Toronto
🇨🇦
Toronto, Ontario, Canada
Jewish General Hospital
🇨🇦
Montreal, Quebec, Canada
Ustav Hematologie a Krevni Transfuze Praha
🇨🇿
Prague, Praha, Czechia
Fakultni Nemocnice Olomouc
🇨🇿
Olomouc, Czechia
Aarhus University Hospital
🇩🇰
Aarhus C, \Aarhus, Denmark
Centre de Lutte Contre le Cancer - Institut Bergonie
🇫🇷
Bordeaux, Aquitaine, France
Centre Hospitalier Universitaire de Nancy Hopital de Brabois
🇫🇷
Vandoeuvre les Nancy, Lorraine, France
Center Hospitalier Universitaire d'Angers
🇫🇷
Angers Cedex 9, PAYS DE LA Loire, France
Universitatsklinikum Jena
🇩🇪
Jena, Thuringen, Germany
Charite Universitatsmedizin Berlin
🇩🇪
Berlin, Germany
Azienda Ospedaliera San Gerardo di Monza
🇮🇹
Monza, Monza E Brianza, Italy
Queen Mary Hospital
🇭🇰
Hong Kong, Hong Kong
Azienda Ospedaliera Ospedali Riuniti Marche Nord
🇮🇹
Pesaro, Pesaro E Urbino, Italy
Azienda Ospedaliera Universitaria San Martino
🇮🇹
Genova, Italy
Azienda Sanitaria Locale di Pescara Ospedale Civile Dello Spirito Santo
🇮🇹
Pescara, Italy
Sapienza Universita Di Roma
🇮🇹
Roma, Italy
Samodzielny Publiczny Szpital Kliniczny Nr 1 we Wroclawiu
🇵🇱
Wroclaw, Dolnoslaskie, Poland
Uniwersyteckie Centrum Kliniczne
🇵🇱
Gdansk, Pomorskie, Poland
Kemerovo Regional Clinical Hospital
🇷🇺
Kemerovo, Russian Federation
Samara State Medical University
🇷🇺
Samara, Russian Federation
Almazov Federal North-West Medical Research Centre of Department of Health of Russian Federation
🇷🇺
Saint Petersburg, Russian Federation
Saratov State Medical University
🇷🇺
Saratov, Russian Federation
Hospital Universitario de La Princesa
🇪🇸
Madrid, Spain
Hospital Universitario Ramon Y Cajal
🇪🇸
Madrid, Spain
Hospital Clinic i Provincial de Barcelona
🇪🇸
Barcelona, Spain
Hospital Clinico Universitario de Valencia
🇪🇸
Valencia, Spain
University Hospital Zurich
🇨🇭
Zurich, Switzerland
Churchill Hospital
🇬🇧
Oxford, England, United Kingdom
Nottingham City Hospital NHS Trust
🇬🇧
Nottingham, England, United Kingdom
Beatson West of Scotland Cancer Centre
🇬🇧
Glasgow, Scotland, United Kingdom

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