A Study Evaluating the Safety, Efficacy and Pharmacokinetics of Venetoclax Combined With Chemotherapy in Participants With B-Cell Non-Hodgkin's Lymphoma (NHL) and DLBCL
- Conditions
- Lymphoma, Non-Hodgkin
- Interventions
- Registration Number
- NCT02055820
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
This is a multicenter, open-label, dose-finding study of venetoclax administered orally in combination with rituximab (R) or obinutuzumab (G) and standard doses of cyclophosphamide, doxorubicin, vincristine and oral prednisone (CHOP) in participants with Non-Hodgkin's Lymphoma (NHL). The study consisted of 2 stages: a dose-finding Phase Ib stage and a Phase II expansion stage. In the Phase I portion of the study, participants were randomized to one of 2 treatment arms venetoclax in combination with R-CHOP (Arm A) and venetoclax in combination with G-CHOP (Arm B) and explored the doses of venetoclax in combination with R-CHOP and G-CHOP. The maximum tolerated dose (MTD) of venetoclax in combination with R-CHOP and G-CHOP was determined during the dose-finding stage. For the Phase II portion of the study, the venetoclax dose for venetoclax + R-CHOP was on a non-continuous dosing schedule as determined by the Phase Ib portion of the study based on safety and tolerability observed in participants treated in the dose escalation portion of the study. On 17 July 2016, Roche/Genentech as the sponsor of Study BO21005 (Goya study), a Phase III study that evaluated G CHOP versus R-CHOP in 1L DLBCL, informed through a press release that the primary endpoint of investigator-assessed PFS was not met. Given these results, Arm B (venetoclax + G-CHOP) was not expanded in Phase II in patients who are first-line with DLBCL.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 267
General Inclusion Criteria:
- At least one bi-dimensionally measurable lymphoma lesion on CT scan defined as > 1.5 cm in its longest dimension, which is also FDG avid by screening PET scan.
- Confirmed availability of archival or freshly biopsied tumor tissue prior to study enrollment
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
- Adequate hematologic function
- For female participants of childbearing potential, agreement to use highly effective forms of contraception
Dose-Escalation Portion of the Study:
- Participants must have histologically confirmed B-cell NHL, except MCL or SLL
- Participants must have never received previous R-CHOP treatment
- Any relapsed/refractory participants that are enrolled during the dose escalation should have received only a single previous treatment regimen
Expansion Portion of the Study:
- Participants must have previously untreated CD20-positive DLBCL and IPI score must be 2-5
General Exclusion Criteria:
- History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products
- Contraindication to receive any of the individual components of CHOP, rituximab or obinutuzumab
- Prior anthracycline therapy
- Participants with ongoing corticosteroid use >30 mg per day of prednisone or equivalent
- CNS lymphoma or primary mediastinal DLBCL
- Vaccination with live vaccines within 28 days prior to randomization
- Chemotherapy or other investigational therapy within 28 days prior to the start of Cycle 1
- History of other malignancy that could affect compliance with the protocol or interpretation of results
- Evidence of significant, uncontrolled concomitant disease
- Significant cardiovascular disease or significant pulmonary disease
- Left ventricular ejection fraction less than (<) 50% as defined by multiple-gated acquisition (MUGA)
- Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 4 weeks prior to Cycle 1 Day 1
- Received the following agents within 7 days prior to the first dose of venetoclax: steroid therapy for anti-neoplastic intent; strong and moderate cytochrome P450 (CYP) 3A4 inhibitors or inducers; grapefruit/grapefruit products, seville oranges or star fruit within 3 days prior to the first dose of venetoclax
- Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis
- Recent major surgery
- Women who are pregnant or lactating
Dose-Escalation Portion of the Study:
- Participants with confirmed mantle cell lymphoma (MCL) or small lymphocytic lymphoma (SLL)
Expansion Portion of the Study:
- Participants with transformed lymphoma (participants with discordant bone marrow involvement (i.e., low grade histology in bone marrow) may be considered after discussion with the Medical Monitor)
- Prior therapy for NHL
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Venetoclax + G-CHOP Arm Venetoclax Phase I: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle will consist of 21 days. Phase II: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle will consist of 21 days. For both phase I and II, participants with ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Venetoclax + G-CHOP Arm Cyclophosphamide Phase I: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle will consist of 21 days. Phase II: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle will consist of 21 days. For both phase I and II, participants with ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Venetoclax + G-CHOP Arm Obinutuzumab Phase I: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle will consist of 21 days. Phase II: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle will consist of 21 days. For both phase I and II, participants with ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Venetoclax + G-CHOP Arm Vincristine Phase I: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle will consist of 21 days. Phase II: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle will consist of 21 days. For both phase I and II, participants with ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Venetoclax + G-CHOP Arm Doxorubicin Phase I: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle will consist of 21 days. Phase II: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle will consist of 21 days. For both phase I and II, participants with ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Venetoclax + R-CHOP Arm Venetoclax Phase I: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle will consist of 21 days. Phase II: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle will consist of 21 days. For both phase I and II, participants with ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Venetoclax + G-CHOP Arm Prednisone Phase I: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle will consist of 21 days. Phase II: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle will consist of 21 days. For both phase I and II, participants with ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Venetoclax + R-CHOP Arm Cyclophosphamide Phase I: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle will consist of 21 days. Phase II: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle will consist of 21 days. For both phase I and II, participants with ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Venetoclax + R-CHOP Arm Rituximab Phase I: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle will consist of 21 days. Phase II: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle will consist of 21 days. For both phase I and II, participants with ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Venetoclax + R-CHOP Arm Doxorubicin Phase I: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle will consist of 21 days. Phase II: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle will consist of 21 days. For both phase I and II, participants with ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Venetoclax + R-CHOP Arm Vincristine Phase I: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle will consist of 21 days. Phase II: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle will consist of 21 days. For both phase I and II, participants with ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Venetoclax + R-CHOP Arm Prednisone Phase I: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle will consist of 21 days. Phase II: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle will consist of 21 days. For both phase I and II, participants with ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
- Primary Outcome Measures
Name Time Method Safety: Number of Participants With Dose-Limiting Toxicities (DLTs) Start of venetoclax administration (Cycle 1 Day 4 or 3 days after first CHOP dose) up to end of Cycle 2 (cycle length = 21 days) DLTs were reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0). Decrease in B cells, lymphopenia, and leukopenia caused by lymphopenia were not considered DLTs but instead were expected outcomes of study treatment. Any Grade \>/= 3 adverse event, that was attributed to having a reasonable possibility of being related to the combined administration of venetoclax plus R-CHOP or G-CHOP, that could not be attributed by the investigator to an alternative, clearly identifiable cause such as tumor progression, concurrent illness or medical condition, or concomitant medication and that occurred during the DLT observation period (start of venetoclax treatment through end of Cycle 2) was considered a DLT for dose-escalation purposes. Grade 3 or 4 neutropenia or thrombocytopenia identified on Day 1 of Cycle 2 or 3, resulting in dose delay were considered DLTs.
Percentage of Previously Untreated DLBCL Participants With Complete Response (CR) Defined by Positron Emission Tomography-Computed Tomography (PET/CT) Scan Using the Modified Lugano Classification Assessed by Independent Review Committee (IRC) Baseline up to end of treatment (up to approximately 6 months) CR was defined as follows according to modified Lugano classification for PET/CT-based response: Lymph nodes and extra-lymphatic sites with score 1, 2, or 3 with or without a residual mass on 5-point scale with 1) no uptake above background; 2) uptake \</= mediastinum; 3) uptake \< mediastinum but \</= liver. No evidence of fluorodeoxyglucose (FDG)-uptake disease in marrow. If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy
Percentage of Participants With CR Defined by PET/CT Scan in Previously Untreated DLBCL Co-Expressing Both Bcl-2 and c-Myc Proteins (DE-DLBCL) Participants Assessed by IRC Baseline up to end of treatment (up to approximately 6 months) CR was defined as follows according to modified Lugano classification for PET/CT-based response: Lymph nodes and extra-lymphatic sites with score 1, 2, or 3 with or without a residual mass on 5-point scale with 1) no uptake above background; 2) uptake \</= mediastinum; 3) uptake \< mediastinum but \</= liver. No evidence of fluorodeoxyglucose (FDG)-uptake disease in marrow. If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy.
- Secondary Outcome Measures
Name Time Method Venetoclax Plasma PK: Minimum Plasma Concentration (Cmin) Within the Dosing Interval Predose (within 30 minutes) & 2, 4, 6, 8 Hr postdose on Cycle 1 Day 4 (cycle length = 21 days) Cmin was determined based on measurement of venetoclax concentrations in plasma over time. Venetoclax exposure was pooled across Phase I and II for the R-CHOP 800 mg cohorts.
Venetoclax Plasma PK: Time to Maximum Observed Plasma Concentration (Tmax) Predose (within 30 minutes) & 2, 4, 6, 8 Hr postdose on Cycle 1 Day 4 (cycle length = 21 days) Tmax was determined based on measurement of venetoclax concentrations in plasma over time. Venetoclax exposure was pooled across Phase I and II for the R-CHOP 800 mg cohorts.
Venetoclax Plasma PK: Area Under the Plasma Concentration-Time Curve (AUC) Predose (within 30 minutes) & 2, 4, 6, 8 hours (Hr) postdose on Cycle 1 Day 4 (cycle length = 21 days) AUC was calculated based on measurement of venetoclax concentration in plasma over time. Venetoclax exposure was pooled across Phase I and II for the R-CHOP 800 mg cohorts.
Data are reported as hour\*micrograms per milliliter (hr\*mcg/mL)Venetoclax Plasma PK: Maximum Observed Plasma Concentration (Cmax) Predose (within 30 minutes) & 2, 4, 6, 8 Hr postdose on Cycle 1 Day 4 (cycle length = 21 days) Cmax was determined based on measurement of venetoclax concentrations in plasma over time. Venetoclax exposure was pooled across Phase I and II for the R-CHOP 800 mg cohorts.
Data are reported as micrograms per milliliterPercentage of Participants With Objective Response Defined as Partial Response (PR) or Complete Response (CR) Defined by Positron Emission Tomography-Computed Tomography (PET/CT) Using the Modified Lugano Classification Assessed by IRC Baseline to end of treatment (up to approximately 6 months) Objective Response defined as PR (partial response) or CR (complete response) at end of treatment.
CR: Lymph nodes and extra-lymphatic sites with score 1, 2 or 3 on a 5-point scale (with a higher score being a worse outcome). No evidence of fluorodeoxyglucose (FDG)-uptake disease in marrow. If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy.
PR: Lymph nodes and extralymphatic sites with score of 4 or 5 on the 5-point scale with reduced uptake compared with baseline and residual mass(es) of any size. CT-based response criteria for PR must also be met. No new lesions. In bone marrow residual uptake could be higher than in normal marrow but must be reduced compared with baseline; persistent focal changes in the marrow to be considered for further evaluation with magnetic resonance imaging (MRI) or biopsy or an interval scan. OR=PR+CRRelative Dose Intensity of Venetoclax Baseline up to Cycle 6 (cycle length = 21 days) Dose intensity was categorized as \< 80%, 80% to \< 85%, 85% to \< 90%, or \>/= 90%.
Prednisone Plasma PK: AUC Predose (within 30 minutes) and 0.5, 1, 2, 4, 6 Hr after prednisone dose on Day 1 of Cycle 1 and 2 (cycle length = 21 days) AUC was determined based on measurement of Predisone concentrations in plasma over time.
Cyclophosphamide PK: Cmax End of Infusion on Cycle 1 Day 1 (cycle length = 21 days) Cmax was determined using the post-dose Cyclophosphamide plasma concentrations on Cycle 1 Day 1.
Prednisone Plasma PK: Cmax Predose (within 30 minutes) and 0.5, 1, 2, 4, 6 Hr after prednisone dose on Day 1 of Cycle 1 and 2 (cycle length = 21 days) Cmax was determined based on measurement of Predisone concentrations in plasma over time.
Rituximab PK: Cmax End of Infusion on Cycle 1 Day 1 (cycle length = 21 days) Cmax was determined using the post-dose rituximab plasma concentrations at the 800 mg Venetoclax Dose using the end of infusion time point on Cycle 1 Day 1.
Percentage of Participants Who Are Alive and Without Disease Progression at Month 12 Month 12 Progressive disease (PD) was determined using the modified Lugano classification criteria. For PET-CT-based PD: Score 4 (uptake moderately \> liver) or 5 (uptake markedly higher than liver and/or new lesions) with an increase in intensity of uptake from baseline in target nodes and nodal lesions, new FDG-uptake foci of extranodal lesions consistent with lymphoma at interim or end-of-treatment assessment, no non-measured lesions, new FDG-uptake foci consistent with lymphoma, new or recurrent FDG-uptake foci in bone marrow. For CT-based PD: \>/= 50% decrease in SPD of up to 6 target measureable nodes and extranodal sites; non-measured lesion should be absent/normal, have regressed, but not increased; no new lesions.
Percentage of Participants With CR Defined by Computed Tomography (CT) Scan Using the Modified Lugano Classification Baseline up to end of treatment (approx. 6 months) CR was defined as follows according to modified Lugano classification for CT-based response: Target nodes/nodal masses must have regressed to \</= 1.5 cm in longest transverse diameter of a lesion (LDi), no extra-lymphatic sites of disease, absence of non-measured lesions, organ enlargement must have regressed to normal, no new lesions, and if the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy.
Prednisone Plasma PK: Tmax Predose (within 30 minutes) and 0.5, 1, 2, 4, 6 Hr after prednisone dose on Day 1 of Cycle 1 and 2 (cycle length = 21 days) Tmax was determined based on measurement of Predisone concentrations in plasma over time.
Vincristine PK: Cmax End of Infusion on Cycle 1 Day 1 (cycle length = 21 days) Cmax was determined using the post-dose Vincristine plasma concentrations.
Safety: Percentage of Participants Maintaining Relative Dose Intensity of CHOP Chemotherapy Baseline up to Cycle 6 (cycle length = 21 days) Maintenance of relative dose intensity was defined as a dose intensity of \>/= 90%.
Rituximab PK: Cmin Within the Dosing Interval Pre-dose on Cycle 2 Day 1 (cycle length = 21 days) Cmin was determined using the pre-dose rituximab plasma concentrations at the 800 mg Venetoclax Dose on Day 1 of Cycle 2.
Obinutuzumab PK: Cmax End of Infusion on Cycle 1 Day 1 (cycle length = 21 days) Cmax was determined using the post-dose obinutuzumab plasma concentrations at the 800 mg Venetoclax Dose using the end of infusion time point on Cycle 1 Day 1.
Doxorubicin PK: Cmax End of Infusion on Cycle 1 Day 1 (cycle length = 21 days) Cmax was determined using the post-dose Doxorubicin plasma concentrations.
Safety: Percentage of Participants With Adverse Events Baseline up to approximately 36 months An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
Trial Locations
- Locations (52)
Memorial Sloan-Kettering Cancer Center
🇺🇸New York, New York, United States
Royal Melbourne Hospital
🇦🇺Parkville, Victoria, Australia
Medizinische Universität Wien
🇦🇹Wien, Austria
BC Cancer Agency Vancouver Centre - PARENT; BC Cancer Agency
🇨🇦Vancouver, British Columbia, Canada
Centre Hospitalier Départemental Les Oudairies
🇫🇷La Roche sur Yon, France
Clinique Victor Hugo; Pharmacie
🇫🇷Le Mans, France
Hopital Claude Huriez - CHU Lille
🇫🇷Lille, France
Hopital Saint Eloi
🇫🇷Montpellier, France
CHU Nantes - Hôtel Dieu; Service Assistance Medicale à la Procreation
🇫🇷Nantes, France
Hôpital Saint-Louis
🇫🇷Paris, France
Centre Hospitalier Lyon Sud
🇫🇷Pierre-Benite, France
CHU Rennes - Hopital Pontchaillou
🇫🇷Rennes cedex 09, France
Centre Henri Becquerel; Hematologie
🇫🇷Rouen, France
Semmelweis Egyetem
ðŸ‡ðŸ‡ºBudapest, Hungary
Azienda Ospedaliera Città della Salute e della Scienza di Torino
🇮🇹Torino, Piemonte, Italy
Azienda Ospedaliera Vincenzo Cervello
🇮🇹Palermo, Sicilia, Italy
Orszagos Onkologiai Intezet
ðŸ‡ðŸ‡ºBudapest, Hungary
Istituto Nazionale per lo Studio e la Cura dei Tumori Fondazione G. Pascale
🇮🇹Napoli, Campania, Italy
Azienda Ospedaliero Universitaria San Martino
🇮🇹Genova, Liguria, Italy
Azienda Ospedaliero Universitaria Pisana; U.O. Farmaceutica
🇮🇹Pisa, Toscana, Italy
Amsterdam UMC Location VUMC
🇳🇱Amsterdam, Netherlands
Erasmus Medisch Centrum
🇳🇱Rotterdam, Netherlands
St. Jude Heritage Healthcare
🇺🇸Fullerton, California, United States
San Juan Oncology Associates
🇺🇸Farmington, New Mexico, United States
Central Coast Medical Oncology
🇺🇸Santa Maria, California, United States
UCLA Jonsson Comprehensive Cancer Center
🇺🇸Los Angeles, California, United States
Debreceni Egyetem; Belgyogyaszati Klinika Hematologiai Tanszek
ðŸ‡ðŸ‡ºDebrecen, Hungary
UMC Utrecht
🇳🇱Utrecht, Netherlands
Concord Repatriation General Hospital
🇦🇺Concord, New South Wales, Australia
Fakultni nemocnice Brno
🇨🇿Brno, Czechia
Hackensack University Medical Center; WFAN - Imus Pediatric Center
🇺🇸Hackensack, New Jersey, United States
LKH - Universitätsklinikum der PMU Salzburg
🇦🇹Salzburg, Austria
Uni of Rochester Medical Center; Wilmot Cancer Center, Pharmacy Department
🇺🇸Rochester, New York, United States
Hospital Universitari Vall d'Hebron
🇪🇸Barcelona, Spain
Fakultni nemocnice Ostrava
🇨🇿Ostrava - Poruba, Czechia
CHU de Quebec - Hôpital de l' Enfant Jésus
🇨🇦Quebec, Canada
Cross Cancer Institute
🇨🇦Edmonton, Alberta, Canada
Hospital Universitario La Paz
🇪🇸Madrid, Spain
Fakultni nemocnice Hradec Kralove
🇨🇿Hradec Kralove, Czechia
Hospital Universitario de Salamanca
🇪🇸Salamanca, Spain
Jewish General Hospital; Research Unit
🇨🇦Montréal, Quebec, Canada
Hospital del Mar
🇪🇸Barcelona, Spain
Peter MacCallum Cancer Centre-East Melbourne
🇦🇺Melbourne, Victoria, Australia
Vseobecna Fakultni Nemocnice v Praze, I. Interni Klinika - Klinika Hematoonkologie VFN a 1. LF UK
🇨🇿Praha 2, Czechia
ICO l´Hospitalet - Hospital Duran i Reynals; Hematology
🇪🇸Barcelona, Spain
Princess Alexandra Hospital
🇦🇺Woolloongabba, Queensland, Australia
Hopital Henri Mondor, Unite Hemopathies lymphoides
🇫🇷Creteil, France
Hôpital de Brabois Adultes
🇫🇷Vandoeuvre-les-nancy, France
Hospital Universitario Ramon y Cajal
🇪🇸Madrid, Spain
The West Clinici
🇺🇸Saint Louis, Missouri, United States
Tennessee Oncology
🇺🇸Nashville, Tennessee, United States
BC Cancer Agency, CSI
🇨🇦Kelowna, British Columbia, Canada