Trial on the Effect of Isatuximab to Lenalidomide/Bortezomib/Dexamethasone (RVd) Induction and Lenalidomide Maintenance in Patients With Newly Diagnosed Myeloma (GMMG HD7)

Sponsor

University of Heidelberg Medical Center (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03617731

Collaborator

(none)

662

Enrollment

Locations

Arms

85.5

Anticipated Duration (Months)

9.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Trial in patients with newly diagnosed myeloma to evaluate the effect of isatuximab in induction therapy with lenalidomide/bortezomib/dexamethasone (RVd) and in lenalidomide maintenance treatment

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: Lenalidomide Drug: Bortezomib Drug: Dexamethasone Drug: Isatuximab	Phase 3

Detailed Description

Prospective, multicentre, randomised, parallel group, open, phase III clinical trial, for patients with confirmed diagnosis of untreated multiple myeloma requiring systemic therapy.

Investigational Medicinal Products: Isatuximab, Lenalidomide

Randomization: Patients are randomized in one of 2 study arms (IA or IB) before induction therapy. Patients randomized in arm IA will receive 3 cycles RVd (Bortezomib (Velcade®), Lenalidomide (Revlimid®, each cycle is 42 days), Dexamethasone). Patients in arm IB will additionally receive the monoclonal antibody Isatuximab in the 3 cycles RVd. After induction therapy patients undergo intensifying therapy according to GMMG standard (usually mobilization therapy followed by stem cell collection and autologous stem cell transplantation).
Randomization: Before maintenance treatment patients are randomized in one of 2 study arms (IIA and IIB): Patients in arm IIA receive Lenalidomide maintenance therapy for three years, patients in arm IIB receive additional Isatuximab.

There are two primary objectives:

to compare the induction regimen (IA vs IB) regarding minimal residual disease (MRD) negativity after induction (assessed by flow cytometry; sensitivity at least 1e-5)
to compare the maintenance strategies (arms IIA vs IIB) regarding progression-free survival (PFS), defined as time from 2nd randomization (prior to maintenance therapy) to progression or death from any cause whichever occurs first.

The duration of the trial for each patients is expected to be 45-48 months (induction and intensification treatment: 6-9 months, 3 months rest between intensification and start of maintenance phase 36 months).

Study Design

Study Type:

Interventional

Actual Enrollment :

662 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

2 x 2 arms, 1. randomization before induction therapy (arm IA and IB), 2. randomization before maintenance therapy (arm IIA and IIB)2 x 2 arms, 1. randomization before induction therapy (arm IA and IB), 2. randomization before maintenance therapy (arm IIA and IIB)

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Randomized Phase III Trial Assessing the Benefit of the Addition of Isatuximab to Lenalidomide / Bortezomib / Dexamethasone (RVd) Induction and Lenalidomide Maintenance in Patients With Newly Diagnosed Multiple Myeloma

Actual Study Start Date :

Oct 18, 2018

Anticipated Primary Completion Date :

May 1, 2025

Anticipated Study Completion Date :

Dec 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: IA Patients in arm IA are treated with 3 cycles RVd (lenalidomide 25 mg/d p.o. d1 - 14 and d22 - 35; bortezomib 1.3 mg/m2 s.c. d1, 4, 8, 11, 22, 25, 29, 32; dexamethasone p.o. 20 mg/d d1-2, 4-5, 8-9, 11-12, 15, 22-23, 25-26, 29-30, 32-33).Treatment repeats every 42 days (d43 = cycle 2 d1). Standard intensification: For all patients, stem cells are mobilized by GMMG Standard protocols (CAD: cyclophosphamide, doxorubicin, dexamethasone) and G-CSF. At least 7.5x106 CD34+ cells/kg body weight are harvested. High dose treatment (melphalan 200mg/m², HDT) followed by autologous stem cell transplantation (ASCT) is started 4 - 6 weeks after CAD. For patients not in CR after HDT1, a second HDT is performed within 3 months.	Drug: Lenalidomide 25 mg per os on day 1-14 and d22-35 in induction cycle 1-3 (Arms IA and IB) 10 mg p.o. on day 1-28 in maintenance cycle 1-3, 15 mg p.o. on day 1-28 in maintenance cycle 4-39 (Arms IIA and IIB) Other Names: Revlimid Drug: Bortezomib all arms: 1,3 mg/m^2 subcutaneous on day 1, 4, 8, 11, 22, 25, 29 32 in 3 induction cycles Other Names: Velcade Drug: Dexamethasone 20 mg per os on day 1,2 and 4,5 and 8,9 and 11,12 and 15 and 22,23 and 25,26 and 29,30 and 32,33 in induction cycles 1-3 (Arms IA and IB). Maintenance cycle 1 on day 1, 8, 15, 22 Dexamethasone 20 mg/d per os (Arm IIA). In Arm IIB Dexamethasone 20 mg i.v. on days of Isatuximab infusion in the first maintenance cycle (d 1, 8, 15, 22), dexamethasone will be administered intravenously as part of the premedication. If an isatuximab dose is skipped or discontinued dexamethasone should be administered orally.
Experimental: IB Patients in arm IB are treated with 3 cycles RVd + Isatuximab (lenalidomide 25 mg/d p.o. d1 - 14 and d22 - 35; bortezomib 1.3 mg/m2 s.c. d1, 4, 8, 11, 22, 25, 29, 32;dexamethasone p.o. 20 mg/d d1-2, 4-5, 8-9, 11-12, 15, 22-23, 25-26, 29-30, 32-33).Isatuximab (10 mg/kg i.v. C1: d 1, 8, 15, 22, 29; C2-3: d 1, 15, 29).Treatment repeats every 42 days (d43 = cycle 2 d1). Standard intensification: For all patients, stem cells are mobilized by GMMG Standard protocols (CAD: cyclophosphamide, doxorubicin, dexamethasone) and G-CSF. At least 7.5x106 CD34+ cells/kg body weight are harvested. High dose treatment (melphalan 200mg/m², HDT) followed by autologous stem cell transplantation (ASCT) is started 4 - 6 weeks after CAD. For patients not in CR after HDT1, a second HDT is performed within 3 months.	Drug: Lenalidomide 25 mg per os on day 1-14 and d22-35 in induction cycle 1-3 (Arms IA and IB) 10 mg p.o. on day 1-28 in maintenance cycle 1-3, 15 mg p.o. on day 1-28 in maintenance cycle 4-39 (Arms IIA and IIB) Other Names: Revlimid Drug: Bortezomib all arms: 1,3 mg/m^2 subcutaneous on day 1, 4, 8, 11, 22, 25, 29 32 in 3 induction cycles Other Names: Velcade Drug: Dexamethasone 20 mg per os on day 1,2 and 4,5 and 8,9 and 11,12 and 15 and 22,23 and 25,26 and 29,30 and 32,33 in induction cycles 1-3 (Arms IA and IB). Maintenance cycle 1 on day 1, 8, 15, 22 Dexamethasone 20 mg/d per os (Arm IIA). In Arm IIB Dexamethasone 20 mg i.v. on days of Isatuximab infusion in the first maintenance cycle (d 1, 8, 15, 22), dexamethasone will be administered intravenously as part of the premedication. If an isatuximab dose is skipped or discontinued dexamethasone should be administered orally. Drug: Isatuximab 10 mg/kg in the vein( i.v) on day 1,8,15, 22, 29 in induction cycle 1 on day 1, 15 and 29 in induction cycle 2 and 3 (Arm IB). 10 mg/kg i.v. on day 1,8, 15 and 22 in maintenance cycle 1, 10 mg/kg i.v. on day 1 and 15 in maintenance cycle 2 and 3, 10 mg/kg i.v. on day 1 in maintenance cycle 4 - 39 (Arm IIB)
Active Comparator: IIA maintenance treatment with Lenalidomide 10mg/d (increased to 15mg/d after 3 months) repeated every 28d. Maintenance treatment is planned for up to 36 months or until progression if progression occurs first.	Drug: Lenalidomide 25 mg per os on day 1-14 and d22-35 in induction cycle 1-3 (Arms IA and IB) 10 mg p.o. on day 1-28 in maintenance cycle 1-3, 15 mg p.o. on day 1-28 in maintenance cycle 4-39 (Arms IIA and IIB) Other Names: Revlimid
Experimental: IIB maintenance treatment with Lenalidomide 10mg/d (increased to 15mg/d after 3 months) + Isatuximab (10 mg/kg; C1: d1, 8, 15, 22; C2-C3: d1 + 15; C4-39:d1, repeated every 28d). Within the trial, maintenance treatment is planned for up to 36 months or until progression if progression occurs first.	Drug: Lenalidomide 25 mg per os on day 1-14 and d22-35 in induction cycle 1-3 (Arms IA and IB) 10 mg p.o. on day 1-28 in maintenance cycle 1-3, 15 mg p.o. on day 1-28 in maintenance cycle 4-39 (Arms IIA and IIB) Other Names: Revlimid Drug: Isatuximab 10 mg/kg in the vein( i.v) on day 1,8,15, 22, 29 in induction cycle 1 on day 1, 15 and 29 in induction cycle 2 and 3 (Arm IB). 10 mg/kg i.v. on day 1,8, 15 and 22 in maintenance cycle 1, 10 mg/kg i.v. on day 1 and 15 in maintenance cycle 2 and 3, 10 mg/kg i.v. on day 1 in maintenance cycle 4 - 39 (Arm IIB)

Outcome Measures

Primary Outcome Measures

MRD negativity after induction Treatment (comparison of arms IA and IB) [18 weeks after start of study treatment]
Detection of minimal residual disease by flow cytometry (sensitivity at least 1e-5)
Progression Free Survival (PFS) after second randomization (arms IIA and IIB) [time from 2. randomization to progression or death from any cause whichever comes first, censored after three years of maintenance therapy]
Response Evaluation by IMWG criteria

Secondary Outcome Measures

to compare the four treatment arms (IA-IIA, IA-IIB, IB-IIA, IB-IIB) regarding Progression free survival (PFS) [time from 1. randomization (study inclusion) to progression or death whichever comes first (assessed up to 79 months)]
Response evaluation by IMWG criteria
to compare all 4 treatment arms (IA-IIA, IA-IIB, IB-IIA, IB-IIB) regarding overall survival (OS) from time of 1.randomization [time from randomisation to time of death from any cause (assessed up to 79 months)]
survival status
Overall survival from second randomization [time from 2. randomization to time of death from any cause (assessed up to 75 months)]
survival status
Complete Response (CR) rates after induction therapy [After induction treatment (18 weeks after start of treatment)]
Response Evaluation by IMWG criteria
Complete Response (CR) after high dose therapy [After high dose therapy (9 or 12 months after start of therapy)]
Response Evaluation by IMWG criteria
Complete Response (CR) during/after maintenance therapy [During/after maintenance therapy (6 months after start of therapy up to 36 months of maintenance therapy)]
Response Evaluation by IMWG criteria
MRD negativity after high dose therapy [After high dose therapy (9 or 12 months after start of therapy)]
Detection of minimal residual disease by flow cytometry (sensitivity at least 1e-5)
MRD negativity during and after maintenance therapy [up to 36 months after start of maintenance therapy]
Detection of minimal residual disease by flow cytometry (sensitivity at least 1e-5)
Best response to treatment during the trial [response assessment after 3 months, 4,5 months, 5,5 months, 9 months (if applicable: 3 months later after 2. high dose therapy) subsequently every 3 months during maintenance treatment, up to 48 months after start of study treatment]
Response evaluation by IMWG criteria
PFS 2 (PFS after next line of therapy) from 2. randomization [time from 2. randomization to time of overall end of trial (up to 75 months)]
Response evaluation by IMWG criteria
Toxicity during induction and maintenance with respect to adverse events of CTC grade >3 (and specific adverse events of CTC grade > 2 as defined in the protocol and serious adverse events [: from first administration of study drug until 30 days after last administration of study drug or any drug of the study treatment or upon start of a new subsequent chemotherapy, whichever occurs first]
toxicity according CTCAE Version v5.0
Quality of Life Assessment [assessed at baseline, after ca. 4.5 months, 9 months, (additionally after 12 months,if a second high dose therapy is administered) after 12 months of maintenance and at end of study (up to 50 months)]
EORTC (European Organization of Research and Treatment of Cancer) -QLQC30 Questionnaire to assess the quality of life of cancer patients. Impairment of daily life is asked in 4 scales from "not at all" (best) to "very much" (worst scale), EORTC-QLQMY20 questionnaire to assess health-related quality of life in patients with multiple myeloma with 4 scales from "not at all (best scale) to "very much" (worst scale); EQ(EuroQol Group)-5D-5L Health questionnaire comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. Additionally a visual analogue scale from 100 (best) to 0 (worst scale) is used to assess the quality of health questionnaires.
Pharmakokinetic analyses of Isatuximab in induction treatment of patients in Arm IB (selected sites only) [Up to 18 weeks in induction treatment (C1: D1, before infusion, at end of infusion, 1 h after infusion, C1 D8,15,22,29 before infusion; C2 and 3:D1 before infusion]
Determination of serum concentration of isatuximab at different timepoints before, during and after isatuximab infusion
Pharmakokinetic analyses of Isatuximab in maintenance treatment of patients in Arm IIB (selected sites only) [Up to 9 months (C1: D1, before infusion, at end of infusion, 1 h after infusion, C1 D8,15,22 before infusion, C2 -9, D1: before infusion]
Determination of serum concentration of isatuximab at different timepoints

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Confirmed diagnosis of untreated multiple myeloma requiring systemic therapy (diagnostic criteria (IMWG updated criteria (2014)1) see appendix IA. For some patients systemic therapy may be required though these diagnostic criteria are not fulfilled. In this case the GMMG study office has to be consulted prior to inclusion.)
Patient is eligible for high dose therapy and autologous stem cell transplantation.
Measurable disease, defined as any quantifiable monoclonal protein value, defined by at least one of the following three measurements:2

Serum M-protein ≥ 10g/l (for IgA ≥ 5g/l)
Urine light-chain (M-protein) of ≥ 200 mg/24 hours
Serum FLC assay: involved FLC level ≥ 10 mg/dl provided sFLC ratio is abnormal

Age 18 - 70 years inclusive
WHO performance status 0-2
Negative pregnancy test at inclusion (females of childbearing potential)
All patients must agree on the requirements regarding the lenalidomide pregnancy prevention plan described in section 6. For all men and females of childbearing potential: patients must be willing and capable to use adequate contraception during the complete therapy.
All patients must

agree to abstain from donating blood while taking lenalidomide and for 28 days following discontinuation of lenalidomide therapy
agree not to share study drug lenalidomide with another person and to return all unused study drug to the investigator or pharmacist

Ability of patient to understand character and individual consequences of the clinical trial
Provide written informed consent (must be available before enrolment in the trial)

Exclusion Criteria

Patient has known hypersensitivity (or contraindication) to dexamethasone, sucrose histidine (as base and hydrochloride salt), boron, mannitol, and polysorbate 80 or any of the components of study therapy that are not amenable to premedication with steroids or H2 blockers that would prohibit further treatment with these agents.
Systemic AL amyloidosis (except for AL amyloidosis of the skin or the bone marrow)
Plasma cell leukemia
Previous chemotherapy or radiotherapy during the past 5 years except local radiotherapy in case of local myeloma progression. (Note: patients may have received a cumulative dose of up to 160 mg of dexamethasone or equivalent as emergency therapy.) Previous therapy due to smouldering myeloma may be acceptable. In this case the GMMG study office has to be consulted prior to inclusion
Severe cardiac dysfunction (NYHA classification III-IV), ejection fraction < 40%
Significant hepatic dysfunction (ASAT and/or ALAT ≥ 3 times normal level and/or serum bilirubin ≥ 1.5 times normal level if not due to hereditary abnormalities as Gilbert's disease), unless related to myeloma.
Patients with active or history of hepatitis B or C
HIV positivity
Patients with active, uncontrolled infections
Patients with severe renal insufficiency (Creatinine Clearance < 30ml/min)
Patients with peripheral neuropathy or neuropathic pain, CTC grade 2 or higher (as defined by the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0)
Patients with a history of active malignancy during the past 5 years with the exception of following malignancies after curative therapy: basal cell carcinoma of the skin, squamous cell skin carcinoma, stage 0 cervical carcinoma or any in situ malignancy
Patients with acute diffuse infiltrative pulmonary and/or pericardial disease
Autoimmune hemolytic anemia with positive Coombs test or immune thrombocytopenia
Platelet count < 75 x 109/l
Haemoglobin < 8.0 g/dl, unless related to myeloma
Absolute neutrophil count (ANC) < 1.0 x 109/l (the use of colony stimulating factors within 14 days before the test is not allowed)
Corrected serum calcium > 14 mg/dl (> 3.5 mmol/l)
Unable or unwilling to undergo thromboprophylaxis
Pregnancy and lactation
Participation in other clinical trials. This does not include long-term follow-up periods without active drug treatment of previous studies during the last 6 months.
Prisoners or subjects who are legally institutionalized, or those unwilling or unable to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions.

No patients will be allowed to enrol in this trial more than once.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Uniklinik RWTH Aachen, Klinik für Hämatologie, Onkologie, Hämostaseologie und Stammzelltransplantation	Aachen	Germany	52074
2	Studienzentrum Aschaffenburg	Aschaffenburg	Germany	63739
3	Helios Klinikum Bad Saarow, Klinik für Hämatologie, Onkologie und Palliativmedizin	Bad Saarow	Germany	15526
4	Charité, Campus Benjamin Franklin , III. Medizinische Abteilung (Hämatologie/Onkologie)	Berlin	Germany	12200
5	Vivantes Klinikum Neukölln, Klinik für Hämatologie und Onkologie	Berlin	Germany	12351
6	HELIOS Klinikum, Klinik für Hämatologie, Onkologie und Immunologie	Berlin	Germany	13125
7	Studiengesellschaft Onkologie Bielefeld GbR	Bielefeld	Germany	33604
8	Klinikum Bielefeld, Klinik für Hämatologie, Onkologie und Palliativmedizin	Bielefeld	Germany	D-33604
9	Medizinische Universitätsklinik, Knappschaftskrankenhaus	Bochum	Germany	D-44892
10	Universitätsklinikum Bonn, Medizinische Klinik und Poliklinik III, Schwerpunkt Onkologie, Hämatologie und Rheumatologie	Bonn	Germany	53105
11	Johanniter Krankenhaus Bonn	Bonn	Germany	53113
12	Zentrum für ambulante Hämatologie und Onkologie (ZAHO)	Bonn	Germany	53113
13	Städtisches Klinikum Braunschweig, Med. Klinik III, Hämatologie und Onkologie	Braunschweig	Germany	38114
14	Klinikum Chemnitz GmbH, Innere Medizin III	Chemnitz	Germany	D-09116
15	Carl-Thiem-Klinikum Cottbus gGmbH, II. Medizinische Klinik	Cottbus	Germany	03048
16	Onkologisches Studienzentrum Darmstadt	Darmstadt	Germany	64283
17	Klinikum Darmstadt, Med. Klinik V, Hämatologie/Onkologie	Darmstadt	Germany	D-64283
18	Universitätsklinikum Carl Gustav Carus Dresden, an der Technischen Universität Dresden, Medizinische Klinik und Poliklinik I	Dresden	Germany	01307
19	HELIOS St. Johannes Klinik, Akademisches Krankenhaus der Heinrich-Heine-Universität Düsseldorf	Duisburg	Germany	47166
20	Marien Hospital Düsseldorf GmbH, Klinik für Onkologie, Hämatologie und Palliativmedizin	Düsseldorf	Germany	40479
21	Universitätsklinikum Düsseldorf, Klinik für Hämatologie,Onkologie und Klin. Immunologie	Düsseldorf	Germany	D-40225
22	Universitätsklinik Erlangen	Erlangen	Germany	91054
23	St. Antonius-Hospital Eschweiler, Klinik für Hämatologie / Onkologie	Eschweiler	Germany	52249
24	Universitätsklinikum Essen, Klinik für Hämatologie	Essen	Germany	D-45147
25	Ev. Krankenhaus Essen-Werden gGmbH, Zentrum für Innere Medizin, Klinik für Hämatologie, Onkologie und Stammzelltransplantation	Essen	Germany	D-45239
26	Gemeinschaftspraxis Prof. Dr. Michael Kiehl und Dipl. Med. Wolfgang Stein	Frankfurt (Oder)	Germany	15236
27	Klinikum Frankfurt (Oder) GmbH	Frankfurt (Oder)	Germany	15236
28	Centrum für Hämatologie und Onkologie Bethanien	Frankfurt am Main	Germany	60389
29	Agaplesion Markus Krankenhaus, Med. Klinik I	Frankfurt am Main	Germany	60431
30	Krankenhaus Nordwest, Institut für Klinisch-Onkologische Forschung	Frankfurt am Main	Germany	60488
31	Universitätsklinikum Frankfurt, Goethe-Universität Medizinische Klinik II	Frankfurt am Main	Germany	60590
32	Klinikum Fulda, Klinisches Studienzentrum GmbH	Fulda	Germany	36043
33	Universitätsklinik der Justus-Liebig-Universität, Medizinische Klinik IV	Gießen	Germany	35385
34	Katholisches Karl-Leisner-Klinikum gGmbH, Wilhelm-Anton-Hospital Goch, Klinik für Hämatologie - Onkologie	Goch	Germany	47574
35	Kath. Krankenhaus Hagen gGmbH, Abt. Hämatologie/Onkologie	Hagen	Germany	D-58095
36	Asklepios Klinik Hamburg St. Georg	Hamburg	Germany	20099
37	Universitätsklinikum Hamburg Eppendorf, Zentrum für Onkologie, Studienzentrale der II. Medizinischen Klinik	Hamburg	Germany	20246
38	Asklepios Klinik Hamburg Altona, II. Med. Klinik	Hamburg	Germany	D-22763
39	Immunologisch-onkologisches MVZ am Siloah Krankenhaus	Hannover	Germany	30449
40	KRH Klinikum Siloah, Klinik für Hämatologie und Onkologie	Hannover	Germany	30459
41	Onkologische Schwerpunktpraxis Heidelberg	Heidelberg	Germany	69115
42	Krankenhaus St. Vincentius der evangelischen Stadtmission Heidelberg, Abt. Hämatologie, Onkologie, Rheumatologie	Heidelberg	Germany	69117
43	University Hospital Heidelberg, Med. Klinik V	Heidelberg	Germany	D-69120
44	SLK Kliniken Heilbronn, Med. Klinik III	Heilbronn	Germany	D-74078
45	Marien Hospital Herne	Herne	Germany	44625
46	Universitätsklinikum des Saarlandes, Innere Medizin I	Homburg (Saar)	Germany	66421
47	Westpfalz-Klinikum GmbH, Klinik für Innere Medizin I	Kaiserslautern	Germany	67655
48	Städtisches Klinikum Karlsruhe	Karlsruhe	Germany	76133
49	Praxisklinik für Hämatologie und Onkologie	Koblenz	Germany	D-56068
50	Uniklinik Köln, Klinik I für Innere Medizin	Köln	Germany	50937
51	Gemeinschaftspraxis für Hämatologie und Onkologie am Caritas Krankenhaus	Lebach	Germany	66822
52	Universitätsklinikum Leipzig AöR, Medizinische Klinik und Poliklinik I-Hämatologie und Zelltherapie, Internistische Onkologie, Hämostaseologie	Leipzig	Germany	04103
53	Med. Klinik A, Klinikum der Stadt Ludwigshafen am Rhein gGmbH	Ludwigshafen am Rhein	Germany	67063
54	Universitätsmedizin der Johannes Gutenberg-Universität Mainz, III. Med. Klinik	Mainz	Germany	D-55131
55	III. Medizinische Klinik Hämatologie und Internistische Onkologie	Mannheim	Germany	68167
56	Mannheimer Onkologie Praxis	Mannheim	Germany	D-68161
57	Philipps-Universität Marburg, Hämatologie/Onkologie/Immunologie	Marburg	Germany	35032
58	Mühlenkreiskliniken (AöR) Johannes Wesling Klinikum Minden, Hämatologie/Onkologie, Hämostaseologie und Palliativmedizin	Minden	Germany	32429
59	Krankenhaus Maria Hilf GmbH, Franziskuskrankenhaus, Med. Klinik I	Mönchengladbach	Germany	D-41063
60	Universitätsklinikum Münster, Med. Klinik A	Münster	Germany	48149
61	Klinikum Osnabrück GmbH	Osnabrück	Germany	49076
62	Brüderkrankenhaus St. Josef Paderborn, Klinik für Hämatologie und Onkologie	Paderborn	Germany	33098
63	Krankenhaus Barmherzige Brüder, Klinik für Onkologie und Hämatologie	Regensburg	Germany	93049
64	Gemeinschaftspraxis für Hämatologie und Onkologie, Onkologisches Zentrum	Saarlouis	Germany	66740
65	Diakonie-Klinikum Schwäbisch Hall gGmbH, Innere Medizin III	Schwäbisch Hall	Germany	74523
66	ZAHO-Zentrum für ambulante Hämatologie und Onkologie, Standort Siegburg	Siegburg	Germany	D-53721
67	Onkologische Schwerpunktpraxis Speyer	Speyer	Germany	D-67346
68	Klinikum Stuttgart, Stuttgart Cancer Center, Tumorzentrum Eva Mayr-Stihl	Stuttgart	Germany	70174
69	Klinikum Mutterhaus der Borromäerinnen gGmbH	Trier	Germany	54290
70	University Hospital Tübingen, Med. Klinik und Poliklinik, Abt. II	Tübingen	Germany	D-72076
71	Bundeswehrkrankenhaus Ulm, Abteilung Innere Medizin - Hämatologie und internistische Onkologie	Ulm	Germany	89081
72	Schwarzwald-Baar Klinikum, Innere Medizin II	Villingen-Schwenningen	Germany	78052
73	Rems-Murr-Kliniken gGmbH	Winnenden	Germany	71364