Studien

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Maher Hanoun

+49 (0)201 723-82530
maher.hanoun@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

GMALL-Studiengruppe

hoelzer@em.uni-frankfurt.de

Schaubstr. 16
60596 Frankfurt

Einschlusskriterien
# Alter mind. 18 Jahre
# Schriftliche Einverständniserklärung des Patienten
# Therapie analog zu einer GMALL Therapieoptimierungsstudie oder einer GMALL-Therapieempfehlung
# Eine der folgenden drei Einschlusskriterien:
# 1. akute lymphatische Leukämie
# 2. andere Leukämien (NK-Zell-Lymphom/Leukämie oder akute biphänotypische Leukämie)
# 3. Non-Hodgkin-Lymphome folgender Subtypen (WHO-Klassifikation): Burkitt-Lymphom (inkl. atypisches Burkitt-Lymphom, Burkitt-like-Lymphom), diffus großzellige B-Zell-Lymphome (insbesondere primär mediastinale DLBCL, DLBCL mit Burkitt-Signatur, c-myc-positive DLBCL), B-lymphoblastisches Lymphom, T-lymphoblastisches Lymphom, Großzellig-anaplastisches Lymphom, Sonstige NHL

Ausschlusskriterien
keine

Studienteilnehmende Mindestalter
18 Jahr(e)

Indikation
ALL - Akute lymphatische Leukämie

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Dr. med. Richard Noppeney

+49 (0)201 723-82530
richard.noppeney@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Klinikum der Universität München, Klinikum Großhadern

Einschlusskriterien
AML gemäß den WHO-Diagnose-Kriterien, einschließlich Akute Promyelozyten-leukämie (APL)
Alter ≥18 Jahre
unterschriebene Einwilligungserklärung

Ausschlusskriterien
keine

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
AML - Akute myeloische Leukämie

Medizinischer Befund
AML

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Dr. med. Richard Noppeney

+49 (0)201 723-82530
richard.noppeney@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Universität Leipzig

Einschlusskriterien
- newly-diagnosed APL (either de novo or therapy-related), within 12 months of diagnosis or relapsed APL, within 12 months of diagnosis of relapse
- confirmed by the presence of the translocation t(15; 17) and/or confirmed by the detection of the fusion transcript of PML/RARa

Ausschlusskriterien
none

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
APL - Promyelozytenleukämie

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Joachim Göthert

+49 (0)201 723-82530
joachim.goethert@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Universitätsklinikum RWTH Aachen

Indikation
MPN - Myeloproliferative Neoplasie

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum, WTZMS - Westdeutsches Tumorzentrum Münster

Prüfarzt (AMG) / Studienleitung (BO)

Dr. med. Richard Noppeney

+49 (0)201 723-82530
richard.noppeney@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Technische Universität Dresden

Einschlusskriterien
- Informed consent
- women or man with a newly diagnosed APL by cytomorphology, confirmed by molecular analysis
- Age ≥18 and ≤ 65 years
- ECOG performance status 0-3
- WBC at diagnosis > 10 GPt/l
- serum total bilirubin ≤ 3.0 mg/dl (≤ 51 µmol/l)
- serum creatinine ≤ 3.0 mg/dl (≤ 260 µmol/l)
- women must fulfill at least one of the following criteria in order to be eligible for trial inclusion:
o Post-menopausal (12 months of natural amenorrhea or 6 months of amenorrhea with Serum FSH > 40 U/ml)
o Postoperative (i.e. 6 weeks) after bilateral ovariectomy with or without hysterectomy
o Continuous and correct application of a contraception method with a Pearl Index of <1% (e.g. implants, depots, oral contraceptives, intrauterine device – IUD).
o Sexual abstinence
o Vasectomy of the sexual partner

Ausschlusskriterien
- patients who are not eligible for chemotherapy as per discretion of the treating physician
- APL secondary to previous radio- or chemotherapy for non-APL disease
- other active malignancy at time of study entry (exception: Basal-Cell Carcinoma)
- lack of diagnostic confirmation of APL at genetic level
- Significant arrhythmias, ECG abnormalities
- other cardiac contraindications for intensive chemotherapy (L-VEF <50%)
- uncontrolled, life-threatening infections
- severe non controlled pulmonary or cardiac disease
- severe hepatic or renal dysfunction
- HIV and/or active hepatitis C infection
- pregnant or breast-feeding patients
- allergy to trial medication or excipients in study medication
- substance abuse; medical, psychological or social conditions that may interfere with the patients participation in the study or evaluation of the study results
- use of other investigational drugs at the time of enrolment or within 30 days before study entry

Studienteilnehmende Mindestalter
18 Jahr(e)

Studienteilnehmende Höchstalter
65 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
APL - Promyelozytenleukämie

Medizinischer Befund
newly diagnosed high-risk acute promyelocytic leukemia (APL)

MedDRA Term
Acute promyelocytic leukaemia

Institute
Klinik für Hämatologie und Stammzelltransplantation, Klinik für Kinderheilkunde III, Westdeutsches Tumorzentrum, WTZMS - Westdeutsches Tumorzentrum Münster

Prüfarzt (AMG) / Studienleitung (BO)

Dr. med. Nina Kristin Steckel

+49 (0)201 723-3712
nina-kristin.steckel@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Novartis Pharma Schweiz AG

+41 41 763 71 11

Suurstoffi 14
6343 Rotkreuz

Einschlusskriterien
- Have undergone alloSCT from any donor source (matched unrelated donor, sibling, haplo-identical) using bone marrow, peripheral blood stem cells, or
cord blood. Recipients of non- myeloablative, myeloablative, and reduced intensity conditioning are eligible
- Clinically diagnosed Grades II to IV acute GvHD as per standard criteria occurring after alloSCT requiring systemic immune suppressive
therapy. Biopsy of involved organs with aGvHD is encouraged but not required for study screening.
- Confirmed diagnosis of corticosteroid refractory aGvHD (confirmed within 48h prior to study treatment start) defined as:
• Patients administered high-dose systemic corticosteroids (methylprednisolone 2 mg/kg/day [or equivalent prednisone dose 2.5 mg/kg/day]), given alone or combined with calcineurin inhibitors (CNI) and either:
• Progressing based on organ assessment after at least 3 days compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD,
OR
• Failure to achieve at a minimum partial response based on organ assessment after 7 days compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD,
OR
• Patients who fail corticosteroid taper defined as fulfilling either one of the following criteria:
• Requirement for an increase in the corticosteroid dose to methylprednisolone =2 mg/kg/day (or equivalent prednisone dose =2.5 mg/kg/day)
OR
• Failure to taper the methylprednisolone dose to <1 mg/kg/day (or equivalent prednisone dose <1.25 mg/kg/day) for a minimum 7 days.

Ausschlusskriterien
- Has received more than one systemic treatment for steriod refractory aGvHD,
- Clinical presentation resembling de novo chronic GvHD or GvHD overlap syndrome with both acute and chronic GvHD features (as defined by Jagasia, et al. 2015)
- Presence of an active uncontrolled infection including significant bacterial, fungal, viral or parasitic infection requiring treatment. Infections are considered controlled if appropriate therapy has been instituted and, at the time of screening, no signs of progression are present. Progression of infection is defined as hemodynamic instability attributable to sepsis, new symptoms, worsening physical signs or radiographic findings attributable to infection.
Persisting fever without other signs or symptoms will not be interpreted as progressing infection.
- Evidence of uncontrolled viral infection including CMV, EBV, HHV-6, HBV, or HCV based on assessment by the treating physicial.
- Presence of relapsed primary malignancy, or who have been treated for relapse after the alloHSCT was performed, or who may require rapid immune suppression withdrawal as pre-emergent treatment of early malignancy relapse.
Other protocol-defined inclusion/exclusion criteria may apply.

Geschlecht
Männlich, Weiblich

Indikation
KIK-Onko

Medizinischer Befund
corticosteroid-refractory acute graft vs. host disease after allogeneic stem cell transplantation

MedDRA Term
Acute graft versus host disease, Acute graft versus host disease in skin, Acute graft versus host disease in intestine, Acute graft versus host disease in liver

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Maher Hanoun

+49 (0)201 723-82530
maher.hanoun@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Goethe-Universität, Frankfurt

Einschlusskriterien
1. Male or female patients, >56 years of age and fit for therapy
2. Newly diagnosed acute lymphoblastic leukemia (>25% marrow blasts, assessed by morphology; i.e., M2 or M3 marrow)
3. Leukemic blasts must have CD22 surface expression of a least 20%, assessed by local/institutional flow cytometry of a bone marrow aspirate sample (assessment of CD22 via the reference lab for immungenetics is strongly recommended). In the case of an inadequate aspirate sample (dry tap), flow cytometry of peripheral blood specimen may be substituted if the patient has circulating blasts; alternatively, CD22 expression may be documented by immunohistochemistry of a bone marrow biopsy specimen
4. No previous ALL-specific treatment with the exception of corticosteroids and/or single dose vincristine and/or a maximum of three doses of cyclophosphamide (cumulative dose of 600mg/m2) and the standard prephase treatment
5. With or without documented CNS involvement
6. Adequate liver function, including total serum bilirubin <2.0 x ULN unless the patient has documented Gilbert syndrome, and aspartate and alanine aminotransferase (AST and ALT) <2.5 x ULNIf organ function abnormalities are considered due to leukemic infiltration of the liver, total serum bilirubin must be < 2.5 x ULN and AST/ALT <5 x ULN
7. Serum creatinine 40 mL/min
8. WHO performance status <2
9. Signed written inform consent 10. Inclusion in GMALL registry

Ausschlusskriterien
1. Philadelphia-chromosome or BCR-ABL positive ALL
2. Burkitt’s or mixed phenotype acute leukemia based on the WHO 2008 criteria
3. Peripheral absolute lymphoblast count >10,000/µL after pre-phase treatment and before start of study medication
4. Known systemic vasculitis (e.g., Wegener’s granulomatosis, polyarteritis nodosa, systemic lupus erythematosus), primary or secondary immunodeficiency (such as HIV infection or severe inflammatory disease)
5. Current or chronic hepatitis B or C infection as evidenced by hepatitis B surface antigen and anti-hepatitis C antibody positivity, respectively, or known seropositivity for human immunodeficiency virus (HIV)
6. Major surgery within <4 weeks before entry on study
7. Unstable or severe uncontrolled medical condition (e.g., unstable cardiac function or unstable pulmonary condition)
8. Concurrent active malignancy other than non-melanoma skin cancer, carcinoma in situ of the cervix, or localized prostate cancer that has been definitely treated with radiation or surgery; patients with previous malignancies are eligible provided that they have been disease free for >2 years
9. Cardiac function, as measured by left ventricular ejection fraction (LVEF) that is less than 45%, or the presence of New York Heart Association (NYHA) stage III or IV congestive heart failure
10. Myocardial infarction <6 months before entry on study
11. History of clinically significant ventricular arrhythmia, or unexplained syncope not believed to be vasovagal in nature, or chronic bradycardic states such as sinoatrial block or higher degrees of AV block unless a permanent pacemaker has been implanted
12. Uncontrolled electrolyte disorders that can confound the effects of a QTc prolonging drug (e.g., hypokalemia, hypocalcemia, hypomagnesemia)
13. History of chronic liver disease (e.g., cirrhosis) or suspected alcohol abuse
14. History of hepatic veno-occlusive disease (VOD) or sinusoidal obstruction syndrome (SOS)
15. Administration of live vaccine <6 weeks before entry on study
16. Evidence of uncontrolled current serious active infection (including sepsis, bacteremia, fungemia) or patients with a recent history (within 4 months) of deep tissue infections such as fasciitis or osteomyelitis
17. Patients who have had a severe allergic reaction or anaphylactic reaction to any humanized monoclonal antibodies or any known hypersensitivity to the active substance or any of its excipients
18. Pregnant females; breastfeeding females; males and females of childbearing potential (a woman is considered of childbearing potential (WOCBP) i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile e.g. after hysterectomy or bilateral ovariectomy. Please refer to chapter 12.4 Contraceptive Requirements.) not using highly effective contraception or not agreeing to continue highly effective contraception for women at least 8 months an for men at least 5 months after the last dose of investigational product19. Participation in other studies involving investigational drug(s) (Phase I-IV) within 4 weeks before study inclusion20. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.

Studienteilnehmende Mindestalter
56 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
ALL - Akute lymphatische Leukämie

Medizinischer Befund
Acute lymphoblastic leukemia, Philadelphia-chromosome and BCR-ABL negative disease, patient aged 56 years or older

MedDRA Term
Acute lymphoblastic leukemia

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Jan Dürig

+49 (0)201 723-82530
Jan.Duerig@sjk.uk-essen.de

Sponsor

Universitätsklinikum Tübingen

Einschlusskriterien
1. Subjects must have newly diagnosed, untreated, symptomatic (according to the revised CRAB criteria 2014), documented myeloma and have measurable disease (serum M-protein ≥ 1 g/dL (for IgA ≥ 0.5 g/dL) or urine M-protein ≥ 200 mg/24 hours) or in case of oligosecretory myeloma: involved FLC level ≥ 10 mg/dl, provided sFLC ratio is abnormal or in case of asecretory myeloma: > 1 focal lesions measurable by MRI
Subjects must have high-risk myeloma defined as followed:
• Presence of one or more of the following cytogenetic abnormalities (determined by FISH):
- Del(17p) in ≥ 10% of purified cells
- t(4;14)
- > 3 copies +1q21
- - t(14;16)
• ISS Stage II or III (all patients)
FISH analysis of external laboratories other than Heidelberg is accepted, a list of laboratories will be filed in the study central.
2. Must be ≥ 18 years at the time of signing the informed consent form.
3. Must be able to adhere to the study visit schedule and other protocol requirements in the investigators opinion.
4. WHO performance status 0-3 (WHO=3 is allowed only if caused by MM and not by co-morbid conditions)
5. Females of childbearing potential (FCBP) (1) must agree to refrain from becoming pregnant for 28 days prior to initiation of study drug, while on study drug and for 30 -150 days* after discontinuation from the study drug by using 2 reliable methods of contraception and must agree to regular pregnancy testing during this timeframe.
(1) A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., who has had menses at any time in the preceding 24 consecutive months) 3) has achieved menarche at some point.
6. Females must agree to abstain from breastfeeding during study participation and 30 150 days* after study drug discontinuation.
7. Males must agree to use a latex condom during any sexual contact with FCBP while participating in the study and for 90 150 days* following discontinuation from this study, even if he has undergone a successful vasectomy.
8. Males must also agree to refrain from donating semen or sperm while on treatment with any study drug and for 90 150 days* after discontinuation from this study treatment.
9. All subjects must agree to refrain from donating blood while on study drug and for 28 days after discontinuation from this study treatment.
10. All subjects must agree not to share medication.
11. All participating subjects have to follow the requirements of the Lenalidomide Pregnancy Prevention Plan (please refer to section 4)
*28 days after last dose of Lenalidomide, 30 days after last dose of Carfilzomib and 150 days (5 Months) after last dose of Isatuximab, for detailsnumber of days differ for Lenalidomide and Carfilzomib, for details see chapter 4.

Ausschlusskriterien
1. Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to antiviral drugs. Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize Carfilzomib), mannitol, sucrose, histidine (as base and hydrochloride salt) and polysorbate 80 or any of the components of study therapy that are not amenable to premedication with steroids and H2 blockers or would prohibit further treatment with these agents.
2. Patients with known systemic amyloidosis (except for AL amyloidosis of the skin or the bone marrow)
3. Administration of systemic chemotherapy, biological, immunotherapy or any investigational agent (therapeutic or diagnostic) for multiple myeloma except bisphosphonate therapy. Emergency treatment with dexamethasone is allowed when the cumulative dexamethasone dose is less or equal 160 mg. It is allowed to include patients in the trial after 1 cycle (4 weeks) of any anti-myeloma first-line treatment.
4. Any of the following laboratory abnormalities:
o Absolute neutrophil count (ANC) < 1,000/µL, unless related to myeloma
o Platelet count < 30,000/ µL (in case of platelets < 50.000 /µl and = 30.000 /µl myeloma bone marrow infiltration should be = 50%)
o Corrected serum calcium > 14 mg/dL (> 3.5 mmol/L); or free ionized calcium > 6.5 mg/dL (> 1.6 mmol/L)
o Serum GOT/AST or SGPT/ALT > 3.0 x upper limit of normal (ULN) or serum total bilirubin > 2.0 mg/dL if not due to hereditary abnormalities as Gilbert’s disease or hereditary hemolysis (Note: if the mentioned limits for bilirubin or ASAT/ALAT are exceeded, but there is no significant hepatic dysfunction at investigator’s discretion, the study office has to be consulted prior to inclusion)
o Patients with severe renal impairment (eGFR < 30 ml/min/1.73 m², MDRD formula or CDK-EPI or Creatinine Clearance < 30 ml/min)
5. Active congestive heart failure (NYHA Class III to IV), symptomatic cardiac ischemia, or conduction abnormalities uncontrolled by conventional intervention. Myocardial infarction within four months prior study entry.
6. Known HIV seropositive, hepatitis C infection, and/or hepatitis B (except for patients with hepatitis B sAg and core antibody receiving and responding to antiviral therapy directed at hepatitis B: these patients are allowed). Patients with a history of hepatitis B infection have to be monitored repetively during treatment. In case of signs of hepatitis B reactivation, antiviral treatment has to be initiated and patients have to be referred to a specialist for treatment and monitoring of hepatitis infection.
7. Acute active, uncontrolled infection
8. Significant neuropathy (Grades 3 to 4, or Grade 2 with pain according CTC V4.03)
9. Second malignancy within the past 5 years except:
- adequately treated basal cell or squamous cell skin cancer
- carcinoma in situ of the cervix
- prostate cancer Gleason Score = 6 with stable PSA over the past 12 months
- breast carcinoma in situ with full surgical resection
- treated medullary or papillary thyroid cancer
10. Patients with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to study entry.
11. Major surgery within 4 weeks prior to cycle 1 day 1 (kyphoplasty is not considered major surgery); subjects should have been fully recovered from any surgical related toxicities.
12. Female patients who are pregnant or lactating
13. Any other clinically significant medical disease or psychiatric condition that, in the Investigator’s opinion, may interfere with protocol adherence or a patient’s ability to give informed consent.
14. Participation in any other clinical trial (with the exclusion of observational, non-interventional studies))

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
MM - Multiples Myelom

Medizinischer Befund
Multiple myeloma

MedDRA Term
Plasma cell myeloma

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Joachim Göthert

+49 (0)201 723-82530
joachim.goethert@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Universitätsklinikum Heidelberg

Einschlusskriterien
• Age ≥ 18 years
• Patients with Ph -chromosome and/or the BCR-ABL fusion gene (either b3a2 and/or b2a2) positive CML
• CML in CP having failed a prior attempt to stop imatinib or other TKIs therapy either within EURO-SKI or not
• Pretreatment at least one year with any TKI after 1st stop
• Written informed consent

Ausschlusskriterien
• Vorheriger hämatologischer Rückfall nach dem ersten TKI-Absetzversuch.
• Versagen jeglichen TKIs entsprechend den aktuellen ELN-Kriterien zu jeglicher Zeit während der CML-Behandlung.
• Vorherige geplante oder durchgeführte allogene Stammzell-transplantation.
• Entwicklung zur akzelerierten Phase oder Blastenkrise zu jeglicher Zeit in der Krankheitsgeschichte.
• Hohes Risiko für Herzerkrankungen entsprechend dem ESC score.
• Beeinträchtigte Herzfunktion oder einer der folgenden (Vor)Geschichten:
• Verwendung eines ventrikulär stimulierten Herzschrittmachers; angeborenes oder in der Familienanamnese vorkommendes Lang-QT-Syndrom; signifikante ventrikuläre oder Vorhof-Tachyarrhythmien in der Vergangenheit oder Gegenwart; klinisch signifikante Ruhe-Bradykardie ( 450 ms zu Studienbeginn, Myokardinfarkt vor Studienbeginn; andere klinisch signifikante Herzkrankheiten (beispielsweise instabile Angina pectoris, Herzinsuffizienz oder nicht beherrschbarer Bluthochdruck),
• Eine Behandlung mit CYP3A4-Inhibitoren oder mit Medi-kamenten, bei denen dokumentiert ist, dass diese die QT- Intervall verlängern, ist kontraindiziert,
• Eine akute Pankreatitis innerhalb eines Jahres vor Studienbeginn oder eine chronische Pankreatitis in der Vorgeschichte,
• Positiver serologischer Hepatitis B Virus Test oder HBV Infektion
• Alle anderen bösartige Erkrankungen, außer diese sind weder klinisch signifikant oder erfordern kein aktives Eingreifen,
• Schwerwiegende oder nicht beherrschbare medizinische Zustände (beispielsweise nicht beherrschbare Diabetes, akute oder chronische Lebererkrankungen, Bauchspeicheldrüsen- oder schwere Nierenerkrankung in keinem Zusammenhang mit einem Tumor, aktive oder nicht beherrschbare Infektionen),
• Frauen, die schwanger sind, stillen, oder im gebärfähigem Alter sind und keinen negativen Schwangerschaftstest zu Beginn der Studie aufweisen. Männliche oder weibliche Patienten im gebärfähigen Alter, die nicht bereit sind, eine wirksame Schwangerschaftsverhütungsmethode zu verwenden.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
CML - chronische myeloische Leukämie

Medizinischer Befund
CML-Patients in chronic phase having failed a prior attempt to stop imatinib or other TKIs therapy either within EURO-SKI or not and are pretreated at least one year with any TKI after 1st stop

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Joachim Göthert

+49 (0)201 723-82530
joachim.goethert@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

GWT-TUD GmbH, Dresden

Ausschlusskriterien
1. Andere Erstlinien Anti CML Behandlung als TKI Therapie (ausgenommen die Therpie mit Hydroxyurea).
2. Andre Zweitlinien-Therapien mit einem Tyrosinkinase Inhibitor (> 1 EMA zugelassener TKI gegen CML, oder jeder andere investigative von der EMA nicht zugelassene TKI)
3. Gleichzeitige Teilnahme an einer weiteren klinischen Prüfung mit einer anderen klinischen Prüfsubstanz innerhalb 4 Wochen vor Beginn und während der gesamten Dauer der Teilnahme an der PONS-Studie
4. Herzerkrankungen die nach NYHA den Klassen 3-4 zuzuordnen sind
5. Kardiale Symptome innerhalb der letzten 12 Monate vor Eintritt in die Studie: Patienten mit folgenden Kriterien sind für die Studie nicht geeignet:
? Krankengeschichte die eine instabile Angina Pectoris, Myocard-Infarkt , TIA, Schlaganfall, periphere arterielle Verschlusserkrankungen oder Lungenempolie aufweisen
? Krankengeschichte mit klinisch signifikanten ventrikulären Arrhythmien (wie zum Beispiel ventrikuläre Tachykardie, ventrikuläre Fibrillation, oder Torsades de pointes)
? Verlängerung des QTc Intervalls im EKG (>450 ms bei Männern, > 470 ms bei Frauen) nach der Friderica-Formel
? Herzinsuffizienz (NYHA Klasse III oder IV) innerhalb von 3 Monaten vor der ersten Dosis Ponatinib.
6. Patienten mit aktiven unkontrollierten psychischen Störungen, einschließlich von Psychosen, schweren Depressionen und bipolaren Störungen
7. Patienten mit unkontrollierter Hypertonie (definiert als anhaltender systolischer Blutdruck > 140 mmHg oder diastolisch > 90 mmHg)
8. Schwangere oder stillende Frauen sind ausgeschlossen.
9. Patienten, die in der Vergangenheit an einer Pankreatitis gelitten haben
10. Patienten in der akzelerierten oder in der Blastenphase, sowie Patienten, bei denen jemals/überhaupt die Blastenphase nachgewiesen werden konnte, sind von der Studie ausgeschlossen. Die von der Studie ausgeschlossenen CML-Phasen sind wie folgt definiert:
? Blastenphase: 30% Blasten oder mehr im peripheren Blut oder im Knochenmark
? Akzelerierte Phase der CML: Bestehen eines oder mehrerer der folgenden Kriterien:
? 15% Blasten im peripheren Blut oder im Knochenmark
? 20% Basophile im peripheren Blut oder im Knochenmark
? nicht Therapie-bedingte Thrombozytopenie < 100 x 109/L
? Nachgewiesene extramedulläre Blastenerkrankung außerhalb der Leber oder der Milz
? Klonale Evolution definiert als das Vorhandensein zusätzlicher Chromosomenannomalien außer dem Ph- Chromosom, wurde historisch als ein Kriterium für die Akzelerierte Phase einbezogen. Patienten jedoch, bei denen die klonale Evolution als einziges Kriterium für die akzelerierte Phase festgestellt wurde, haben eine signifikant bessere Prognose. Daher können Patienten mit klonaler Evolution als einzigem Kriterium für die akzelerierte Phase und keinerlei weiteren Kriterien, in die Studie aufgenommen werden, müssen aber separat analysiert werden.
11. Patienten, die eine Unverträglichkeit gegenüber dem Wirkstoff oder einem der anderen Bestandteile der Prüfsubstanz aufweisen.
12. Patienten, die aufgrund einer gerichtlichen oder verwaltungsbehördlichen Anordnung in einer Anstalt untergebracht sind
13. Patienten, die vom Sponsor, der Prüfstelle oder dem Prüfer anhängig sind,

Studienteilnehmende Mindestalter
18 Jahr(e)

Indikation
CML - chronische myeloische Leukämie

Medizinischer Befund
Adult patients (age = 18) with Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) who have proven to be resistant or intolerant to prior first line Tyrosine Kinase Inhibitor Treatment

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Joachim Göthert

+49 (0)201 723-82530
joachim.goethert@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Friedrich Schiller Universität, Jena

Ausschlusskriterien
- Allogene Stammzelltransplantation
- Bekannte Beeinträchtigung der Herzfunktion, einschließlich:
o kongenitales Long-QT-Syndrom
o Vorgeschichte/Vorliegen einer signifikanten ventrikulären oder atrialen Tachyarrhythmie
o Myokardinfarkt innerhalb 12 Monate vor Therapiestart
o QTc >450 msec im Screening EKG
o Vorliegen einer klinisch signifikanten oder symptomatischen Bradykardie
o Familiengeschichte von plötzlichem idiopathischen Tod
o Patienten mit Ruhe-QTcF =450 msec (männlich) oder =460 msec (weiblich) in der Vortherapie, oder unbestimmbaren QTcF Intervall
- Patienten mit unkorrigierter Hypokaliämie oder Hypomagnesämie
- Andere klinisch signifikante Herzerkrankung (z.B. instabile Angina pectoris, Herzdekompensation, unkontrollierter Bluthochdruck).
- Akute oder chronische virale Hepatitis mit moderater oder schwerer hepatischer Beeinträchtigung (Child-Pugh scores >6), auch wenn kontrolliert
- Andere derzeitige unkontrollierte Krankheiten (z.B. aktive oder unkontrollierte Infektionen, akute oder chronische Leber- oder Nierenerkrankungen), die zu einem inakzeptablen Sicherheitsrisiko führen können oder eine prüfplankonforme Durchführung gefährden
- Beeinträchtigte Magen-Darm-Funktion oder Erkrankungen, die die Absorption der Prüfmedikation beeinträchtigen können (z. B. Geschwür, unkontrollierte Übelkeit, Erbrechen und Durchfall, Malabsorptions-Syndrom, Dünndarm-Resektion oder Magen-Bypass).
- Bekannte akute oder chronische Pankreatitis
- Einnahme von Medikamenten, die bekanntermaßen zu einer starken Induktion oder Inhibition des CYP450-Isoenzyms CYP3A4 führen.
- Patienten mit Operation = 2 Wochen vor Start der Studienmedikation, oder ausstehender Erholung von Nachwirkungen einer solchen Operation
- Schwangere, stillende oder potentiell gebärfähige Patienten ohne Nutzung effektiver Verhütungsmethoden. Potentiell gebärfähige Patienten benötigen einen negativen Serum-Schwangerschaftstest innerhalb von 14 Tagen nach Studienstart. Postmenopausale
Patienten müssen bereits für mindestens 12 Monate amenorrhoisch sein um als nicht gebärfähig zu gelten. Alle Patienten müssen einer effektiven Verhütungsmethode während, sowie mind. 2 Wochen nach Absetzen der Studienmedikation, zustimmen. Es ist nötig, dass sexuell aktive Männer beim Geschlechtsverkehr während und bis 2 Wochen nach Beendigung der Einnahme der Studienmedikation Kondome verwenden und in diesem Zeitraum kein Kind zeugen. Ein Kondom muss ebenfalls von vasektomierten Männern verwendet werden, um den Übergang des Medikaments über die Samenflüssigkeit zu verhindern. Weiblichen Partnern von männlichen Patienten wird empfohlen, hochwirksame Methoden der Empfängnisverhütung zu verwenden.)
- Bekannte Infektion mit dem humanen Immundefizienzvirus (HIV). Die Testung ist nicht verpflichtend.
- Bekannte ernsthafte Hypersensitivität gegenüber Imatinib, Nilotinib oder Dasatinib
- Patienten mit einer malignen Erkrankung, die zurzeit klinisch signifikant ist oder zurzeit eine aktive Behandlung erfordert.
- Patenten, die nicht bereit oder nicht in der Lage sind, den Anforderungen des Prüfplans Folge zu leisten.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
CML - chronische myeloische Leukämie

Medizinischer Befund
CML

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Maher Hanoun

+49 (0)201 723-82530
maher.hanoun@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

GWT-TUD GmbH, Dresden

Einschlusskriterien
1. Adult patients, 18-75 years of age
2. Diagnosis of high risk MDS including oligoblastic non-proliferative (WBC <13 Gpt/l) AML up to 29% of bone marrow blasts
3. Bone marrow blasts = 5% (central morphology Düsseldorf)
4. IPSS score intermediate-2 or high
5. alloHCT intended within the next 6 months
6. ECOG performance status of 0 or 1
7. Signed informed consent
8. Laboratory values fulfilling all of the following:
- Serum creatinine < 2.0 mg/dL- Serum total bilirubin < 2.0 mg/dL
- Serum alanine aminotransferase or aspartate aminotransferase < 3 times the ULN9. Cardiac ejection fraction (LVEF) = 50% by echocardiography
10. Contraception:
- Female subjects of childbearing potential† must agree to use a medically acceptable method of contraception from signature of ICF (for at least 1 months prior to the first dose of CPX-351) and consent of female patients to use a medically acceptable method of contraception throughout the entire study period and for 6 months following the last dose of CPX-351. Medically acceptable methods of contraception that may be used by the patient include diaphragm and spermicide, intrauterine device (IUD), condom and vaginal spermicide, hormonal contraceptives (patients must be stable on hormonal contraceptives for at least the prior 3 months), surgical sterilization, or post-menopausal (=2 years of amenorrhea). Medically acceptable methods of contraception that may be used by the male partner of a female patient are condom and spermicide or vasectomy (>6 months prior to Day-1) and are to be used throughout the entire study period and for 6 months following the last dose of CPX-351.
- Male patients must be willing to refrain from sperm donation for 6 months following the last dose of CPX-351 and must use adequate contraception throughout the entire study period and for 6 months following the last dose of CPX-351.
- Combined oral contraceptive pills are not recommended. It is recommended that during the study two medically accepted methods of contraception (e.g. as hormonal contraceptive methods along with a condom) apply.

†A female subject or a female partner of a male subject is considered to have childbearing potential unless she meets at least one of the following criteria: Age =50 years and naturally amenorrhoeic for = 1 year (amenorrhoea following cancer therapy does not rule out childbearing potential), premature ovarian failure confirmed by a specialist gynecologist, previous bilateral salpingo-oophorectomy or hysterectomy, XY genotype, Turner syndrome or uterine agenesis.

Ausschlusskriterien
1. Patients with history of myeloproliferative neoplasms (MPN) (defined as a history of essential thrombocytosis or polycythemia vera, or idiopathic myelofibrosis prior to the diagnosis of AML) or combined MDS/MPN are not eligible.
2. WHO-2016 defined AML entities: AML with t(15;17), PML-RARA; AML with t(8;21), RUNX1-RUNX1T1, AML with inv(16)/t(16;16), CBFß-MYH11; AML with biallelic CEBPA mutation; AML with mutated FLT3 or NPM1.
3. Clinical evidence of active CNS leukaemia (assessment of CSF is not mandatory for screening).
4. Patients with a “currently active” second malignancy other than non-melanoma skin cancers. Patients are not considered to have a “currently active” malignancy if they have completed therapy more than 2 years ago and are disease free.
5. Any major surgery or radiation therapy within four weeks prior screening.
6. Patients with prior treatment of either CPX-351, hypomethylating agents, cytarabine or intensive chemotherapy for high-risk MDS or AML.
7. Patients with prior cumulative anthracycline exposure of greater than 368 mg/m2 daunorubicin (or equivalent).
8. Recent (<30 days) or planned live vaccinations during the clinical trial
9. Any serious medical condition, laboratory abnormality or psychiatric illness that would prevent obtaining informed consent.
10. Creatinine clearance < 30 ml/min
11. Active or uncontrolled infection. Patients with an infection receiving treatment (antibiotic, antifungal or antiviral treatment) may be entered into the study but must be afebrile and hemodynamically stable for =72 hrs.
12. Current evidence of invasive fungal infection (blood or tissue culture); patients with recent fungal infection must have a subsequent negative cultures to be eligible; known HIV (new testing not required) or evidence of active hepatitis B or C infection (with rising transaminase values).
13. Hypersensitivity to cytarabine, daunorubicin or liposomal products.
14. History of Wilson’s disease or other copper-metabolism disorder, unless the therapy outweighs the risks.15. Female patients who are pregnant or lactating.

Studienteilnehmende Mindestalter
18 Jahr(e)

Studienteilnehmende Höchstalter
75 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
MDS - Myelodysplastisches Syndrom, AML - Akute myeloische Leukämie

Medizinischer Befund
Untreated patients with higher risk MDS and oligoblastic AML eligible and intended for allogeneic HCT within the next 6 months

MedDRA Term
Acute myeloid leukemia, Myelodysplastic syndromes

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Joachim Göthert

+49 (0)201 723-82530
joachim.goethert@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

AOP Orphan Pharmaceuticals AG, Wien

Einschlusskriterien
1. Patients who receive ropeginterferon alfa-2b in the frame of clinical routine and according to its approved labelling: monotherapy in adults (≥ 18 years old) for the
treatment of PV without symptomatic splenomegaly and according to the recommendations in the product information for ropeginterferon alfa-2b (Annex 1)
2. Patient’s medical history is available
3. Patient provides written informed consent prior to study entry

Ausschlusskriterien
1. Patients with any contraindication to ropeginterferon alfa-2b treatment according to the product information for ropeginterferon alfa-2b (Annex 1)
2. Patients involved in any study with another investigational product or therapy (in the prior 30 days)
3. Previous ropeginterferon alfa-2b treatment
4. Patient is a family member or employee of the Investigator

Indikation
MPN - Myeloproliferative Neoplasie

Medizinischer Befund
Polycythämia Vera

Institut
Klinik für Hämatologie und Stammzelltransplantation

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Alexander Röth

+49 (0)201 723-82530
alexander.roeth@uk-essen.de

Hufelandstraße 55
45147 Essen

Indikation
PNH - Paroxysmale nächtliche Hämoglobinurie

Institute
Klinik für Hämatologie und Stammzelltransplantation, WTZMS - Westdeutsches Tumorzentrum Münster

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Alexander Carpinteiro

+49 (0)201 723-82530
alexander.carpinteiro@uk-essen.de

Hufelandstr 55
45147 Essen

Sponsor

Caelum Biosciences, Inc., USA

Einschlusskriterien
Key Inclusion Criteria:
1. AL amyloidosis stage IIIa based on the European Modification of the 2004 Standard Mayo Clinic Staging who also have NT-proBNP ≥ 650 ng/L at the time of Screening.
2. Measurable hematologic disease at Screening as defined by at least one of the following:
a. dFLC > 4 mg/dL or
b. iFLC > 4 mg/dL with abnormal Kappa/Lambda ratio or
c. SPEP m-spike > 0.5 g/dL
3. Histopathological diagnosis of amyloidosis based on polarizing light microscopy of green bi-refringent material in Congo red stained tissue specimens AND confirmation of AL derived amyloid deposits by at least one of the following:
a. Immunohistochemistry/Immunofluorescence
b. Mass spectrometry or
c. Characteristic electron microscopy appearance/Immunoelectron microscopy
4. Cardiac involvement as defined by:
a. Documented clinical signs and symptoms supportive of a diagnosis of heart failure in the setting of a confirmed diagnosis of AL amyloidosis in the absence of an alternative explanation for heart failure
AND
b. At least one of the following:
i. Endomyocardial biopsy demonstrating AL cardiac amyloidosis or
ii. Echocardiogram demonstrating a mean left ventricular wall thickness (calculated as [IVSd+LPWd]/2) of > 12 mm at diastole in the absence of other causes (e.g., severe hypertension, aortic stenosis), which would adequately explain the degree of wall thickening or
iii. Cardiac MRI with gadolinium contrast agent diagnostic of cardiac amyloidosis
5. Planned first-line treatment for plasma cell dyscrasia is a cyclophosphamide-bortezomib-dexamethasone (CyBorD)-based regimen administered as SoC
6. WOCBP must have a negative pregnancy test during Screening and must agree to use highly effective contraception (Section 6.9) from Screening to at least 5 months following the last study drug administration or 12 months following the last dose of her PCD therapy, whichever is longer
7. Men must be surgically sterile or must agree to use highly effective contraception and refrain from donating sperm from Screening to at least 5 months following the last study drug administration or 12 months following the last dose of their PCD therapy, whichever is longer

Ausschlusskriterien
1. Have any other form of amyloidosis other than AL amyloidosis
2. Received prior therapy for AL amyloidosis or multiple myeloma. A maximum exposure of 2 weeks of a CyBorD-based PCD treatment after screening laboratory samples are obtained and prior to randomization is allowed.
3. Has POEMS syndrome or multiple myeloma defined as clonal bone marrow plasma cells > 10% from a bone marrow biopsy (performed = 3 months prior to signing the ICF or during screening) or biopsy proven (performed = 3 months prior to signing the ICF or during screening) bony or extramedullary plasmacytoma AND any one or more of the following CRAB features:
a. Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder (e.g., multiple myeloma and POEMS syndrome), specifically:
i. Hypercalcemia: serum calcium > 0.25 mmol/L (> 1 mg/dL) higher than the ULN or > 2.75 mmol/L (> 11 mg/dL) OR
ii. Renal insufficiency: creatinine clearance 177 mol/L (> 2 mg/dL) OR
iii. Anemia: hemoglobin value of > 20g/L below the lowest limit of normal, or a hemoglobin value < 100 g/L OR
iv. Bone lesions: one or more osteolytic lesion on imaging tests (performed = 3 months prior to signing the ICF or during screening): skeletal radiography, CT, or PET/CT, or MRI. If bone marrow has < 10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement OR
b. Any one of the following biomarkers of malignancy:
i. 60% or greater clonal plasma cells on bone marrow examination OR
ii. More than one focal lesion on MRI that is at least 5mm or greater in size
4. Have supine systolic blood pressure 30 mmHg despite medical management (e.g., midodrine, fludrocortisones) in the absence of volume depletion

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
AL-Amyloidose

Medizinischer Befund
stage IIIa cardiac AL amyloidosis

MedDRA Term
Cardiac amyloidosis

Institute
Klinik für Hämatologie und Stammzelltransplantation, WTZMS - Westdeutsches Tumorzentrum Münster

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Alexander Carpinteiro

+49 (0)201 723-82530
alexander.carpinteiro@uk-essen.de

Hufelandstr 55
45147 Essen

Sponsor

Caelum Biosciences, Inc., USA

Einschlusskriterien
1. AL amyloidosis stage IIIb based on the European Modification of the 2004 Standard Mayo Clinic Staging at the time of Screening, which includes NT-proBNP > 8,500 ng/L.
2. Measurable hematologic disease at Screening as defined by at least one of the following:
a. Involved/uninvolved free light chain difference (dFLC) > 4 mg/dL OR
b. Involved free light chain (iFLC) > 4 mg/dL with abnormal Kappa/Lambda ratio OR
c. Serum protein electrophoresis (SPEP) m-spike > 0.5 g/dL
3. Histopathological diagnosis of amyloidosis based on polarizing light microscopy of green bi-refringent material in Congo red stained tissue specimens AND confirmation of AL derived amyloid deposits by at least one of the following:
a. Immunohistochemistry/Immunofluorescence OR
b. Mass spectrometry OR
c. Characteristic electron microscopy appearance/Immunoelectron microscopy
4. Cardiac involvement as defined by:
a. Documented clinical signs and symptoms supportive of a diagnosis of heart failure in the setting of a confirmed diagnosis of AL amyloidosis in the absence of an alternative explanation for heart failure
AND
b. At least one of the following:
i. Endomyocardial biopsy demonstrating AL cardiac amyloidosis OR
ii. Echocardiogram demonstrating a mean left ventricular wall thickness (calculated as [IVSd+LPWd]/2) of > 12 mm at diastole in the absence of other causes (e.g., severe hypertension, aortic stenosis), which would adequately explain the degree of wall thickening OR
iii. Cardiac magnetic resonance imaging (MRI) with gadolinium contrast agent diagnostic of cardiac amyloidosis
5. Planned first-line treatment for plasma cell dyscrasia is cyclophosphamide-bortezomib-dexamethasone (CyBorD)-based regimen administered as SoC.
6. Women of childbearing potential (WOCBP) must have a negative pregnancy test during Screening and must agree to use highly effective contraception from Screening to at least 5 months following the last study drug administration or 12 months following the last dose of her anti-PCD therapy, whichever is longer
7. Men must be surgically sterile or must agree to use highly effective contraception and refrain from donating sperm from Screening to at least 5 months following the last study drug administration or 12 months following the last dose of their PCD therapy, whichever is longer

Ausschlusskriterien
1. Have any other form of amyloidosis other than AL amyloidosis
2. Received prior therapy for AL amyloidosis or multiple myeloma. A maximum exposure of 2 weeks of a CyBorD-based PCD treatment after Screening laboratory samples are obtained and prior to randomization is allowed.
3. Has POEMS syndrome OR multiple myeloma defined as clonal bone marrow plasma cells > 10% from a bone marrow biopsy (performed = 3 months prior to signing the ICF or during Screening) OR biopsy-proven (performed = 3 months prior to signing the ICF or during Screening) bony or extramedullary plasmacytoma AND any one or more of the following CRAB features:
a. Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, (e.g. multiple myeloma and PEOMS syndrome) specifically:
i. Hypercalcemia: serum calcium > 0.25 mmol/L (> 1 mg/dL) higher than the ULN or > 2.75 mmol/L (> 11 mg/dL) OR
ii. Renal insufficiency: creatinine clearance 177 µmol/L (> 2 mg/dL) OR
iii. Anemia: hemoglobin value of > 20 g/L below the lowest limit of normal, or a hemoglobin value < 100 g/L OR
iv. Bone lesions: one or more osteolytic lesion on imaging tests (performed = 3 months prior to signing the ICF or during Screening): skeletal radiography, CT, or PET/CT, or MRI. If bone marrow has < 10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement OR
b. Any one of the following biomarkers of malignancy:
i. 60% or greater clonal plasma cells on bone marrow examination OR
ii. More than one focal lesion on MRI that is at least 5mm or greater in size
4. Have supine systolic blood pressure 30 mmHg despite medical management (e.g., midodrine, fludrocortisones) in the absence of volume depletion

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
AL-Amyloidose

Medizinischer Befund
stage IIIb cardiac AL amyloidosis

MedDRA Term
Cardiac amyloidosis

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum, WTZMS - Westdeutsches Tumorzentrum Münster

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Maher Hanoun

+49 (0)201 723-82530
maher.hanoun@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Technische Universität Dresden

Einschlusskriterien
Alle Phasen:
 unterschriebene Einwilligungserklärung nach Aufklärung,
 ECOG 0-2,
 Lebenserwartung > 14 Tage,
 Adäquate Leber- und Nierenfunktion
o ALAT/ASAT ≤ 2.5 x ULN;
o Bilirubin < 2 x ULN;
o Creatinin 40 mL/min
Leukozytenzahl < 30 x 109/L. (Hinweis: Hydroxyharnstoff ist erlaubt, um
dieses Kriterium zu erfüllen)
zusätzlich Phase-II-Teil (MAGNOLIA):
 neudiagnostizierte AML nach WHO-Kriterien und entweder
o t(8;21)/RUNX1-RUNX1T1 oder
o inv(16) oder
o t(16;16)/CBFB-MYH11
 Männer und Frauen im Alter von 18 bis ≤ 70 Jahren.
zusätzlich Phase II Studie (MAGMA):
 neudiagnostizierte AML nach WHO-Kriterien und entweder
o FLT3-ITD oder
o FLT3-TKD,
o Negativität für Mutationen im CBF-Gen (z.B. t(8;21)/RUNX1-
RUNX1T1 or inv(16) or t(16;16)/CBFB-MYH11)
 Männer und Frauen im Alter von 18 bis ≤ 70 Jahren,
CAVE: Patienten mit CBF-/FLT3-Co-Mutation werden dem Studienteil
MAGNOLIA zugeordnet.

Ausschlusskriterien
Alle Phasen:
· vorangegangene antineoplastische AML-Therapien, außer
Hydroxyharnstoff,
· vorangegangene Behandlung mit Anthrazyklinen,
· ZNS-Beteiligung,
· Unkontrollierte Infektion,
· Einnahme starker Induktoren von CYP3A4/5, die nicht vor
Studieneinschluss abgesetzt oder ersetzt werden können.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
AML - Akute myeloische Leukämie

Medizinischer Befund
Patienten mit neudiagnostizierter akuter myeloischer Leukämie (AML) und\nzytogenetischen Anomalien bzw. Fusionstranskript der Core-binding-factor-\nGene (CBF) oder eine FLT3-Mutation, die für eine kurative intensive\nErstlinientherapie geeignet sind

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Bastian von Tresckow

+49 (0)201 723-82530
bastian.vontresckow@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Genmab A/S, Dänemark

Einschlusskriterien
1. Patient must be 18 years of age or older. Note: In countries where the legal age is 21 years of
age; only patients 21 years of age or older are eligible.
2. Criterion modified as per Amendment 8
2.1 Patient must meet the following entry criteria for the applicable expansion or
optimization cohort:
a. For expansion part R/R aNHL cohort:
i. Documented CD20+ mature B-cell neoplasm according to WHO classification
(Swerdlow et al., 2016) or WHO classification 2008 based on representative
pathology report
1. Diffuse large B-cell lymphoma (de novo or transformed from all indolent
subtypes including Richter’s transformation), including:
a. Patients with “double-hit” or “triple-hit” DLBCL (technically classified in
WHO 2016 as HGBCL, with MYC and BCL2 and/or BCL6 translocations)
Note: Other double-/triple-hit lymphomas are not eligible
2. Other aggressive B-NHL (beginning in Stage 2):
a. Primary mediastinal (thymic) large B-cell lymphoma (PMBCL)
b. High-grade B-cell lymphoma
c. Follicular lymphoma grade 3B (FL 3B)
ii. Relapsed or refractory disease and previously treated with at least 2 lines of systemic
antineoplastic therapy including at least 1 anti-CD20 monoclonal antibodycontaining
therapy
Note: Relapsed disease is defined as disease that has recurred ≥6 months after
completion of therapy. Refractory disease is defined as disease that either progressed
during therapy or progressed within 6 months (<6 months) of completion of therapy.
iii. Either failed prior autologous hematopoietic stem cell transplantation (HSCT), or
ineligible for autologous HSCT due to age, ECOG performance status,
comorbidities, and/or insufficient response to prior treatment
b. For expansion part R/R iNHL cohort:
i. Documented CD20+ mature B-cell neoplasm according to WHO classification
Swerdlow et al., 2016 (Swerdlow et al., 2016) or WHO classification 2008 based on
representative pathology report
1. Histologic confirmed FL grade 1, 2, or 3A at initial diagnosis without clinical or
pathological evidence of transformation
2. Marginal zone lymphomas (nodal, extranodal, and splenic)
3. Small lymphocytic lymphoma
ii. Relapsed or refractory disease and previously treated with at least 2 lines of systemic
antineoplastic therapy including at least 1 anti-CD20 monoclonal
antibody-containing therapy
Note: Relapsed disease is defined as disease that has recurred ≥6 months after
completion of therapy. Refractory disease is defined as disease that either progressed
during therapy or progressed within 6 months (<6 months) of completion of therapy.
iii. Previously treated with an alkylating agent or lenalidomide
iv. Relapsed or refractory to the last prior line therapy. Previous lymphoma therapy is
defined as 1 of the following: At least 2 months of single-agent therapy, at least
2 consecutive cycles of combination therapy, autologous HSCT,
immunomodulatory therapy, or radioimmunotherapy
c. For expansion part R/R MCL cohort:
i. Documented CD20+ MCL according to WHO classification (Swerdlow et al., 2016)
or WHO classification 2008 based on representative pathology report with either
cyclin D1 overexpression or presence of the translocation t(11;14).
ii. Stage II-IV with a need for treatment.
iii. Previously treated with at least 2 prior lines of systemic antineoplastic therapy
including at least 1 prior anti-CD20 mAb-containing regimen.
iv. Previously treated with a BTKi and either progressing (relapsed or refractory) or
intolerant to BTKi
v. Relapsed or refractory to the most recent line of therapy.
Note: Relapsed disease is defined as disease that has recurred ≥6 months after
completion of therapy. Refractory disease is defined as disease that either progressed
during therapy or progressed within 6 months (<6 months) of completion of therapy.
vi. Bridging therapy to reduce tumor burden should be considered for patients with
leukemic disease or high burden of disease due to likely increased risk of severe
CRS in these patients. Additional corticosteroid prophylaxis for CRS should also be
considered for such patients during the first cycle.
d. Criterion modified as per Amendment 8
d.1 Criterion modified as per Amendment 9
d.2 Criterion applies to optimization part subjects only: subjects must have
documented CD20+ DLBCL, NOS (de novo or transformed from FL) (for
DLBCL cohort), FL Grade 1, 2, or 3A (for FL cohort), or, only if cohort is
opened: MCL (for MCL cohort), according to WHO 2016 classification
3. Measurable disease:
a. Fluorodeoxyglucose (FDG)-avid lymphomas: Measurable disease with computerized
tomography (CT) (or magnetic resonance imaging [MRI]) scan with involvement of
2 or more clearly demarcated lesions/nodes with a long axis >1.5 cm and short axis
>1.0 cm (or 1 clearly demarcated lesion/node with a long axis >2.0 cm and short axis
≥1.0 cm) AND FDG positron emission tomography (PET) scan that demonstrates
positive lesion(s) compatible with CT (or MRI) defined anatomical tumor sites
b. FDG-nonavid lymphomas: Measurable disease with CT (or MRI) scan with
involvement of 2 or more clearly demarcated lesions/nodes with a long axis >1.5 cm
and short axis >1.0 cm or 1 clearly demarcated lesion/node with a long axis >2.0 cm
and short axis ≥1.0 cm.
4. Criterion modified as per Amendment 8
4.1 ECOG performance status 0, 1, or 2 (see Appendix 5). For MCL: ECOG PS <2
required for participation.
5. Criterion modified as per Amendment 9
5.1 Lymphocyte counts <5×109/L. For MCL subjects with leukemic disease: lymphocyte
counts <50×109/L at screening; however, lymphocyte counts must be reduced to below
<10×109/L before C1D1 (first epcoritamab dose administration) by any cytoreductive
treatment, including leukapheresis.
6. Platelet counts ≥75×109/L or, in the presence of bone marrow involvement or splenomegaly,
≥50×109/L
7. Absolute neutrophil counts ≥1.0×109/L; growth factor support allowed in case of bone marrow
involvement
8. Criterion modified as per Amendment 8
8.1 Patient must meet the following criteria regarding time since previous anti-neoplastic
agent(s):
a. At least 4 weeks from last dose of non-investigational systemic chemotherapy (except
when used as bridging therapy during screening in MCL cohort)
b. At least 4 weeks or 5 half-lives from last dose of other non-investigational
antineoplastic agents, whichever is shorter (except any anti-CD20 mAb or BTKi)
c. At least 5 half-lives from last dose of investigational agents except for prior chimeric
antigen receptor T-cell (CAR-T) therapy from which 30 days must pass prior to first epcoritamab administration.
9. Resolution of toxicities from prior therapy to a grade that does not contraindicate trial
participation in the opinion of the investigator
10. Criterion modified as per Amendment 8
10.1 If receiving glucocorticoid treatment at screening, must be a maximum daily dose of
prednisone 10 mg (or equivalent) and a total of no more than 140 mg over the last 14
days prior to the first dose of epcoritamab, unless for disease control
11. Before the first dose of epcoritamab, during the trial and for 12 months after last
administration of epcoritamab, a woman must be either:
a. Not of childbearing potential*: premenarchal; postmenopausal (>45 years of age with
amenorrhea for at least 12 months or any age with amenorrhea for at least 6 months
and a serum follicle stimulating hormone [FSH] level >40 IU/L or mIU/mL);
permanently sterilized (e.g., bilateral tubal occlusion [which includes tubal ligation
procedures as consistent with local regulations], hysterectomy, bilateral salpingectomy,
bilateral oophorectomy); or otherwise be incapable of pregnancy
b. Of childbearing potential and practicing a highly effective method of birth control (as
defined by the EU Clinical Trial Facilitation Group) consistent with local regulations
regarding the use of birth control methods for patients participating in clinical trials:
e.g., established use of oral, injected or implanted combined (estradiol and
progesterone containing) hormonal contraception; placement of an intrauterine device
(IUD) or intrauterine system (IUS); male partner sterilization (the vasectomized partner
should be the sole partner for that patient); true abstinence (when this is in line with the
preferred and usual lifestyle of the patient)
*If the childbearing potential changes after start of the trial (e.g., woman who is not
heterosexually active becomes active, premenarchal woman experiences menarche) a
woman must begin a highly effective method of birth control, as described under 31b.
12. A man who is sexually active with a woman of childbearing potential must agree to use a
barrier method of birth control (that is the use of condom) during the trial and for 12 months
after receiving the last dose of epcoritamab
13. Women must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction
during the trial and for 12 months after receiving the last dose of epcoritamab. Men must also
not donate sperm during the trial and for 12 months after receiving the last dose of epcoritamab
14. The patient understands the purpose of the trial and procedures required for the trial and is
capable of giving signed informed consent as which includes compliance with the requirements
and restrictions listed in the informed consent form (ICF) and in this protocol
15. The patient must consent to provide sample(s) for evaluation of DNA.
16. Life expectancy >3 months on SOC treatment.
17. Access to intensive care management for treatment of CRS symptoms (ie, hypotension and/or
hypoxia), if required.

Ausschlusskriterien
1. Primary central nervous system (CNS) lymphoma or CNS involvement by lymphoma at
screening as confirmed by mandatory magnetic resonance imaging (MRI)/computed
tomography (CT) scan (brain) and, if clinically indicated, by lumbar puncture.
2. Known past or current malignancy other than inclusion diagnosis, except for:
a. Cervical carcinoma of Stage 1B or less.
b. Non-invasive basal cell or squamous cell skin carcinoma.
c. Non-invasive, superficial bladder cancer.
d. Prostate cancer with a current PSA level <0.1 ng/mL.
e. Any curable cancer with a complete response (CR) of >2 years duration
3. AST, and/or ALT >3 × upper limit of normal
4. Total bilirubin >1.5 × upper limit of normal, unless bilirubin rise is due to Gilbert’s
syndrome or of non-hepatic origin
5. Criterion modified as per Amendment 8
5.1 Estimated CrCl <45 mL/min (see Appendix 1)
6. Criterion modified as per Amendment 8
6.1 Criterion modified as per Amendment 9
6.2 Known clinically significant cardiovascular disease, including:
• Onset of unstable angina pectoris within 6 months of signing ICF
• Acute myocardial infarction within 6 months of signing ICF
• Congestive heart failure (grade III or IV as classified by the New York Heart
Association (see Appendix 2) and/or known decrease ejection fraction of <45%
• Stroke or intracranial hemorrhage within 6 months prior to signing ICF
• In case of any history of cardiovascular disease, a cardiology consult is required
within 60 days of enrollment.
• For patients who are =75 years old, 2 or more active cardiovascular diseases (any
type, = Grade 2) (MCL only)
7. Criterion modified as per Amendment 8
7.1 Ongoing active bacterial, viral, fungal, mycobacterial, parasitic, or other infection
requiring systemic treatment (excluding prophylactic treatment) at the time of
enrolment or within the previous 2 weeks prior to the first dose of epcoritamab,
including COVID-19 infection. Note that a past COVID-19 infection may be a risk
factor, but if resolved and the subject is vaccinated, it may be allowable to enroll the
subject
8. Confirmed history or current autoimmune disease or other diseases resulting in permanent
immunosuppression or requiring permanent immunosuppressive therapy. Low-dose (=10 mg/day) prednisolone (or equivalent) for rheumatoid arthritis or similar conditions is
allowed
9. Seizure disorder requiring therapy (such as steroids or anti-epileptics)
10. Any prior therapy with an investigational bispecific antibody targeting CD3 and CD20
11. Prior treatment with chimeric antigen receptor T-cell (CAR-T) therapy within 30 days prior
to first epcoritamab administration
12. Eligible for curative intensive salvage therapy followed by high dose chemotherapy with
HSCT rescue
13. Autologous HSCT within 100 days prior to first epcoritamab administration, or any prior
allogeneic HSCT or solid organ transplantation
14. Criterion modified as per Amendment 8
15. Criterion modified as per Amendment 8
15.1 Known human immunodeficiency virus (HIV) infection; HIV testing is required at
screening only if required per local health authorities or institutional standards.
16. Criterion modified as per Amendment 8
16.1 Exposed to live or live attenuated vaccine within 4 weeks prior to signing ICF;
Examples of live vaccines include, but are not limited to, the following: measles,
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
Calmette–Guérin, and typhoid vaccine. Seasonal influenza vaccines for injection are
generally killed virus vaccines and are allowed; however, intranasal influenza
vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
Experimental and/or non authorized SARS-CoV-2 vaccinations are not allowed.
17. Pregnancy or breast feeding
18. Criterion modified as per Amendment 8
18.1 Patient is known or suspected of not being able to comply with the study protocol (eg,
because of alcoholism, drug dependency, or psychological disorder) or has any
condition for which, in the opinion of the sponsor or investigator, participation would
not be in the best interest of the patient (e.g., could compromise their well-being) or
that could prevent, limit, or confound the protocol-specified assessments
19. Contraindication to all uric acid lowering agents

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
DLBCL - Diffuses großzelliges B-Zell-Lymphom

Medizinischer Befund
• Aggressive relapsed or refractory B-NHL (aNHL cohort) including:\n• Diffuse large B-cell lymphoma (DLBCL)\n• High grade B-cell lymphoma (HGBCL)\n• Primary mediastinal B-cell lymphoma (PMBCL)\n• Follicular lymphoma (FL) grade 3B\n• Indolent relapsed or refractory B-NHL (iNHL cohort) including:\n• FL grades 1-3A\n• Marginal zone lymphoma (MZL)\n• Small lymphocytic lymphoma (SLL)\n• Mantle cell lymphoma (MCL)

MedDRA Term
B-cell lymphoma refractory

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Alexander Röth

+49 (0)201 723-82530
alexander.roeth@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Klinikum Stuttgart

Einschlusskriterien
1. Immunkompetente Patienten und Patientinnen mit Erstdiagnose eines primären B-Zell- Lymphoms (DLBCL) des zentralen Nervensystems
2. Patienten und Patientinnen Alter 18-65 Jahre unabhängig vom ECOG oder 66-70 Jahre mit ECOG Performance Status ≤ 2
3. Histologisch oder zytologisch gesicherte Diagnose eines primären B-Zell-Lymphoms des zentralen Nervensystems durch den lokalen Pathologen. Diagnosensicherung mittels stereotaktischer oder offener Biopsie, Liquorzytologie oder Vitrektomie
4. Krankheit ausschließlich lokalisiert in ZNS, Liquor oder den Hirnnerven.
5. Mindestens eine messbare Läsion
6. Patienten ohne Vorbehandlung (eine bereits erfolgte oder noch andauernde Behandlung mit Steroiden ist erlaubt)
7. Unterzeichnung der Einwilligungserklärung entsprechend den internationalen Richtlinien und der nationalen Gesetzgebung durch den Patienten oder einen autorisierten gesetzlichen Vertreter – für den Fall, dass der Patient krankheitsbedingt nicht in der Lage dazu ist.
8. Die Fähigkeit, die Art der Studie und deren Inhalte zu verstehen
9. Sexuell aktive Patienten und Patientinnen im fortpflanzungs-fähigen Alter, die zugestimmt haben, während Ihrer gesamten Studienteilnahme adäquat zu verhüten

Ausschlusskriterien
1. Kongenitale oder erworbene Immunschwäche einschließlich HIV-Infektion und Organtranplantationen in der Vergangenheit.
2. Systemische Lymphom-Manifestation (außerhalb des ZNS)
3. Isoliertes okuläres Lymphom ohne Manifestation im Hirnparenchym oder im Rückenmark
4. Andere bösartige Erkrankungen; ausgenommen sind chirurgisch entfernte Karzinome in situ der Zervix, Karzinome der Haut und andere bösartige Tumoren, die sich seit mindestens 5 Jahren in kompletter Remission befinden.
5. Diagnostiziertes Non-Hodgkin Lymphom in der Vergangenheit
6. Inadäquate renale Funktion (Kreatinin-Clearance < 60 ml/min).
7. Inadequates Knochenmark, inadäquate kardiale Leistung, inadäquate Leber- oder Lungenfunktion gemäß Einschätzung Prüfer/Prüferin
8. Active hepatitis B or C Erkrankung.
9. Laufende Behandlung mit anderen Studienmedikamenten oder Teilnahme an einer klinischen Studie innerhalb der letzten 30 Tage vor Beginn dieser Studie.
10. Flüssigkeitsansammlung im 3. Raum > 500 ml.
11. Überempfindlichkeit gegenüber der Studienmedikation oder einen anderen Bestandteil der Behandlung.
12. Einnahme von Medikamenten, die mit großer Wahrscheinlichkeit zu Wechselwirkungen mit der Studienmedikation führen
13. Bekannter oder anhaltender Missbrauch von Arzneimitteln, Drogen oder Alkohol
14. Nicht geschäftsfähiger Patient ,der Art, Bedeutung und Konsequenzen der Studie nicht erfassen und verstehen kann und keinen gesetzlichen Betreuer hat.
15. Teilnahme an der Vorgängerstudie Matrix
16. Personen, die sich in einem Abhängigkeitsverhältnis zum Sponsor und/oder Prüfarzt/Prüfärztin befinden
17. Jeglicher familiärer, soziologischer oder geographischer Umstand, der potentiell die ordnungsgemäße protokollgerechte Durchführung der Studie und der Nachbeobachtung gefährdet
18. Bestehende oder geplante Schwangerschaft, Stillzeit
19. Geschlechtsreife Patienten, die sich weigern, für die Dauer der Studienteilnahme Verhütungsmittel zu verwenden: Intrauterinpassar; Hormonverhütung in Verbindung mit einer mechanischen Verhütungsmethode

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
ZNS - Lymphom mit Befall des zentralen Nervensystems

Medizinischer Befund
Primäres diffuses großes B-Zell-Lymphom (DLBCL) des zentralen Nervensystems ist eine seltene Erkrankung der zerebalen Parenchyma, Leptomeninges, der Augen oder des Rückenmarks. Sie macht 4-6% aller Non-Hodgkin Lymphome (NHL) und 3-4% aller primären Hirntumore aus. Die Inzidenz von PZNSL ist in den vergangenen 30 Jahren angestiegen vor allem bei immunkompeten Patienten. Die durchschnittliche Überlebensrate bei unbehandelten Patienten liegt bei 3 Monaten.

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Joachim Göthert

+49 (0)201 723-82530
joachim.goethert@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Universitätsklinikum Jena

Einschlusskriterien
1. Adult patients (age ≥18 years) with CML in any phase who are initiating ponatinib monotherapy, or for whom ponatinib monotherapy was initiated after ponatinib approval in Germany. [The decision to prescribe ponatinib must have been made prior to enrolment in the study. Patients enrolled in the retrospective part of the study may or may not be still on ponatinib treatment at the time informed consent is given. These retrospective patients should have started treatment after 02.02.2015.].
2. Patients who have the ability to understand the requirements of the study, and provide written informed consent to comply with the study data collection procedures.
3. Patients with a minimum life expectancy of 3 months

Ausschlusskriterien
Patients are not eligible for participation in the study if they meet any of the following exclusion criteria:
1. Patients previously treated with investigational ponatinib (within a clinical trial)
2. Patients receiving an investigational agent
4. Patients who are pregnant and/or breastfeeding
5. Patients unable to sign the informed consent

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
CML - chronische myeloische Leukämie

Medizinischer Befund
Chronic Myeloid Leukemia, Chronic Phase

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Dr. med. Julia von Tresckow

+49 (0)201 723-82530
julia.vontresckow@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Incyte Corporation, DE, USA

Einschlusskriterien
1. Age ≥ 18 years. For Japan, aged 20 years or older at the time of signing the ICF.
2. Ability to comprehend and willingness to sign a written ICF for the study.
3. Histologically confirmed Grade 1, 2, or 3a FL or histologically confirmed nodal MZL, splenic MZL, or extranodal MZL (CD19+ and CD20+ by flow cytometry or immunohistochemistry) as assessed locally (Swerdlow et al 2016).
Note: Participants with gastric MZL and evidence of Helicobacter pylori must have a documented nonresponse to antibiotic therapy.
4. Willingness to avoid pregnancy or fathering children based on the criteria below.
a. Male participants with reproductive potential must agree to take appropriate precautions to avoid fathering children (with at least 99% certainty) from screening through 180 days (6 months) after the last dose of study treatment, even if they have undergone a successful vasectomy, and must refrain from donating sperm during this period. Permitted methods that are at least 99% effective in preventing pregnancy (see Appendix A) should be communicated to the participants and their understanding confirmed.
b. WOCBP participants:
− Must commit either to abstain continuously from heterosexual sexual intercourse or agree to take appropriate precautions to avoid pregnancy (by using 2 different methods of birth control: one with at least 99% certainty and an additional effective [barrier] method) starting at least 4 weeks before taking the study treatment, while taking the study treatment, during breaks (dose interruptions), and for at least 180 days (6 months) after stopping the study treatment. Permitted methods that are at least 99% effective in preventing pregnancy and the permitted additional effective (barrier) methods (see Appendix A) should be communicated to the participants and their understanding confirmed.
Note: Because of the increased risk of venous thromboembolism, combined oral contraceptive pills are not recommended. If a participant is currently using combined oral contraception, the participant should switch to one of the effective methods listed in Appendix A. The risk of venous thromboembolism continues for 4 to 6 weeks after discontinuing combined oral contraception.
− Must have a negative serum pregnancy test at screening (within 10-14 days of the first study drug treatment) and before the first dose on Day 1 (within 24 hours of initiating treatment with lenalidomide).
− Agree to ongoing pregnancy testing during the course of the study; weekly during the first month of study drug treatment, then monthly thereafter for women with regular menstrual cycles or every 2 weeks for women with irregular menstrual cycles (even if true abstinence is the chosen method of birth control) up to and including the EOT visit.
− Must refrain from breastfeeding and donating oocytes during the course of study and for 180 days (6 months) after the last dose of study treatment.
c. A woman not considered to be of childbearing potential as defined in Appendix A is
eligible.
Note: The participants should be informed about the option of donation and cryopreservation of germ cells before the study if applicable.
5. All participants must:
a. Have an understanding that lenalidomide could have a potential teratogenic risk.
b. Abstain from donating blood while taking study treatment and for 28 days after discontinuation of study treatment.
c. Not share study medication with another person.
d. Agree to be counseled about pregnancy precautions and risk of fetal exposure.
e. In the opinion of the investigator, be able and willing to receive adequate mandatory prophylaxis and/or therapy for thromboembolic events (eg, aspirin 70-325 mg daily or low-molecular-weight heparin). Participants unable or unwilling to take any prophylaxis are not eligible.
f. In the opinion of the investigator, be able to understand and comply with all study-related procedures, medication use, and evaluations.
g. In the opinion of the investigator, not have a history of noncompliance or be considered potentially unreliable and/or uncooperative.
6. Tumor tissue sufficient for retrospective central pathology review and correlative studies must be provided to participate in this study. A fresh biopsy is preferred if clinically feasible but if not, an archival specimen is acceptable (refer to the Laboratory Manual).
Note: a fresh biopsy must be performed if the relapse is within 24 months from the initial diagnosis (POD24) to exclude transformed cases and potentially misdiagnosed cases.
7. Must have been previously treated with at least 1 prior systemic anti-CD20 immunotherapy or chemo-immunotherapy. This includes treatments such as the following: rituximab monotherapy or chemotherapy plus immunotherapy with rituximab or obinutuzumab, with or without maintenance. Note: At least 4 doses of anti-CD20 immunotherapy must have been given in prior therapy. Note: Systemic therapy does not include, for example, local involved field radiotherapy for limited stage disease, HBV/HCV therapy, or H pylori eradication.
8. Must have documented relapsed, refractory, or PD after treatment with systemic therapy (a participant in remission [in CR or PR] after the last prior treatment line would not be
eligible).
a. Relapsed lymphoma: relapsed after initial response of CR to prior therapy.
b. Refractory lymphoma: achieved less than PR to the last treatment or achieved a CR or PR that lasted less than 6 months before lymphoma progression.
c. Progressive lymphoma: PD after initial response of PR or SD to prior therapy.
9. Must be in need of treatment for relapsed, refractory, or PD as assessed by the investigator. Refer to GELF criteria (see Appendix G) as a guidance for participants with FL only.
10. Participants must have at least 1 measurable disease site. A radiographically measurable lymphadenopathy is defined as at least 1 nodal lesion > 1.5 cm in longest diameter or at least 1 extranodal lesion > 1.0 cm in longest diameter (Cheson et al 2014). The lesion must be confirmed to be measurable by CT and/or PET (for participants with PET-positive lesions) at the latest at the time of randomization.
Note: Participants with PET-negative lesions that are measureable by CT are eligible and followed-up with CT only as described in Section 8.2.3.
11. ECOG performance status of 0 to 2.
12. Participants with laboratory values at screening defined in Table 6.

Ausschlusskriterien
Participants are excluded from the study if any of the following criteria apply:
1. Women who are pregnant or breastfeeding. For Japan, women who are breastfeeding and wish to enroll must discontinue breastfeeding at least 90 days before receiving study drug/treatment. They must also refrain from breastfeeding during the course of study and for 90 days after the last dose of study treatment.
2. Any histology other than FL and MZL or clinical evidence of transformed lymphoma by INV assessment.
3. History of radiation therapy to = 25% of the BM for other diseases.
4. History of prior nonhematologic malignancy except for the following:
a. Malignancy treated with curative intent and with no evidence of active disease for more than 2 years before screening.
b. Adequately treated lentigo maligna melanoma without current evidence of disease or adequately controlled nonmelanomatous skin cancer.
c. Adequately treated carcinoma in situ without current evidence of disease.
5. Congestive heart failure (left ventricular ejection fraction of < 50%, assessed by 2D-echocardiography or MUGA scan.
6. Participants with:
a. Known positive test result for HCV (with anti-HCV serology testing) and a positive test for HCV RNA.
Note: Participants with positive serology must have been tested for HCV RNA and are eligible only in the case of negative HCV RNA.
b. Known positive test result for chronic HBV infection (defined by HBsAg positivity).
Note: Participants with occult or prior HBV infection (defined as negative HBsAg and positive total HBcAb) may be included if HBV DNA was undetectable, provided that they are willing to undergo monthly ongoing DNA testing. Antiviral prophylaxis may be administered as per institutional guidelines. Participants who have protective titers of HBsAb (HBsAb positive, HBcAb negative, and HBsAg negative) after vaccination or previously cured hepatitis B are eligible.
c. Seropositivity for or history of active viral infection with human immunodeficiency virus.
7. Active systemic infection (including SARS-CoV-2–positive test).
8. Participants in a severely immunocompromised state.
9. Known CNS lymphoma involvement.
10. Uncontrolled intercurrent illness.
11. History or evidence of clinically significant cardiovascular, CNS, and/or other systemic disease that would, in the investigator's opinion, preclude participation in the study or compromise the participant's ability to give informed consent.
12. Life expectancy < 6 months.
13. History or evidence of rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
14. Major surgery (excluding lymph node biopsy) within 28 days prior to signing the ICF unless the participant is recovered at the time of signing the ICF.
15. Any systemic antilymphoma and/or investigational therapy within 28 days prior to the start of Cycle 1.
16. Administration of a live vaccine within 28 days prior to the start of study treatment (Cycle 1 Day 1).
17. Prior use of lenalidomide in combination with rituximab.
18. History of hypersensitivity to compounds of similar biological or chemical composition to tafasitamab, immunomodulatory drugs, rituximab, other mAbs, and/or the excipients contained in the study drug formulations.
19. Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study treatment and attending required study visits; pose a significant risk to the participant; or interfere with interpretation of study data.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
NHL ind. - indolentes Non-Hodgkin Lymphom

Medizinischer Befund
follikuläres Lymphom \nMarginalzonenlymphom

MedDRA Term
In situ follicular lymphoma, Marginal zone lymphoma

Institut
Klinik für Hämatologie und Stammzelltransplantation

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Maher Hanoun

+49 (0)201 723-82530
maher.hanoun@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Goethe-Universität, Frankfurt

Einschlusskriterien
Patients must meet inclusion criteria to be eligible to enroll in this study:
1. Age ≥ 18 years
2. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
3. Availability of patient-specific molecular MRD markers of immunoglobulin/T-cell receptor gene rearrangements as assessed with a sensitivity of at least 10E-04
4. Diagnosis of Ph-negative, CD19-positive B-precursor acute lymphoblastic leukemia
according to WHO classification:
 Refractory BCP-ALL to primary induction therapy, including at least three cycles of standard chemotherapy
 Untreated first relapse of BCP-ALL with first remission duration < 12 months or
 Second or greater relapse of BCP-ALL or refractory relapse or
 Relapse of BCP-ALL any time after allogeneic HSCT or
 Positivity of MRD marker of immunoglobulin/T-cell receptor gene rearrangements of greater than 0.1% if in first or second remission of BCP-ALL
5. Willingness to participate in the registry of the German Multicenter Study Group for Adult ALL (GMALL)

Ausschlusskriterien
Selected Exclusion Criteria:
Patients meeting any of the following exclusion criteria are not eligible to enroll in this study:
1. Patients with diagnosis of Philadelphia positive BCP-ALL according to WHO classification
2. Patients with diagnosis of Burkitt´s Leukemia according to WHO classification
3. Patients with extramedullary relapse; non-bulky lymph node (< 7.5 cm diameter) involvement will be accepted
4. Patients with CNS involvement at relapse (as determined by CSF analysis)
5. Patients with suspected or histologically confirmed testicular involvement at relapse
6. Current autoimmune disease of any kind or history of autoimmune disease with potential CNS involvement
7. Prior or concomitant therapy with BH3 mimetics
8. Prior therapy with anti CD19 therapy, unless administered in MRD-positive setting (i.e. with bone marrow blasts = 5%)
9. History or presence of clinically relevant CNS pathology such as epilepsy, childhood or adult seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome, or psychosis. History of CNS leukemia that is controlled at relapse may be enrolled in this study.
10. History of malignancy other than ALL within 5 years prior to start of protocol-specified therapy with the exception of:
11. Malignancy treated with curative intent and with no known active disease present for 2 years before enrollment and felt to be at low risk for recurrence by the treating physician including
12. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
13. Adequately treated cervical carcinoma in situ without evidence of disease
14. Adequately treated breast ductal carcinoma in situ without evidence of disease
15. Prostatic intraepithelial neoplasia without evidence of prostate cancer.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
ALL - Akute lymphatische Leukämie

Medizinischer Befund
relapsed\/refractory B cell precursor acute lymphoblastic leukemia (BCP-ALL)

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Bastian von Tresckow

+49 (0)201 723-82530
bastian.vontresckow@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Miltenyi Biomedicine GmbH, Bergisch Gladbach

Einschlusskriterien
1. Histologically proven DLBCL and associated subtypes, according to the World Health Organisation (WHO) 2016 classification including:
• DLBCL not otherwise specified (NOS).
• High-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (double hit lymphoma/triple hit lymphoma).
• High-grade BCL, NOS.
• Primary (thymic) large mediastinal BCL.
• Disease transformed from an earlier diagnosis of low-grade lymphoma (e.g. an indolent pathology such as follicular lymphoma, marginal zone lymphoma) into DLBCL with DLBCL disease progression subsequent to DLBCL directed systemic treatment.
2. Relapsed or refractory disease after first-line chemoimmunotherapy:
• Refractory disease is defined as no CR to first-line therapy.
- PD as best response after at least 4 full cycles of R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone) cycles as first-line therapy.
- Stable disease (SD) after 6 R-CHOP cycles as first-line therapy.
- PR as best response after at least 6 R-CHOP cycles and biopsy-proven disease progression (except where prohibited due to comorbidities) within ≤ 12 months from the completion of the first-line therapy.
• Relapsed disease defined as complete remission to a first-line therapy followed by biopsy-proven disease progression (except where prohibited due to comorbidities) within ≤ 12 months from the completion of the first-line therapy.
3. Participants must have received adequate first-line therapy containing at least the combination of an anthracycline-based regimen and rituximab (anti-CD20 monoclonal antibody). Local therapies (e.g. radiotherapies) will not be considered as line of therapy if performed during the same line of treatment.
4. Archival paraffin-embedded tumour tissue acquired ≤ 3 years prior to screening for central pathology review to confirm DLBCL diagnosis and for analysis of CD20/CD19 expression must be made available for participation in this study. If archival paraffin-embedded tumour tissue is not available, fresh tumour tissue sample (preferred) or core-needle biopsy for this protocol must be made available.
5. Participants deemed ineligible to receive HDC followed by ASCT based on the treating physician’s assessment and meeting the following criteria:
• Age ≥ 18 years and
- Prior ASCT (as first-line consolidation) or
- Haematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) > 3.
• Age ≥ 65 years and 1 of the criteria below:
- Prior ASCT (as first-line consolidation), or
- Comorbidities as assessed by an HCT-CI score > 3, or
- Impaired cardiac function (left ventricular ejection fraction (LVEF) < 50%), or
- Impaired renal function (creatinine clearance [CrCl] < 60 mL/min) as determined by the MDRD (Modification of Diet in Renal Disease) formular, or
- Impaired pulmonary function (diffusing capacity for carbon monoxide or forced expiratory volume in 1 second of 66% to 80%) or dyspnoea on slight activity, or
- Eastern Cooperative Oncology Group (ECOG) performance status > 1.
Documentation of the reason for ineligibility for ASCT must be present in the participant’s source data.
In addition, all participants must fulfil the following criteria:
6. Age ≥ 18 years.
7. Measurable disease according to Lugano criteria. The lesion must be positive on a positron emission tomography scan.
8. Estimated life expectancy of > 3 months for other reasons than the primary disease.
9. Woman of childbearing potential (WOCBP) must agree to use highly effective contraceptive measures (Pearl index < 1) or practice true sexual abstinence from any heterosexual intercourse (True abstinence is only acceptable if it is in line with the preferred and usual life style of the participant.) or must have a vasectomised partner as the sole sexual partner (The vasectomised partner must have received medical assessment of the surgical success.) for at least 1 month before the study start, during the study and in the 12 months following the last dose of study treatment. A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Highly effective methods of contraception include hormonal contraceptives (oral, intravaginal, transdermal, injectable, implantable) and intrauterine devices or systems (e.g. hormonal and non-hormonal) and bilateral tubal occlusion. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. oophorectomy. A post-menopausal state is defined as no menses for 12 months without an alternative medical cause. WOCBP must refrain from egg donation throughout the study until 12 months after the last dose of study treatment. WOCBP must refrain from egg donation throughout the study until 12 months after the last dose of study treatment.

FOR FULL LIST OF INCLUSION CRITERIA PLEASE REFER TO THE STUDY PROTOCOL

Ausschlusskriterien
1. Contraindications for R-GemOx and BR plus polatuzumab vedotin as judged by the treating physician.
2. Prior chimeric antigen receptor therapy or other genetically modified T-cell therapy.
3. ECOG performance status > 2.
4. Absolute neutrophil count < 1,000/µL (unless secondary to bone marrow involvement by DLBCL as demonstrated by bone marrow biopsy required for screening).
5. Platelet count < 50,000/µL (unless secondary to bone marrow involvement by DLBCL as demonstrated by bone marrow biopsy required for screening).
6. Absolute lymphocyte count < 100/µL.
7. Participants who have CNS lymphoma involvement in present or past medical history.
8. Known history of infection with human immunodeficiency virus or active infection with hepatitis B (hepatitis B surface antigen positive).
9. Known history of infection with hepatitis C virus unless treated and confirmed to be polymerase chain reaction negative.
10. Active infection with SARS-CoV-2.
11. Known history or evidence of severely immunocompromised state; i.e. corticosteroid treatment > 10 mg/day for more than 6 months.
12. Has received vaccination with live virus vaccines within 6 weeks prior to randomisation.
13. Prior CD19 targeted therapy
14. Known history or presence of seizure activities or on active antiseizure medications within the previous 12 months.
15. Presence of CNS disease that, in the judgement of the investigator, may impair the ability to evaluate neurotoxicity.
16. Known history or presence of autoimmune CNS disease, such as multiple sclerosis, optic neuritis or other immunologic or inflammatory disease.
17. Known history or presence of cerebral vascular accident (CVA) within 12 months prior to randomisation. Note: In case of history of CVA > 12 months prior to leukapheresis, then the participant must not have any unstable or life-threatening neurological deficits.
18. Participants with Richter's transformation or Richter's syndrome.
19. Participants who are concurrently on any other experimental treatments or during the previous 4 weeks or 5-half-lives.
20. Clinical heart failure with New York Heart Association class = 2 or LVEF < 30%.
21. Resting peripheral oxygen saturation < 90% on room air.
22. Liver dysfunction as indicated by total bilirubin, aspartate aminotransferase and/or alanine aminotransferase > 5 × institutional upper limit of normal (ULN)
23. Serum creatinine = 2.0 × ULN or CrCl < 30 mL/min calculated according to the modified formula of MDRD.
24. Pregnant or breast-feeding woman.
25. Prior history of malignancies other than DLBCL, unless the participant has been free of the disease for = 3 years prior to screening. Exceptions to the = 3-year time limit include history of the following:
• Basal cell carcinoma of the skin.
• Squamous cell carcinoma of the skin.
• Carcinoma in situ of the cervix.
• Carcinoma in situ of the breast.
• Carcinoma in situ of the bladder.
• Incidental histological finding of untreated localized (T1a or T1b) prostate cancer under surveillance .
26. History of severe immediate hypersensitivity reaction against any drug or its ingredients/impurities that is scheduled to be given during study participation e.g. as part of the mandatory lymphodepletion protocol, premedication for infusion, or rescue medication/salvage therapies for treatment-related toxicities.
27. Any medical condition likely to interfere with assessment of safety or efficacy of study treatment.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
DLBCL - Diffuses großzelliges B-Zell-Lymphom

Medizinischer Befund
Relapsed\/refractory diffuse large B cell lymphoma (R-R DLBCL)

MedDRA Term
B-cell lymphoma refractory, B-cell lymphoma recurrent

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Dr. med. Julia von Tresckow

+49 (0)201 723-82530
julia.vontresckow@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Deutsche CLL Studiengruppe (DCLLSG), Universitätsklinik Köln

Einschlusskriterien
01. Documented CLL/SLL³ requiring treatment according to iwCLL criteria1.
02. Age at least 18 years.
03. At least one of the following risk factors: 17p- deletion, TP53 mutation, complex karyotype (defined as defined as the presence of 3 or more chromosomal aberrations in 2 or more metaphases.
04. Life expectancy ≥ 6 months.
05. Eastern Cooperative Oncology Group (ECOG) performance status of 0 -2.
06. Ability and willingness to provide written informed consent and to adhere to the study visitschedule and other protocol requirements.
07. Adequate bone marrow function indicated by a platelet count >30 x10^9/l (unless directlyattributable to CLL infiltration of the bone marrow, proven by bone marrow biopsy).
08. GFR >30 ml/min directly measured with 24hr urine collection, calculated according to the modified formula of Cockcroft and Gault (for men: GFR ≈ ((140 - age) x bodyweight) / (72 x creatinine), for women x 0, 85) or an equally accurate method. For patients with creatinine values within the normal range the calculation of the clearance is not necessary. Dehydrated patients with an estimated creatinine clearance less than 30 ml/min may be eligible if a repeat estimate after adequate hydration is > 30 ml/min.
9. Adequate liver function as indicated by a total bilirubin ≤ 2 x, AST/ALT ≤ 2.5 x the institutional ULN value, unless directly attributable to the patient’s CLL or to Gilbert’s Syndrome.
10. Negative serological testing for hepatitis B (HBsAg negative and anti-HBc negative; patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBVDNA PCR is performed every month until 12 months after last treatment cycle), negative testing for hepatitis C RNA within 6 weeks prior to registration.

³ Patients with SLL are eligible with confirmation of clonal b-cells in the peripheral blood by immunophenotyping. Patients with
SLL without any leukemic manifestation are not eligible.

Ausschlusskriterien
01. Any prior CLL-specific therapies (except corticosteroid treatment administered due to necessary immediate intervention; within the last 10 days before start of study treatment, only dose equivalents up to 20 mg prednisolone are permitted).
02. Transformation of CLL (Richter‘s transformation).
03. Known central nervous system involvement.
04. An individual organ/system impairment score of 4 as assessed by the CIRS definition limiting the ability to receive the treatment regimen of this trial with the exception of eyes, ears, nose, throat organ system (note that symptoms related to CLL should not be included in the patient’s screening CIRS score). Investigators should consult the General Rules for Severity Rating as well as the Organ-Specific Categories when assigning scores for certain conditions (i.e., pulmonary embolism) and consider the level of morbidity associated with a patient’s condition. Current life-threatening illness, medical condition, or organ system dysfunction which, in the Investigator’s opinion, could compromise the subject’s safety or put the study at risk.
05. Decompensated hemolysis, defined as ongoing hemoglobin drop in spite of prednisolone or intravenous immunoglobulins (IVIG) being administered for hemolysis. Prior treatment with rituximab also for other indications than CLL is not permitted.
06. Patients with a history of confirmed progressive multifocal leukoencephalopathy.
07. Malignancies other than CLL currently requiring systemic therapies, not being treated with curative intent before (unless the malignant disease is in a stable remission due to the discretion of the treating physician) or showing signs of progression after curative treatment.
08. Patients with active infections requiring IV treatment (Grade 3 or 4) within the last 2 months prior to enrollment.
09. Patients with known infection with human immunodeficiency virus (HIV).
10. Requirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/inducers.
11. Anticoagulant therapy with warfarin or phenoprocoumon, (alternative anticoagulation is allowed (e.g. DOACs), but patients must be properly informed
about the potential risk of bleeding under treatment with acalabrutinib).
12. Requirement of treatment with a PPI (proton pump inhibitor). If treatment with an acid reducing agent is required, consider using an antacid (e.g., calcium carbonate) or an H2- receptor antagonist (e.g. ranitidine or famotidine) instead.
13. History of stroke or intracranial hemorrhage within 6 months prior to registration.
14. Use of investigational agents which might interfere with the study drug within 28 days prior to registration.
15. Vaccination with live vaccines 28 days prior to registration.
16. Major surgery less than 30 days before start of treatment.
17. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies, known sensitivity or allergy to murine products.
18. Known hypersensitivity to any active substance or to any of the excipients of one of the
drugs used in the trial.
19. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment; further pregnancy testing will be performed regularly see chapter 2.3.1.5).
20. Fertile men or women of childbearing potential unless:
a. surgically sterile or = 2 years after the onset of menopause.
b. willing to use two methods of reliable contraception including one highly effective contraceptive method (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 18 months after the end of study treatment.
21. Inability to swallow a large number of tablets.
22. Legal incapacity.
23. Prisoners or subjects who are institutionalized by regulatory or court order or persons who are in dependence to the sponsor or an investigator.

Studienteilnehmende Mindestalter
18 Jahr(e)

Indikation
CLL - Chronische lymphatische Leukämie

Medizinischer Befund
Chronic lymphocytic leukemia (CLL): High risk patients defined as having at least one of the following risk factors: 17p-deletion, TP53-mutation or complex karyotype

Institute
Klinik für Hämatologie und Stammzelltransplantation, Klinik für Kinderheilkunde III, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Thomas Schroeder

+49 (0)201 723-82530
thomas.schroeder@uk-essen.de

Hufelandstr. 55
45147 Essen

Sponsor

MEDAC, medac Gesellschaft für klinische Spezialpräparate mbH, Hamburg

Einschlusskriterien
- Subject had a previous allogeneic HSCT as indicated for malignant or non-malignant haematological disease, irrespective of human leukocyte antigen match.
- Subject has been clinically diagnosed with Grade II to IV aGvHD at the Screening Visit.
- Subject has experienced failure of previous first line aGvHD treatment (ie, SR aGvHD), defined as:
a. aGvHD progression within 3 to 5 days of therapy onset with ? 2 mg/kg/day of prednisone equivalent or
b. failure to improve within 5 to 7 days of treatment initiation with ? 2 mg/kg/day of prednisone equivalent or
c. incomplete response after > 28 days of immunosuppressive treatment including at least 5 days with ? 2 mg/kg/day of prednisone equivalent.
- Male or female subject who is ? 12 years of age and ? 15 kg at the Screening Visit.
- Subject has an estimated life expectancy > 28 days at the Screening Visit (compliance to be re-confirmed at the Baseline Visit).
- Subject, if female and of childbearing potential, agrees to use a highly effective contraceptive measure starting at the Screening Visit and continuing throughout the entire trial period. The definition of women of childbearing potential (WOCBP) and a complete list of highly effective contraceptive measures are included in an appendix to the protocol.
- Subject, if a fertile male, agrees to sexual abstinence or to use a condom during sexual activity with their female partner of childbearing potential or pregnant partner. Additionally, if their partner is a WOCBP, then their partner has to use an additional highly effective contraceptive method during sexual activity starting at the Screening Visit and continuing throughout the entire trial period. The definition of fertile men and a complete list of highly effective contraceptive measures are included in an appendix to the protocol.
- Subject or parent(s) / legal guardian(s) have read, understood, and signed the informed consent form (and informed assent form, if applicable) according to national regulations.

Ausschlusskriterien
- Subject has overt relapse or progression or persistence of the underlying disease at the Screening Visit.
- Subject has received the last HSCT for a solid tumour disease.
- Subject has GvHD overlap syndrome at the Screening Visit.
- Subject has received systemic first line treatment for aGvHD other than steroids and a prophylaxis with other than calcineurin inhibitors, anti thymocyte globulin (ATG), mycophenolate mofetil (MMF), methotrexate (MTX), and or cyclophosphamide before the Screening Visit (compliance
to be re-confirmed at the Baseline Visit).
- Subject has a known pregnancy (as confirmed by a positive pregnancy test at the Screening Visit) and or is breastfeeding at the Screening Visit.
- Subject has received treatment with any other investigational agent within 30 days or 5 half-lives (whichever is longer) before the Screening
Visit (compliance to be confirmed for the period between the Screening Visit and the Baseline Visit at the Baseline Visit).

Studienteilnehmende Mindestalter
12 Jahr(e)

Geschlecht
Männlich

Indikation
KIK-Onko

Medizinischer Befund
Steroid refractory Acute Graft versus host Disease

MedDRA Term
Acute graft versus host disease

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Dr. med. Rudolf Trenschel

+49 (0)201 723-82530
rudolf.trenschel@uk-essen.de

Hufelandstraße 55
45147 Essen

Indikation
MM - Multiples Myelom

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Dr. med. Rudolf Trenschel

+49 (0)201 723-82530
rudolf.trenschel@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Universitätsklinikum Hamburg-Eppendorf, KdöR

+49 (0)40 7410-0
INFO@UKE.DE

Martinistraße 52
20251 Hamburg

Einschlusskriterien
1. Acute Myeloid Leukemia (AML) intermediate or high risk according to ELN or Acute Lymphoblastic Leukemia (ALL) high risk according to ESMO guidelines in 1. CR or AML/ALL in 2. CR, or high risk MDS (according to IPSS-R) in 1. CR or 2. CR.
2. Patients age: 18 - 70 years at time of inclusion (female and male)
3. Patients understand and voluntarily sign an informed consent form
4. ECOG ≤ 2
5. 10/10 HLA-matched unrelated donor [9/10 mismatch is allowed if HLA mismatch is located in DQB1 (by high resolution typing)] and haploidentical (≥ 5/10 and ≤ 8/10 HLA) relative matched donor available at least 4 weeks after completion of induction and/or consolidation therapy. The mismatch related donor should not be older than 65 years of age.
6. Females/Males who agree to comply with the applicable contraceptive requirements of the protocol

Ausschlusskriterien
1. Severe renal, hepatic, pulmonary or cardiac disease, such as:
- total bilirubin, SGPT or SGOT > 3 times upper the normal level
- left ventricular ejection fraction < 30 %
- creatinine clearance < 30 ml/min
- DLCO < 35 % and/or receiving supplementary continuous oxygen
2. Positive serology for HIV
3. Pregnant or lactating women (positive serum pregnancy test)
4. Age < 18 and = 71 years.
5. Uncontrolled invasive fungal infection at time of screening (baseline)
6. Serious psychiatric or psychological disorders
7. Participation in another study with ongoing use of unlicensed investigational product from 28 days before study enrollment
8. Uncontrolled severe autoimmune disease or uncontrolled other malignancy
9. Availability of an HLA-identical sibling as donor source

Studienteilnehmende Mindestalter
18 Jahr(e)

Studienteilnehmende Höchstalter
70 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
AML - Akute myeloische Leukämie

Medizinischer Befund
Acute Myeloid Leukemia

MedDRA Term
Acute myeloid leukemia

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Thomas Schroeder

+49 (0)201 723-82530
thomas.schroeder@uk-essen.de

Hufelandstr. 55
45147 Essen

Sponsor

DKMS gemeinnützige GmbH, Tübingen

Einschlusskriterien
- Signed written Informed Consent.
- Age ≥ 18 years.
- One of the following eligible diagnoses:
*AML in CR1 with intermediate or adverse risk genetic abnormalities (according to the ELN 2017 guidelines), or undefined risk.
*AML of any ELN risk category after hematological or molecular relapse, or with primary refractory disease.
*AML arising from myelodysplastic syndrome (MDS) or a myeloproliferative neoplasia, except if favourable genetic abnormalities (according to ELN 2017 guidelines) are present.
* Therapy-related myeloid neoplasia (t-MN), except if favourable genetic abnormalities (according to ELN 2017 guidelines) are present.
* MDS with intermediate risk, high risk or very high risk disease (according to the IPSS-R Score) regardless of treatment status.
* MDS/MPN and CMML-1/CMML-2 regardless of treatment status.
- The left ventricular ejection fraction (LVEF) was assessed ≥40% at last echocardiography.
- Transplantation with Peripheral Blood Stem Cells (PBSC) scheduled to be performed 4 to 14 days after date of randomization.
- The scheduled donor is unrelated to the patient, and matched or partially matched (with not more than one allele or antigen mismatch) at HLA-A, -B, -C, or -DRB1.

Ausschlusskriterien
- Anamnestic intravenous or subcutaneous exposure to rabbit immunoglobin-preparations (e.g. Grafalon or Thymoglobuline) or known hypersensitivity to rabbit protein.
- Known hypersensitivity to cyclophosphamide.
- Prior allogeneic hematopoietic transplantation.
- Patients who receive supplementary continuous oxygen at the time of randomization.
- Symptomatic heart failure (NYHA =2) at the time of randomization.
- Uncontrolled viral, bacterial or fungal infection with progression or no clinical improvement at the time of randomization.
- Pregnant or breast-feeding women.
- Patients unable or unwilling to be sexual abstinent or use effective contraception methods from enrollment to minimum six months after the last dose of the IMP.
- Simultaneous participation in another interventional clinical trial with an investigational medicinal product.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
MDS - Myelodysplastisches Syndrom, AML - Akute myeloische Leukämie

Medizinischer Befund
AML, t-MN, MDS, MDS\/MPN, CMML-1\/CMML-2

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Bastian von Tresckow

+49 (0)201 723-82530
bastian.vontresckow@uk-essen.de

Hufelandstraße 55
45147 Essen

Einschlusskriterien
1. Signed informed consent, by the patient or an authorized legal guardian in case the patient is temporarily not competent due to his or her disease, obtained before any study-related activities. Study-related activities are any procedures that are carried out as part of the study, including activities to determine suitability for the study.
2. Patients of either gender aged > 18 years.
3. Body weight < 180 kg.
4. At least one measurable lymphoma manifestation in the CNS, either contrast-enhanced lesion in the brain parenchyma or measurable meningeal lesion.
5. Histologically confirmed diagnosis of relapsed or refractory primary central nervous system lymphoma (PCNSL) or histologically confirmed diagnosis of relapsed or refractory secondary central nervous system lymphoma (SCNSL) with only isolated CNS involvement (at initial diagnosis of relapse).
6. Recurrent or refractory CNSL
1. For recurrent disease, comprising new lesions or recurrent CNSL after a complete response (CR) at that site, there are no maximum number of recurrences.
2. Refractory CNSL comprises patients with non-responding CNSL (no objective response rate (ORR), no progressive disease (PD)) to frontline therapy, or progressive disease after an initial, partial response (PR).
7. Stored stem cells with at least ≥ 2 x 106 CD34+ cells/kg of body weight.
8. If sexually active female patient of childbearing potential: patient agrees to take adequate contraceptive measures during study participation and agrees to continue use of this method for the duration of the study and for six months after the last dose.
9. Female patient without childbearing potential: documented history (e.g., tubal ligation or hysterectomy) or is post-menopausal.
10. For male patient whose partner is of child-bearing potential: patient is willing to ensure that he and his partner use effective contraception during the study and for six months after 90Y-PTT treatment.
11. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
12. Confirmed presence of CXCR4 on technically evaluable tumor lesions documented by a visually CXCR4-positive [68Ga]Ga-PentixaFor positron emission tomography (PET) scan within two months prior to enrolment in the study or during Screening.
13. Blood test results as follows:
1. Absolute neutrophil count: > 1.0 x 109/L
2. Hemoglobin: ≥ 8 g/dL
3. Platelets: ≥ 75 x 109/L
4. Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (ALP): ≤ 3 x ULN (upper limit of normal)
5. Serum creatinine: ≤ 2 x ULN and Cockcroft Gault calculated glomerular filtration rate (GFR) ≥ 50 mL/min
6. Bilirubin: ≤ 3 x ULN

Ausschlusskriterien
1. Known or suspected hypersensitivity to study product(s) or related products.
2. Contraindication for contrast-enhanced magnetic resonance imaging (MRI) as set out in the relevant institutional guidelines (e.g., pacemaker, defibrillator, aneurysm clip, metal in the body, renal insufficiency, severe claustrophobia etc.) or contraindication for the use of gadolinium contrast for MRI.
3. Previous participation in this study. Participation is defined as signed informed consent.
4. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using an adequate contraceptive method (adequate contraceptive measures as required by local regulation or practice). A pregnancy test will be performed at the start of the study for all female patients of childbearing potential (i.e., not surgically sterile or two years postmenopausal).
5. Male of reproductive age who or whose partner(s) is not using an adequate contraceptive method (adequate contraceptive measures as required by local regulation or practice).
6. Participation in any clinical study of an approved or non-approved investigational medicinal product (IMP) within the last 30 days (or = 5 terminal elimination half-lives of previous IMP, whichever is longer) before screening.
7. Any disorder (e.g., active infection, unstable angina pectoris, cardiac arrhythmia (excluding atrial fibrillation and atrial flutter, uncontrolled congestive heart failure), poorly controlled hypertension, poorly controlled diabetes mellitus [HbA1c = 9%], etc.) or laboratory findings, except for conditions associated with CNS lymphoma, which in the investigator's opinion might jeopardize patient's safety or compliance with the protocol.
8. Presence of active infection at screening, or history of serious infection within the previous six weeks. Patients with uncontrolled human immunodeficiency virus (HIV) infection as well as acute or chronic active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection are excluded (Note: Patients on antiretroviral therapy (ART) with controlled HIV infection (defined as sufficient ART compliance, non-measurable HIV and CD4+ T helper cells > 200/Micro Liter) may be enrolled, if considered eligible for study treatment by the investigator.).
9. SCNSL with systemic involvement.
10. Chronic use (> 21 days) of immunosuppressive drugs, e.g., steroids for systemic autoimmune disease, due to previous organ transplantation, or other clinically evident form of immunodeficiency. Patients receiving only acute treatment (less than 21 days) with corticosteroids can be included.
11. Any mental condition rendering the patient unable to understand the nature, scope, and possible consequences of the study, and/or evidence of an uncooperative attitude without designated legal representative.

Studienteilnehmende Mindestalter
18 Jahr(e)

Studienteilnehmende Höchstalter
120 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
ZNS - Lymphom mit Befall des zentralen Nervensystems

Medizinischer Befund
CNS Lymphoma

Institute
Klinik und Poliklinik für Strahlentherapie, Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Dr. med. Julia von Tresckow

+49 (0)201 723-82530
julia.vontresckow@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Ruprecht-Karls-Universität Heidelberg

Einschlusskriterien
• Centrally reviewed CD20-positive follicular lymphoma grade 1/2 or 3a based on WHO classification (2008)
• Untreated (radiation-, chemo- or immunotherapy) nodal follicular lymphoma (including involvement of Waldeyer´s ring)
• Age: ≥18 years
• ECOG: 0-2
• Stage: clinical stage I or II (Ann Arbor classification) based on FDG-PET Staging
• Risk profile: Largest diameter of the lymphoma ≤ 7 cm (sectional images)
• Written informed consent and willingness to cooperate during the course of the trial
• Adequate bone marrow capacity: ANC ≥ 1.5 x 103/ml, thrombocytes ≥ 100000 x 10 3/ml, hemoglobin ≥ 10 g/dL
• Capability to understand the intention and the consequences of the clinical trial
• Adequate contraception for men and women of child-bearing age during therapy and 18 months thereafter

Ausschlusskriterien
• Extra nodal manifestation of follicular lymphoma
• Secondary cancer in the patient's medical history (exclusion: basalioma, spinalioma, melanoma in situ, bladder cancer T1a, non-metastasized solid tumor in constant remission, which was diagnosed >3 years ago)
• Serious disease interfering with a regular therapy according to the study protocol, e.g: congenital or acquired immune-deficiency syndromes, active infections including viral hepatitis, uncontrolled concomitant diseases including significant cardiovascular or pulmonary disease
• Severe psychiatric disease
• Pregnancy / lactation
• Known hypersensitivity against Obinutuzumab or Rituximab drugs with similar chemical structure or any other additive of the pharmaceutical formula of the study drug
• Active hepatitis B infection (inactive hepatitis B infections require additional prophylactic anti-viral medication for 1 year (e.g. Lamivudin, Entecavir, Tenofovir)
• Participation in another interventional trial or follow-up period of a competing trial which can influence the results of this current trial
• Creatinine > 1.5 times the upper limit of normal (ULN)
(unless creatinine clearance normal), or calculated
creatinine clearance < 40 mL/min
• AST or ALT > 2.5 × ULN
• Total bilirubin = 1.5 × ULN
• INR > 1.5 × ULN
• PTT or aPTT > 1.5 × the ULN

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
NHL - Non-Hodgkin-Lymphom

Medizinischer Befund
nodal follicular lymphoma grade 1 or grade 2 in the clinical stage I or II (Ann Arbor classification)

MedDRA Term
Non-Hodgkin's lymphoma stage II, Non-Hodgkin's lymphoma stage I

Institut
Klinik für Hämatologie und Stammzelltransplantation

Prüfarzt (AMG) / Studienleitung (BO)

Dr. med. Ferras Alashkar

+49 (0)201 723-82530
ferras.alashkar@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Agios Pharmaceuticals Inc., USA

Einschlusskriterien
• To compare the durability of the effect of mitapivat versus placebo on transfusion burden
• To evaluate the effect of mitapivat versus placebo on additional measures of transfusion burden
• To evaluate the effect of mitapivat versus placebo on iron metabolism
• To evaluate the safety of mitapivat
• To evaluate the pharmacokinetic and pharmacodynamic effects of mitapivat

Ausschlusskriterien
1. Pregnant or breastfeeding.
2. Documented history of homozygous or heterozygous HbS or HbC.
3. Prior exposure to gene therapy or prior bone marrow or stem cell transplantation.
4. Currently receiving treatment with luspatercept; the last dose must have been administered =36 weeks before randomization.
5. Currently receiving treatment with hematopoietic stimulating agents; the last dose must have been administered =36 weeks before randomization.
6. History of any malignancy, except for nonmelanomatous skin cancer in situ, cervical carcinoma in situ, or breast carcinoma in situ. Subjects must not have active disease or received anticancer treatment =5 years before providing informed consent.
7. History of active and/or uncontrolled cardiac or pulmonary disease =6 months before providing informed consent, including but not limited to:
a. New York Heart Association Class III or IV heart failure or clinically significant dysrhythmia
b. Myocardial infarction or unstable angina pectoris; hemorrhagic, embolic, or thrombotic stroke; deep venous thrombosis; or pulmonary or arterial embolism
c. Heart rate–corrected QT interval using Fridericia’s method =450 milliseconds (males) or =470 milliseconds (females), except for right or left bundle branch block
d. Severe pulmonary fibrosis as defined by severe hypoxia, evidence of right-sided heart failure, and radiographic pulmonary fibrosis >50%
e. Severe pulmonary hypertension as defined by severe symptoms associated with hypoxia, right-sided heart failure, and oxygen indicated
8. Hepatobiliary disorders, including but not limited to:
a. Liver disease with histopathological evidence of cirrhosis or severe fibrosis
b. Clinically symptomatic cholelithiasis or cholecystitis (prior cholecystectomy is not exclusionary)
c. History of drug-induced cholestatic hepatitis
d. Aspartate aminotransferase >2.5 × upper limit of normal (ULN); unless due to hemolysis and hepatic iron deposition) and alanine aminotransferase >2.5 × ULN (unless due to hepatic iron deposition)
9. Estimated glomerular filtration rate <45 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology Collaboration creatinine equation.
10. Nonfasting triglycerides >440 mg/dL (5 mmol/L).
11. Active infection requiring systemic antimicrobial therapy at the time of providing informed consent. If antimicrobial therapy is required during the Screening Period, screening procedures should not be performed while antimicrobial therapy is being administered, and the last dose of antimicrobial therapy must be administered =7 days
before randomization.
12. Positive test for hepatitis C virus (HCV) antibody (Ab) with evidence of active HCV infection, or positive test for hepatitis B surface antigen.
13. Positive test for HIV-1 Ab or HIV-2 Ab.
14. History of major surgery (including splenectomy) =6 months before providing informed consent and/or a major surgical procedure planned during the study.
15. Current enrollment or past participation (=12 weeks before administration of the first dose of study drug or a time frame equivalent to 5 half-lives of the investigational treatment, whichever is longer) in any other clinical study involving an investigational treatment or device.
16. Receiving strong cytochrome P450 (CYP)3A4/5 inhibitors that have not been stopped for =5 days or a time frame equivalent to 5 half-lives (whichever is longer), or strong CYP3A4 inducers that have not been stopped for =4 weeks or a time frame equivalent to 5 half-lives (whichever is longer), before randomization.
17. Receiving anabolic steroids, including testosterone preparations, that have not been stopped for at least 4 weeks before randomization. Testosterone replacement therapy to treat hypogonadism is allowed; the testosterone dose and preparation must be stable for =12 weeks before randomization.
18. Known allergy to mitapivat or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, mannitol, and magnesium stearate).
19. Any medical, hematological, psychological, or behavioral condition(s) or prior or current therapy that, in the opinion of the Investigator, may confer an unacceptable risk to participating in the study and/or could confound the interpretation of the study data.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Anämie

Medizinischer Befund
Transfusion-Dependent Alpha- or Beta-Thalassemia

MedDRA Term
Transfusion dependent thalassemia

Institut
Klinik für Hämatologie und Stammzelltransplantation

Prüfarzt (AMG) / Studienleitung (BO)

Dr. med. Ferras Alashkar

+49 (0)201 723-82530
ferras.alashkar@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Agios Pharmaceuticals Inc., USA

Einschlusskriterien
Subjects are eligible to be included in the study only if all the following criteria apply:
1. ≥18 years of age at the time of providing informed consent.
2. Documented diagnosis of thalassemia (β-thalassemia with or without α-globin gene
mutations, HbE/β-thalassemia, or α-thalassemia/HbH disease) based on Hb electrophoresis, Hb high-performance liquid chromatography, and/or DNA analysis from the subject’s medical record. If this information is not available from the subject’s medical record, the test(s) can be performed by a local laboratory during the Screening
Period. If a local laboratory is unable to perform the test(s), results from the comprehensive α- and β-globin genotyping performed by the study central laboratory can be used.
3. Hb concentration ≤10.0 g/dL (100.0 g/L), based on an average of at least 2 Hb concentration measurements (separated by ≥7 days) collected during the Screening Period.
4. Non–transfusion dependent, defined as ≤5 RBC units during the 24-week period before randomization, and no RBC transfusions ≤8 weeks before providing informed consent or during the Screening Period.
5. If taking hydroxyurea, the hydroxyurea dose must be stable for ≥16 weeks before randomization.
6. Women of childbearing potential (WOCBP) and men with partners who are WOCBP must be abstinent of sexual activities that may result in pregnancy as part of their usual lifestyle or agree to use 2 forms of contraception, 1 of which must be considered highly effective, from the time of providing informed consent, throughout the study, and for 28 days after the last dose of study drug for women and 90 days after the last dose of study drug for men. The second form of contraception can be an acceptable barrier method.
7. Written informed consent before any study-related procedures are conducted and willing to comply with all study procedures for the duration of the study.

Ausschlusskriterien
Subjects are excluded from the study if any of the following criteria apply:
1. Pregnant or breastfeeding.
2. Documented history of homozygous or heterozygous HbS or HbC.
3. Prior exposure to gene therapy or prior bone marrow or stem cell transplantation.
4. Currently receiving treatment with luspatercept; the last dose must have been administered =12 weeks before randomisation.
5. Currently receiving treatment with hematopoietic stimulating agents; the last dose must have been administered =12 weeks before randomisation.
6. History of any malignancy, except for nonmelanomatous skin cancer in situ, cervical carcinoma in situ, or breast carcinoma in situ. Subjects must not have active disease or received anticancer treatment =5 years before providing informed consent.
7. History of active and/or uncontrolled cardiac or pulmonary disease =6 months before providing informed consent, including but not limited to:
a. New York Heart Association Class III or IV heart failure or clinically significant dysrhythmia
b. Myocardial infarction or unstable angina pectoris; hemorrhagic, embolic, or thrombotic stroke; deep venous thrombosis; or pulmonary or arterial embolism
c. Heart rate–corrected QT interval using Fridericia’s method =450 milliseconds (males) or =470 milliseconds (females), except for right or left bundle branch block
d. Severe pulmonary fibrosis as defined by severe hypoxia, evidence of right-sided heart failure, and radiographic pulmonary fibrosis >50%
e. Severe pulmonary hypertension as defined by severe symptoms associated with
hypoxia, right-sided heart failure, and oxygen indicated
8. Hepatobiliary disorders, including but not limited to:
a. Liver disease with histopathological evidence of cirrhosis or severe fibrosis
b. Clinically symptomatic cholelithiasis or cholecystitis (prior cholecystectomy is not
exclusionary)
c. History of drug-induced cholestatic hepatitis
d. Aspartate aminotransferase (AST) >2.5 × upper limit of normal (ULN); unless due to
hemolysis and hepatic iron deposition) and alanine aminotransferase (ALT) >2.5 ×
ULN (unless due to hepatic iron deposition)
9. Estimated glomerular filtration rate <45 mL/min/1.73 m2 by Chronic Kidney Disease
Epidemiology Collaboration creatinine equation.
10. Nonfasting triglycerides >440 mg/dL (5 mmol/L).
11. Active infection requiring systemic antimicrobial therapy at the time of providing informed consent. If antimicrobial therapy is required during the Screening Period, screening procedures should not be performed while antimicrobial therapy is being administered, and the last dose of antimicrobial therapy must be administered =7 days before randomization.
12. Positive test for hepatitis C virus (HCV) antibody (Ab) with evidence of active HCV infection, or positive test for hepatitis B surface antigen (HBsAg).
13. Positive test for HIV-1 Ab or HIV-2 Ab.
14. History of major surgery (including splenectomy) =16 weeks before providing informed consent and/or a major surgical procedure planned during the study.
15. Current enrollment or past participation (=12 weeks before administration of the first dose of study drug or a time frame equivalent to 5 half-lives of the investigational study drug, whichever is longer) in any other clinical study involving an investigational
treatment or device.
16. Receiving strong CYP3A4/5 inhibitors that have not been stopped for =5 days or a time frame equivalent to 5 half-lives (whichever is longer), or strong CYP3A4 inducers that have not been stopped for =4 weeks or a time frame equivalent to 5 half-lives (whichever is longer), before randomisation.
17. Receiving anabolic steroids, including testosterone preparations, that have not been stopped for at least 4 weeks before randomisation. Testosterone replacement therapy to treat hypogonadism is allowed; the testosterone dose and preparation must be stable for =10 weeks before randomisation.
18. Known allergy to mitapivat or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, mannitol, and magnesium stearate).
19. Any medical, hematological, psychological, or behavioral condition(s) or prior or current therapy that, in the opinion of the Investigator, may confer an unacceptable risk to participating in the study and/or could confound the interpretation of the study data.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Anämie

Medizinischer Befund
Non–Transfusion-Dependent Alpha- or Beta-Thalassemia

MedDRA Term
Non-transfusion dependent thalassemia

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Christine Hanoun

+49 (0)201 723-82530
christine.hanoun@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Pfizer Inc., USA

Einschlusskriterien
- Diagnosis of MM as defined according to IMWG criteria (Rajkumar, 2014) - with measurable disease at diagnosis as defined by serum M protein ≥0.5 g/dL (5 g/L), by urine M protein ≥200 mg/24 hours, or by serum FLC assay with involved FLC level ≥10 mg/dL, provided serum FLC ratio is abnormal.
History of induction therapy and autologous stem cell transplant. Randomization must occur within 120 days from the stem cell transplant. For participants who receive consolidation therapy after ASCT, randomization must occur within 60 days of consolidation and within 7 months from ASCT.
- Partial Response or better according to IMWG criteria at the time of randomization
- MRD positive (≥10^-5) at screening by central laboratory NGS test (ClonoSEQ assay)
Must have an archival bone marrow aspirate sample(s) that identified the dominant malignant (index) clone that is used to track MRD status.
This sample should preferably be collected before induction treatment (eg, at diagnosis) or before transplant.
- ECOG performance status ≤ 1
- Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade ≤ 1
- Not pregnant and willing to use contraception

Ausschlusskriterien
- Plasma cell leukemia
- Amyloidosis, Waldenström's macroglobulinemia, or POEMS syndrome
- Known active CNS involvement or clinical signs of myelomatous meningeal involvement.
- Previous MM maintenance treatment
- Prior treatment with BCMA targeted therapy
- Any other active malignancy within 3 years prior to enrolment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ or Stage 0/1 with minimal risk of recurrence per the investigator.
- Active, uncontrolled bacterial, fungal, or viral infection, including (but not limited to) HBV, HCV, and known HIV or AIDS-related illness
- Previous administration with an investigational drug or vaccine within 30 days (or as determined by the local requirement) or 5 half lives preceding the first dose of study intervention used in this study (whichever is longer)

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
MM - Multiples Myelom

Medizinischer Befund
MULTIPLE MYELOMA

MedDRA Term
Multiple myeloma

Institut
Klinik für Hämatologie und Stammzelltransplantation

Prüfarzt (AMG) / Studienleitung (BO)

Dr. med. Ferras Alashkar

+49 (0)201 723-82530
ferras.alashkar@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Agios Pharmaceuticals Inc., USA

Einschlusskriterien
• Age ≥16 years; subjects age 16 or 17 years must physically have completed puberty.
• Documented diagnosis of SCD (HbSS, HbSC, HbS/β0-thalassemia, HbS/β+ thalassemia, or other sickle cell syndrome variants).
• At least 2 sickle cell pain crises (SCPCs) and no more than 10 SCPCs in the past 12 months.
• Hemoglobin ≥5.5 and ≤10.5 g/dL.
• If taking hydroxyurea, the hydroxyurea dose must be stable for at least 90 days before starting study drug.
• Women capable of becoming pregnant and men with partners who are women that are capable of becoming pregnant must agree to use 2 forms of contraception.
• Other protocol-defined inclusion criteria may apply.

Ausschlusskriterien
• Pregnant or breastfeeding.
• Receiving regularly scheduled transfusions.
• Hepatobiliary disorders including but not limited to significant liver disease or gallbladder disease.
• Severe kidney disease.
• Prior exposure to gene therapy or prior bone marrow or stem cell transplantation.
• Currently receiving treatment for SCD (eg, voxelotor, crizanlizumab, L glutamine), with the exception of hydroxyurea. The last dose of such therapies must have been administered at least 90 days before starting study drug.
• Currently receiving treatment with hematopoietic stimulating agents; the last dose must have been administered at least 90 days before starting study drug.
• Received treatment on another investigational trial within 90 days prior to start of study drug or plans to participate in another investigational drug trial.
• Taking medications that are strong inhibitors of CYP3A4/5 or strong inducers of CYP3A4 that cannot be stopped in an acceptable timeframe before starting study drug (timeframe will be discussed with your doctor).
• Other protocol defined exclusion criteria may apply.

Studienteilnehmende Mindestalter
16 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Anämie

Medizinischer Befund
Sickle Cell Disease

MedDRA Term
Sickle Cell Disease

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Andreas Hüttmann

+49 (0)201 723-82530
Andreas.Huettmann@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Universitätsmedizin Berlin

Augustenburger Platz 1
13353 Berlin

Einschlusskriterien
Alle Patienten mit PTLD

Ausschlusskriterien
keine

Studienteilnehmende Mindestalter
Jahr(e)

Studienteilnehmende Höchstalter
99 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
NHL - Non-Hodgkin-Lymphom

Medizinischer Befund
Posttransplantations-Lymphoproliferative Erkrankungen (PTLD)

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Thomas Schroeder

+49 (0)201 723-82530
thomas.schroeder@uk-essen.de

Hufelandstr. 55
45147 Essen

Sponsor

MEDAC, medac Gesellschaft für klinische Spezialpräparate mbH, Hamburg

Einschlusskriterien
1. Jene, die AML oder MDS haben und sich einer ersten allogenen HSZT unterziehen.
2. Jene, die einen passenden verwandten, passenden nicht verwandten oder haploidentischen Spender zur Verfügung haben.
3. Erwachsene beiderlei Geschlechts im Alter von 18 bis 70 Jahren.
4. Karnofsky-Index von > 60%.
5. Jene, die eine schriftliche Patienteninformation und Einwilligungserklärung abgegeben haben.
6. Jene, die eine angemessene Herzfunktion vorweisen, z. B. linksventrikuläre Ejektionsfraktion von > 40 %, entsprechend durch Multi-Gated Acquisition (MUGA) oder durch Echokardiographie beurteilt; und ein Fridericia-korrigiertes QTc (QTcF)-Intervall von < 470 ms aufweisen.
7. Jene, die bereit sind, während der Behandlung und für mindestens 6 Monate nach der Verwendung einer hochwirksamen Methode der Empfängnisverhütung wie Kondome, Implantate, Injektionen, kombinierte orale Kontrazeptiva, Intrauterinpessaren, sexuelle Abstinenz oder Vasektomie zuzustimmen, wenn es sich um gebärfähige Frauen (definiert gemäß den Richtlinien der Clinical Trials Facilitation and Coordination Group als fruchtbare Frau, nach der Menarche und bis zur Postmenopause, sofern nicht dauerhaft steril) und reproduktionsfähige Männer handelt.
8. Gebärfähige Frauen, die einen negativen Schwangerschaftstest vorweisen.

Ausschlusskriterien
Ausschlusskriterien: Teilnehmer, die eines der folgenden Ausschlusskriterien erfüllen, werden nicht für die Aufnahme in die Studie berücksichtigt:
1. Teilnehmer, die innerhalb von 3 Wochen vor dem geplanten Tag -7 als nicht für eine allogene HSZT geeignet angesehen werden, z. B. aufgrund einer schweren Begleiterkrankung:
- Teilnehmer, die eine mittelschwere oder schwere Nierenfunktionsstörung haben, z. B. Dialysepatienten, Nierentransplantationen in der Vorgeschichte, oder eine errechnete Kreatinin-Clearance (Cockcroft-Gault Formel) von < 60 ml/min haben. (Siehe im Protokoll Sektion 3.5.2.1 für die Berechnungs Details)
- Teilnehmer mit schwerwiegender Lungenfunktionsstörung, Diffusionskapazität der Lunge für Kohlenmonoxid (DLCOSB [Hämoglobin-adjustiert]) oder forcierter Exspirationsfluss (FEV1) von < 50 % oder schwere Dyspnoe im Ruhezustand oder Notwendigkeit einer Sauerstoffergänzung.
- Teilnehmer, die schwere Leberfunktionsstörung haben, angezeigt durch Hyperbilirubinämie > 3 x ONG oder Alanin-Aminotransferase (ALT) oder Aspartat-Aminotransferase (AST) > 5 x ONG.
- Teilnehmer, bei denen eine Behandlung mit Anti-Thymozyten-Globulin (ATG) während der Dauer der Treosulfan-Behandlung geplant ist.
2. Teilnehmer, die eine bekannte koronare Herzkrankheit, einen Myokardinfarkt in der Vorgeschichte, Herzfunktionsstörungen, einschließlich Kardiomyopathien, Herzinsuffizienz (New York Heart Association Klasse II und höher) und Herzrhythmusstörungen (einschließlich paroxysmalem und permanentem Vorhofflimmern), interventrikuläre Leitungsverzögerung und / oder Schenkelblock (QRS-Dauer > 120 ms) aufweisen.
3. Teilnehmer, die eine deutliche Verlängerung des QT/QTc-Intervalls zu zu Beginn der Studie (z. B. wiederholte Demonstration eines QTc-Intervalls > 450 ms) aufweisen.
4. Teilnehmer mit Vorgeschichte zusätzlicher Risikofaktoren für Torsades de Pointes (z. B. Herzinsuffizienz, Hypokaliämie, Long-QT-Syndrom in der Familienanamnese).
5. Teilnehmer, die Begleitmedikamente verwenden, von denen bekannt ist, dass sie das QT/QTc-Intervall verlängern (wie auf www.crediblemeds.org aufgeführt).
6. Teilnehmer, die eine aktive maligne Beteiligung des zentralen Nervensystems aufweisen.
7. Teilnehmer, die HIV-positiv sind oder eine aktive, nicht kontrollierte Infektionskrankheit in Behandlung haben, einschließlich Pilzinfektion, aktive virale Leberinfektion und bekannte Virusinfektion mit Coronavirus 2 (SARS-CoV-2) mit schwerem akuten respiratorischen Syndrom während der 6 Monate vor der Aufnahme.
8. Teilnehmer, die zuvor eine allogene HSZT hatten.
9. Teilnehmer, die Pleuraerguss oder Aszites von > 1,0 l haben.
10. Teilnehmer, die schwanger sind oder sich in der Stillzeit befinden.
11. Teilnehmer, die unkontrollierte oder schwere interkurrente Erkrankungen haben.
12. Teilnehmer, die eine bekannte Überempfindlichkeit gegen Treosulfan, Fludarabin und / oder verwandte Inhaltsstoffe haben.
13. Teilnehmer, die innerhalb von 4 Wochen vor Tag -7 an einer anderen experimentellen Arzneimittelstudie teilnehmen (außer denen für COVID-19-Impfstoffe). Diese Ausnahme dient der Wahrung der Interessen des Teilnehmers, da diese Bevölkerungsgruppe einem hohen Risiko für COVID-19-Komplikationen ausgesetzt ist, wenn die Krankheit auftritt. Einzelheiten zum COVID-19-Impfstoff (einschließlich Impfstoffname, Charge und Hersteller, Dosis, Datum der Verabreichung und ob der rechte oder linke Arm injiziert wurde) sollten als Begleitmedikation erfasst werden, um eine bessere Beurteilung der Gesamtwirkung der COVID-19-Impfung zu ermöglichen zu onkologischen Studienergebnissen.
14. Teilnehmer, die nicht kooperatives Verhalten oder Nichteinhaltung zeigen.
15. Teilnehmer, die psychiatrische Erkrankungen haben, die die Fähigkeit beeinträchtigen könnten, eine Patienteninformation und Einwilligungserklärung abzugeben.
16. Jede Kontraindikation für Treosulfan und/oder Fludarabin (wie in der aktuellen Version der Zusammenfassung der Merkmale des Arzneimittels [SmPC] angegeben).

Studienteilnehmende Mindestalter
18 Jahr(e)

Studienteilnehmende Höchstalter
70 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
MDS - Myelodysplastisches Syndrom, AML - Akute myeloische Leukämie

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Joachim Göthert

+49 (0)201 723-82530
joachim.goethert@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Novartis Pharma Schweiz AG

+41 41 763 71 11

Suurstoffi 14
6343 Rotkreuz

Einschlusskriterien
1. Signed informed consent must be obtained prior to participation in the study.

2. Male or female patients ≥18 years of age.

3. Patients with CML-CP within 3 months of diagnosis.

4. Diagnosis of CML-CP (ELN 2020 criteria) with cytogenetic confirmation of the Philadelphia chromosome
Documented chronic phase CML will meet all the below criteria Baccarani et al 2013:
- < 15% blasts in peripheral blood and bone marrow,
- < 30% blasts plus promyelocytes in peripheral blood and bone marrow,
- < 20% basophils in the peripheral blood,
- PLT count ≥ 100 x 10^9/L (≥ 100,000/mm3), except treatment induced thrombocytopenia
- No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly.

5. Evidence of typical BCR::ABLI transcript [e14a2 and/or e13a2] which is amenable to standardized RQ-PCR quantification by the central laboratory assessment. However, if a local qualitative assay, validated according to local regulation, from an accredited local laboratory has confirmed evidence of typical BCR::ABLI transcript [e14a2 and/or e13a2], 4. ECOG performance status of 0 or 1.

6. ECOG performance status of 0 or 1.

7. Adequate end organ function as defined by:
- Total bilirubin (TBL) < 3 x ULN; patients with Gilbert's syndrome may only be included if TBL ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN,
- CrCl ≥ 30 mL/min as calculated using Cockcroft-Gault formula, Serum lipase ≤ 1.5 x ULN. For serum lipase > ULN - ≤ 1.5 x ULN, value must be considered not clinically significant and not associated with risk factors for acute pancreatitis.

8. Patients must have the following laboratory values within normal limits or corrected to within normal limits with supplements prior to randomization:
- Potassium (potassium increase of up to 6.0 mmol/L is acceptable if associated with CrCl* ≥ 90 mL/min),
- Total calcium (corrected for serum albumin); (calcium increase of up to 12.5 mg/dl or 3.1 mmol/L is acceptable if associated with CrCl* ≥ 90 mL/min),
- Magnesium (magnesium increase of up to 3.0 mg/dL or 1.23 mmol/L if associated with CrCl* ≥ 90 mL/min),
- For patients with mild to moderate renal impairment (CrCl* ≥ 30 mL/min and <90 mL/min) - potassium, total calcium (corrected for serum
albumin) and magnesium should be within normal limits or corrected to within normal limits with supplements prior to randomization.
- CrCl as calculated using Cockcroft-Gault formula.

Ausschlusskriterien
1. Previous treatment of CML with any other anticancer agents including chemotherapy and/or biologic agents or prior stem cell transplant, with the
exception of hydroxyurea and/or anagrelide.
2. Known cytopathologically confirmed CNS infiltration (in absence of suspicion of CNS involvement, lumbar puncture not required).
3. Impaired cardiac function or cardiac repolarization abnormality including but not limited to any one of the following:
- History of myocardial infarction (MI), angina pectoris, coronary artery bypass graft (CABG) within 6 months prior to starting study treatment.
- Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block).
- QTcF = 450 ms (male patients), =460 ms (female patients) on the average of three serial baseline ECG (using the QTcF formula). If QTcF = 450 ms and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTcF.
- Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:
- Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia.
- Concomitant medication(s) with a "Known risk of Torsades de Pointes" per www.crediblemeds.org that cannot be discontinued or replaced 7 days prior to starting study drug by safe alternative medication.
- Inability to determine the QTcF interval.
4. Severe and/or uncontrolled concurrent medical disease that in the opinion of the Investigator could cause unacceptable safety risks or
compromise compliance with the protocol (e.g. uncontrolled diabetes, active or uncontrolled infection; uncontrolled arterial or pulmonary
hypertension, uncontrolled clinically significant hyperlipidemia).
5. History of significant congenital or acquired bleeding disorder unrelated to cancer.
6. Major surgery within 4 weeks prior to study entry or patients who have not recovered from prior surgery.
7. History of other active malignancy within 3 years prior to study entry with the exception of previous or concomitant basal cell skin cancer and
previous carcinoma in situ treated curatively.
8. History of acute pancreatitis within 1 year prior to randomization or medical history of chronic pancreatitis.
9. History of chronic liver disease leading to severe hepatic impairment, or ongoing acute liver disease.
10. Known history of chronic Hepatitis B (HBV), or chronic Hepatitis C (HCV) infection. Testing for Hepatitis B surface antigen (HBs Ag) and
Hepatitis B core antibody (HBc Ab/anti HBc) will be performed at screening. If anti-HBc is positive, HBV-DNA evaluation will be carried out at
screening. A patient having positive HBV-DNA will not be enrolled in the study. Also, a patient with positive HBsAg will not be enrolled in the
study. HCV Ab testing will also be performed at screening. For details on the criteria see Appendix 4.
11. History of Human Immunodeficiency Virus (HIV) unless well-controlled on a stable dose of anti-retroviral therapy at the time of screening.

12. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study treatment (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery).

13. Participation in a prior investigational study within 30 days prior to randomization or within 5 half-lives of the investigational product, whichever is longer.

14. Pregnant or nursing (lactating) women

15. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment and for a period of time after stopping study medication. For asciminib, this period of time is 3 days after last dose; if local regulations or locally approved prescribing information differ from the protocol required duration of contraception, the longer duration must be followed and the same requirements will be described in the ICF.Participants taking nilotinib should be willing to follow contraception requirements in the locally-applicable prescribing information for nilotinib.
Highly effective contraception methods include:

-Total abstinence (when this is in line with the preferred and usual lifestyle of the participant. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post- ovulation methods) and withdrawal are not acceptable methods of contraception.

- Female bilateral tubal ligation, female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or total hysterectomy, at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.

-Male partner's sterilization (at least 6 months prior to screening). For female participants on the study, the vasectomized male partner should be the sole partner for that participant
-Use of oral, (estrogen and progesterone), injected, or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception.

In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.

Women are considered post-menopausal if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate history of vasomotor symptoms). Women are considered not of child bearing potential if they are post-menopausal or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks prior to enrollment on the study. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered to be not of child bearing potential.

Sexually active males taking study treatment do not require contraception.

16. Known hypersensitivity to the study treatment.

Note: The Investigator has the discretion to include/exclude a patient in the study, who will be found to have symptoms representative of COVID-19 or tested positive for COVID-19 during the screening phase. Such patients should be managed as per the country specific guidelines related to COVID-19. For patients who test positive for COVID-19, re-testing is recommended before initiating study treatment.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
CML - chronische myeloische Leukämie

Medizinischer Befund
newly diagnosed Philadelphia Chromosom positive chronic Myelogeneous Leukämia in chronic Phase

MedDRA Term
Chronic myelogenous leukemia

Institute
Klinik für Hämatologie und Stammzelltransplantation, Klinik für Kinderheilkunde III, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Dirk Reinhardt

+49 (0)201 723-3784
dirk.reinhardt@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Syndax Pharmaceuticals

646-690-7620
clinicaltrials@syndax.com

43rd Street 211 East
NY 10017 New York

Einschlusskriterien
Participants must have active acute leukemia (bone marrow blasts ≥5% or reappearance of blasts in peripheral blood) as defined by the National Comprehensive Cancer Network (NCCN) in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Lymphoblastic Leukemia (Version 1.2020) and Acute Myeloid Leukemia (Version 3.2020), or acute leukemia harboring an MLL rearrangement, NUP98 rearrangement, or NPM1c mutation that have detectable disease in the bone marrow.

* Phase 1:
- Arm A: Participants not receiving any strong CYP3A4 inhibitor/inducers or fluconazole.
- Arm B: Participants receiving itraconazole, ketoconazole, posaconazole, or voriconazole (strong CYP3A4 inhibitors) for antifungal prophylaxis.
- Arm C: Participants receiving SNDX-5613 in combination with cobicistat.
- Arm D: Participants receiving fluconazole (moderate CYP3A4 inhibitor).
- Arm E: Participants not receiving any weak, moderate, or strong CYP3A4 inhibitors/inducers.
- Arm F: Participants receiving isavuconazole (moderate CYP3A4 inhibitor) for antifungal prophylaxis.
* Phase 2:
- Cohort 2A: Documented R/R ALL/MPAL with an MLLr translocation.
- Cohort 2B: Documented R/R AML with an MLLr translocation.
- Cohort 2C: Documented R/R AML with NPM1c.
* White blood cell count below 25,000/ microliter at time of enrollment. Participants may receive cytoreduction prior to enrollment per protocol-specified criteria.
* Male or female participants aged ≥30 days old.
* Eastern Cooperative Oncology Group (ECOG) performance status score 0-2 or Karnofsky/Lansky score ≥50.
* Any prior treatment-related toxicities resolved to ≤Grade 1 prior to enrollment, with the exception of ≤Grade 2 neuropathy or alopecia.
* Radiation Therapy: At least 60 days from prior total body irradiation (TBI), craniospinal radiation and/or ≥50% radiation of the pelvis, or at least 14 days from local palliative radiation therapy (small port).
* Stem Cell Infusion: At least 60 days must have elapsed from hematopoietic stem cell transplant and at least 4 weeks must have elapsed from donor lymphocyte infusion.
* Immunotherapy: At least 42 days since prior immunotherapy, including tumor vaccines and checkpoint inhibitors, and at least 21 days since receipt of chimeric antigen receptor therapy or other modified T cell therapy.
* Antileukemia Therapy: At least 14 days, or 5 half-lives, whichever is shorter, since the completion of antileukemic therapy.
* Hematopoietic Growth Factors: At least 7 days since the completion of therapy with short-acting hematopoietic growth factors and 14 days with long-acting growth factors.
* Biologics: At least 90 days, or 5 half-lives, whichever is shorter, since the completion of therapy with an antineoplastic biologic agent.
* Steroids: At least 7 days since systemic glucocorticoid therapy, unless receiving physiologic dosing (equivalent to ≤10 mg prednisone daily) or cytoreductive therapy.
* Adequate organ function.
* If of childbearing potential, willing to use a highly effective method of contraception or double barrier method from the time of enrollment through 120 days following the last study drug dose.

Ausschlusskriterien
Participants meeting any of the following criteria are not eligible for study participation:
* Active diagnosis of acute promyelocytic leukemia.
* Isolated extramedullary relapse.
* Active central nervous system disease (cytologic, such as any blasts on cytospin, or radiographic).
* Detectable human immunodeficiency virus (HIV) viral load within the previous 6 months. Participants with a known history of HIV 1/2 antibodies must have viral load testing prior to study enrollment.
* Hepatitis B or C.
* Pregnant or nursing women.
* Cardiac Disease:
- Any of the following within the 6 months prior to study entry: myocardial infarction, uncontrolled/unstable angina, congestive heart failure (New York Heart Association Classification Class =II), life-threatening, uncontrolled arrhythmia, cerebrovascular accident, or transient ischemic attack.
- Corrected QT interval (QTc) >450 milliseconds.
* Gastrointestinal Disease:
- any gastrointestinal issue of the upper GI tract that might affect oral drug absorption or ingestion (that is, gastric bypass, gastroparesis, etc).
- Cirrhosis with a Child-Pugh score of B or C.
* Graft-Versus-Host Disease (GVHD): Signs or symptoms of acute or chronic GVHD >Grade 0 within 4 weeks of enrollment. All transplant participants must have been off all systemic immunosuppressive therapy and calcineurin inhibitors for at least 4 weeks prior to enrollment. Participants may be on physiological doses of steroids.
* Concurrent malignancy in the previous 2 years with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (for example, breast carcinoma, cervical cancer in situ, melanoma in situ) treated with potentially curative therapy, or concurrent low-grade lymphoma, that is asymptomatic and lacks bulky disease and shows no evidence of progression, and for which the participant is not receiving any systemic therapy or radiation.
* In Phase 1 and Phase 2: Participants requiring the concurrent use of medications known or suspected to prolong the QT/QTc interval, with the exception of drugs with low risk of QT/QTc prolongation that are used as standard supportive therapies (for example, diphenhydramine, famotidine, ondansetron, Bactrim) and the azoles permitted in the relevant arms of Phase 1.

Studienteilnehmende Mindestalter
30 Tag(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
KIK-Onko

Medizinischer Befund
Acute Myeloid Leukemia\nAcute Lymphoblastic Leukemia\nMixed Lineage Acute Leukemia\nMixed Phenotype Acute Leukemia\nAcute Leukemia of Ambiguous Lineage

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Bastian von Tresckow

+49 (0)201 723-82530
bastian.vontresckow@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Universitätsklinikum Köln

Einschlusskriterien
Histologically confirmed first relapse of cHL or primary refractory cHL

4.1 INCLUSION CRITERIA
Potential participants are eligible to be enrolled in the clinical trial only if all of the following criteria apply:
1. Histologically confirmed first relapse of cHL or primary refractory cHL (primary refractory = no response to first-line therapy or recurrence within 3 months after end of first-line therapy)

2. No previous treatment for r/r HL

3. Patient is considered to be eligible for autologous stem cell transplantation by the investigator

4. Age ≥18 and <65 years on the day of signing the patient information and informed consent form (ICF)

5. Written informed consent for the clinical trial provided by the participant

6. Agreement of patient to use of their personal data and tissue material for the clinical trial, with due regard for data protection

7. Presence of measurable disease - Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions

8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the date of enrollment.

9. Estimated life expectancy > 3 months

10. A female participant is eligible to participate if she is not pregnant (see 12.1.4), not breastfeeding, and either
a.) Not a woman of childbearing potential (WOCBP) as defined in 12.1.4
OR
b.) A WOCBP who agrees to follow the contraceptive guidance in 12.1.4 during the treatment period and for at least 6 months after the last dose of trial treatment.

11. A male participant must agree to use contraception as detailed in 12.1.4 of this protocol during the treatment period and for at least 6 months after the last dose of trial treatment and refrain from donating sperm during this period.

Ausschlusskriterien
Nodular lymphocyte-predominant Hodgkin lymphoma or composite lymphoma

.2 EXCLUSION CRITERIA
Potential participants cannot be enrolled in the clinical trial if any of the following criteria apply:

1. Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) or composite
lymphoma

2. Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent
directed to another stimulatory or co-inhibitory T-cell receptor (e.g. CTLA-4, OX-40,
CD137)

3. Prior allogenic tissue or solid organ transplant

4. Severe hypersensitivity (= grade 3) to pembrolizumab and/or any of its excipients

5. History or current evidence of any condition, therapy, or laboratory abnormality that
might confound the results of the clinical trial, interfere with the patient’s participation
for the full duration of the clinical trial, or is not in the best interest of the subject to
participate, in the opinion of the treating investigator
including:

NEUROLOGICAL/PSYCHIATRIC DISORDERS
• Symptomatic neurologic disease compromising normal activities of daily living
or requiring medications
• Active central nervous system (CNS) metastases and/or carcinomatous
meningitis
except for / permitted to enroll are patients with:
previously treated brain metastases provided they are radiologically stable, i.e.
without evidence of progression for at least 4 weeks by repeat imaging (note
that the repeat imaging should be performed during the pre-enrollment phase),
clinically stable and without requirement of steroid treatment for at least 14 days
prior to enrollment.
• Prior cerebral injury
• Epilepsy
• Psychiatric disorders, that would interfere with cooperation with requirements
of the clinical trial

CARDIAC DISORDERS
• History of one or more of the following within 6 months prior to enrollment:
o Myocardial infarction, or
o Unstable symptomatic ischemic heart disease, or
o Thromboembolic events (e.g. deep vein thrombosis, pulmonary
embolism, or symptomatic cerbrovascular events), or
o Any other serious cardiac condition (e.g. pericardial effusion, restrictive cardiomyopathy), that, in opinion of the investigator, would potentially
interfere with the completion of treatment according to the protocol
• Ongoing arrhythmias of grade > 2,
except for / permitted to enroll are patients with:
o Chronic stable atrial fibrillation on stable anticoagulant therapy
• Left-ventricular ejection fraction < 50% (recent evidence within 6 months prior
to enrollment)
• Heart failure NYHA (New York Heart Association) III or IV
• Q-wave infarction, unless identified 6 or more months prior to first dose of trial
treatment
• QTc interval > 480 msec
• Uncontrolled hypertension > 180/100 mmHg despite appropriate medication (i.e
at least 3 different antihypertensive agents)
PULMONARY DISORDERS
• Chronic obstructive pulmonary disease with global insufficiency
• Has a history of (non-infectious) pneumonitis/interstitial lung disease that
required steroids
• Active pneumonitis/interstitial lung disease or another chronic lung disease
which results in a severely impaired lung function as defined by spirometry, i.e.
forced expiratory volume in one second (FEV1) and diffusing capacity of the
lung for carbon monoxide (DLCO) (< 60% of the normal predicted value of FEV1
and DLCO)
INFECTIOUS DISORDERS
• Active infection requiring systemic therapy
• Concurrent active Hepatitis B (defined as HBsAg positive and/or detectable
HBV DNA) and Hepatitis C virus (defined as anti-HCV Ab positive and
detectable HCV RNA) infection.
Note: Hepatitis B and C screening tests are not required unless there is a known
history of HBV and/or HCV infection and /or as mandated by local health
authority
CRITERIA FOR ENROLLMENT - EXCLUSION CRITERIA
Confidential GHSG – Pembro-CORE Pilot Trial Protocol V1.0 (15 May 2023) 29
• Known history of testing positive for human immunodeficiency virus (HIV) or
known acquired immunodeficiency syndrome (AIDS)
MALIGNANT DISORDERS
• Prior malignancy, other than cHL, active within the previous 5 years,
except for / permitted to enroll are subjects with locally curable cancers that
have been apparently cured, e.g.:
o Basal or squamous cell skin cancer
o Superficial bladder cancer
o Carcinoma in situ of the prostate, cervix or breast
AUTOIMMUNE DISORDERS
Active autoimmune disease that has required systemic treatment in the past 2
years (i.e. with use of disease modifying agents, corticosteroids or
immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency, etc.) is not considered a form of systemic treatment and is
allowed.
except for / permitted to enroll are subjects with:
o Vitiligo
o Type I diabetes mellitus
o Psoriasis not requiring systemic treatment
o Conditions not expected to recur in the absence of an external trigger
6. Abnormal organ function (except for HL-related disorders) reflected by the following
laboratory values obtained within 7 days prior to enrollment:
• Leukocytes = 2 x 109/L
• Neutrophils < 1.5 x 109/L
• Thrombocytes < 100 x 109/L
• Hemoglobin < 9.0 g/dL
• Serum creatinine < 1.5 x upper limit of normal (ULN) or creatinine clearance
(CrCl) = 60 mL/min (if using the Cockcroft-Gault formula below):
Female CrCl = (140 - age in years) x weight in kg x 0.85
72 x serum creatinine in mg/dL
Male CrCl = (140 - age in years) x weight in kg x 1.00
72 x serum creatinine in mg/dL
CRITERIA FOR ENROLLMENT - EXCLUSION CRITERIA
30 GHSG – Pembro-CORE Pilot Trial Protocol V1.0 (15 May 2023) Confidential
• Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) > 3 x ULN
• Total Bilirubin < 2.5 x ULN (except subjects with Gilbert Syndrome, who can
have total bilirubin > 3.0 mg/dL)
• Fasting blood sugar > 200 mg/dL
• International normalized ratio (INR) OR prothrombin time (PT) / Activated partial
thromboplastin time (aPTT) > 1.5 × ULN
unless participant is receiving anticoagulant therapy as long as PT or aPTT is
within therapeutic range of intended use of anticoagulants
7. Diagnosis of immunodeficiency or chronic systemic steroid therapy (in dosing
exceeding 10 mg daily of prednisone equivalent) or any other form of
antineoplastic/immunosuppressive therapy within 7 days prior to enrollment
except for / permitted are:
o Adrenal replacement doses = 10 mg daily prednisone equivalents in the
absence of active autoimmune disease
o A brief course of systemic corticosteroids for prophylaxis or for treatment
of non-autoimmune conditions
o Inhaled or topical steroids

8. Prior systemic anti-cancer therapy including investigational agents within 4 weeks prior
to enrollment
Note: Participants must have recovered from all AEs due to previous therapies to =
grade 1 or baseline. Participants with = grade 2 neuropathy may be eligible.
Participants with endocrine-related AEs Grade =2 requiring treatment or hormone
replacement may be eligible
Note: If participants had major surgery, they must have recovered adequately from the
procedure and/or any complications from the surgery prior to starting trial intervention.

9. Current or prior participation in a clinical trial of an investigational agent or use of
investigational device within 4 weeks prior to enrollment.
Note: Participants who have entered the follow-up phase of an investigational clinical
trial may participate as long as it has been 4 weeks after the last dose of the previous
investigational agent.

10. Prior radiotherapy within 2 weeks prior to enrollment.
Participants must have recovered from all radiation-related toxicities, not require
corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted
for palliative radiation (= 2 weeks of radiotherapy) to non-CNS disease.
CRITERIA FOR ENROLLMENT - EXCLUSION CRITERIA
Confidential GHSG – Pembro-CORE Pilot Trial Protocol V1.0 (15 May 2023) 31

11. Live vaccine or live-attenuated vaccine within 30 days prior to enrollment and while
participating in the trial.
Note: Administration of killed vaccines is allowed. Any licensed COVID-19 vaccine
(including for Emergency Use) in a particular country is allowed in the study as long
as they are mRNA vaccines, replication-incompetent adenoviral vaccines, or
inactivated vaccines. These vaccines will be treated just as any other concomitant
therapy

12. Patient’s lack of accountability and inability to appreciate the nature, meaning and
consequences of the clinical trial and to formulate his/her own wishes correspondingly

13. Non-compliance, e.g. due to
• Drug dependency or substance abuse that would interfere with cooperation with
requirements of the clinical trial
• Refusal of blood products during treatment
• Change of residence to abroad
• Any similar circumstances that appear to make protocol treatment or long-term
follow-up impossible

14. Pregnancy (for details please see 12.1.4), breastfeeding, or expecting to conceive or
father children within the projected duration of the clinical trial, starting with the preenrollment
visit through 6 months after the last dose of trial treatment

15. Patients who have a relationship of dependence or employer-employee relationship to
the sponsor or the investigator

16. Committal to an institution on judicial or official order

17. Has not adequately recovered from major surgery or has ongoing surgical
complications

Studienteilnehmende Mindestalter
18 Jahr(e)

Studienteilnehmende Höchstalter
65 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
HD - Hodgkin Lymphom

Medizinischer Befund
First-relapsed or Refractory Classical Hodgkin Lymphoma

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Bastian von Tresckow

+49 (0)201 723-82530
bastian.vontresckow@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Universität des Saarlandes

Studienteilnehmende Mindestalter
60 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
DLBCL - Diffuses großzelliges B-Zell-Lymphom

Medizinischer Befund
Diffuse Large B-cell lymphoma (DLBCL)

Institut
Klinik für Hämatologie und Stammzelltransplantation

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Alexander Röth

+49 (0)201 723-82530
alexander.roeth@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Novartis Pharmaceuticals

+1 888-669-6682
novartis.email@novartis.com

1000 S Pine Island Rd #410
33324 Florida

Einschlusskriterien
- Signed informed consent must be obtained prior to participation in the study.
- Male and female participants ≥ 18 years of age, at the time of ICF signatures and with a diagnosis of PNH confirmed by treating physician.
- Stable regimen (dose and intervals) of anti-C5 antibody treatment (either eculizumab or ravulizumab) for at least 6 months prior to screening
- Mean hemoglobin level ≥10 g/dL
- Vaccination against Neisseria meningitidis and S. pneumoniae infection are required prior to the start of iptacopan treatment.
- If not received previously, vaccination against Haemophilus influenzae infections is recommended, if available and according to local regulations.
- Ability to communicate well with the investigator, to understand and comply with the requirements of the study
- Other protocol -defined inclusion criteria may apply at the end.

Ausschlusskriterien
- Participation in any other investigational drug trial or use of other investigational drugs at the time of enrollment
- Patients requiring red blood cell transfusion in the 6 months prior to screening or during screening
- History of stem cell transplantation or any solid organ transplantation
- Active systemic bacterial, viral (incl. COVID-19) or fungal infection within 14 days prior to study drug administration
- Presence of fever = 38.0 °C (100.4 °F) within 7 days prior to study drug administration
- Human immunodeficiency virus (HIV) infection (known history of HIV or test positive for HIV antibody at Screening)
- A history of recurrent invasive infections caused by encapsulated organisms, e.g. meningococcus or pneumococcus
- Unstable medical condition including, but not limited to, myocardial ischemia, active gastrointestinal bleeding, coexisting chronic anemia unrelated to PNH, or unstable thrombotic event not amenable to active treatment as judged by the investigator at Screening.
- History of cancer of any part of the body within the past 5 years,
- Ongoing drug or alcohol abuse that could interfere with patient's participation in the trial.
- Any medical condition deemed likely to interfere with the patient's participation in the study
- Female patients who are pregnant or breastfeeding, or intending to conceive during the course of the study

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
PNH - Paroxysmale nächtliche Hämoglobinurie

Medizinischer Befund
Paroxysmal Nocturnal Hemoglobinuria

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Dr. med. Julia von Tresckow

+49 (0)201 723-82530
julia.vontresckow@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Loxo Oncology

Einschlusskriterien
- Confirmed diagnosis of CLL/SLL requiring therapy per iwCLL 2018 criteria
- Previous treatment with at least one line of therapy that may include a covalent Bruton's tyrosine kinase (BTK) inhibitor
- Platelets greater than or equal to (≥)50 x 10⁹/liter (L), hemoglobin ≥8 grams/deciliter (g/dL) and absolute neutrophil count ≥1.0 x 10⁹/L
- Adequate organ function
- Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2
- Estimated creatinine clearance ≥30 milliliters per minute (mL/min)

Ausschlusskriterien
- Known or suspected Richter's transformation at any time preceding enrollment
- Prior therapy with a non-covalent (reversible) BTK inhibitor
- Patients requiring therapeutic anticoagulation with warfarin or another Vitamin K antagonist
- Current treatment with strong cytochrome P450 (CYP) 3A4 (CYP3A4) inhibitors or inducers
- Prior therapy with venetoclax
- Central nervous system (CNS) involvement
- Active uncontrolled systemic bacterial, viral, fungal, or parasitic infection
- Known human immunodeficiency virus (HIV) infection, regardless of cluster of differentiation 4 (CD4) count
- Allogeneic stem cell transplantation (SCT) or chimeric antigen receptor (CAR)-T within 60 days
- Active hepatitis B or hepatitis C
- Known active cytomegalovirus (CMV) infection
- Uncontrolled immune thrombocytopenic purpura (ITP) or autoimmune hemolytic anemia (AIHA)
- Significant cardiovascular disease
- Vaccination with a live vaccine within 28 days prior to randomization
- Patients with the following hypersensitivity:
- Known hypersensitivity to any component or excipient of pirtobrutinib and venetoclax
- Prior significant hypersensitivity to rituximab
- Known allergy to allopurinol and inability to take uric acid lowering agent

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
CLL - Chronische lymphatische Leukämie, SLL - kleinzelliges lymphozytisches Lymphom

Medizinischer Befund
Chronic Lymphocytic Leukemia (CLL)\nSmall Lymphocytic Lymphoma (SLL)

MedDRA Term
Chronic lymphocytic leukemia

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Bastian von Tresckow

+49 (0)201 723-82530
bastian.vontresckow@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

IKF Klinische Krebsforschung GmbH am Krankenhaus Nordwest

Einschlusskriterien
* Patient has provided written informed consent and is able and willing to comply with the study protocol and protocol mandated hospitalizations according to ICH and local regulations.
* Patient is above 60 years of age
* Patient is not eligible for a fully dosed R-CHOP
* Patient has histologically confirmed aggressive B-cell lymphoma.
* Patient has at least one measurable FDG PET-positive lymphoma manifestation; defined as lesional maximum FDG uptake higher than the maximum FDG uptake in unaffected liver parenchyma as measured in a reference volume-of-interest with >10 mL
* Baseline biopsy material is available for central review.
* Female patients considered as women of childbearing potential (WOCBP, see section 5.2.7 for definition) and male patients with female partners considered as WOCBP must:
- agree to either remain completely abstinent (refrain from heterosexual intercourse) or to use at least one effective contraceptive methods that results in a failure rate of < 1% per year
- refrain from donating ova (female patients) or donating sperm (male patients)
- in case of male patients with pregnant female partners, remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures such as a condom to avoid exposing the embryo.
* Patient did not receive any prior lymphoma therapy.
* Patient has an ECOG performance status of ≤ 2.
* Patient has with treatment a life expectancy (in the opinion of the investigator) of at least 12 weeks.
* Patient has adequate liver function
* Patient as adequate hematological function
* Patient has adequate renal function
* Patients has negative serologic and/or polymerase chain reaction (PCR) test results for:
- Acute or chronic hepatitis B (HBV) infection.
- Hepatis C virus (HCV) and human immunodeficiency virus (HIV)
* Patient has no active SARS-CoV-2 infection.

Ausschlusskriterien
* Patient with chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL) (including CD20+ ALL), lymphoblastic lymphoma, Richter's transformation, Burkitt lymphoma.
* Patient = 60 years
* Patient with known active infection, or reactivation of a latent infection, whether bacterial (e.g., tuberculosis), viral (including, but not limited to severe pneumonia, COVID-19, Epstein-Barr virus [EBV], cytomegalovirus [CMV], hepatitis B, hepatitis C, and HIV], fungal, mycobacterial, or other pathogens (excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with IV antibiotics (for IV antibiotics this pertains to completion of last course of antibiotic treatment) within 4 weeks prior to study enrollment.
* Patient with current > Grade 1 peripheral neuropathy.
* Patient with history of confirmed progressive multifocal leukoencephalopathy (PML).
* Patient with history of leptomeningeal disease.
* Patient with current or history of CNS lymphoma.
* Patient with current or history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease with exceptions.
* Patient with another invasive malignancy in the last 2 years (with the exception of basal cell carcinoma and tumors deemed by the Investigator to be of low likelihood for recurrence), with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate 90%), such as adequately-treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.
* Patient with significant or extensive history of cardiovascular disease (such as New York Heart Association (NYHA) Class = II cardiac disease, congestive heart failure, myocardial infarction or cerebrovascular accident within the past 3 months, unstable arrhythmias, or unstable angina or history of multiple cardiovascular events) or significant pulmonary disease (including obstructive pulmonary disease and history of bronchospasm).
* Patient with active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, or multiple sclerosis (see addendum for a more comprehensive list of autoimmune diseases and immune deficiencies), with exceptions.
* Patient with uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently).
* Patient with history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic.
Prior/Concomitant Therapy:
* Patient received treatment with any other standard anti-cancer radiotherapy/chemotherapy including investigational therapy (defined as treatment for which there is currently no regulatory authority approved indication) within 4 weeks or five times the elimination half-life of the product, whichever is longer, prior to study enrollment.
* Patient with prior solid organ transplantation.
* Patient with prior allogeneic stem cell transplantation.
* Patient with prior treatment with targeted therapies (e.g., tyrosine kinase inhibitors, systemic immunotherapeutic/immunostimulating agents, including, but not limited to, CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies, radio-immunoconjugates, antibody-drug conjugates, immune/cytokines, and monoclonal antibodies) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to study enrollment.
* Patient with toxicities from prior anti-cancer therapy including immunotherapy that did not resolve to = Grade 1 except for alopecia, endocrinopathy managed with replacement therapy and stable vitiligo.
* Patient with any history of immune related = Grade 3 AE except for endocrinopathy managed with replacement therapy.
* Patient with ongoing corticosteroid use 25 mg/day of prednisone or equivalent within 4 weeks prior and during study treatment.
* Patient with treatment with systemic immunosuppressive medication (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with exceptions.
* Patient who received administration of a live, attenuated vaccine within 4 weeks prior to study enrollment infusion or anticipation that such a live, attenuated vaccine will be required during the study or within 5 months after the last dose of study treatment.
Other Exclusions:
* Patient with history of illicit drug or alcohol abuse within 12 months prior to screening, in the Investigator's judgment.
* Patient with history of severe allergic anaphylactic reactions to chimeric or humanized monoclonal antibodies or recombinant antibody-related fusion proteins.
* Patient with known hypersensitivity to Chinese hamster ovary (CHO) cell products or to any component of the rituximab, obinutuzumab, polatuzumab vedotin and/or glofitamab formulation and/or to the contrast agents used in the study.
* Female patient is pregnant or breast feeding. Female patients of childbearing potential must have a negative serum pregnancy test result within 7 days prior to initiation of study treatment.
* Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.
* Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].
* Patients who are dependent on the sponsor, the investigator or the trial site.

Studienteilnehmende Mindestalter
61 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
DLBCL - Diffuses großzelliges B-Zell-Lymphom

Medizinischer Befund
Lymphoma, Large B-Cell, Diffuse\naggressive large B-cell lymphoma

MedDRA Term
Diffuse large B-cell lymphomas

Institute
Klinik für Neurologie, Klinik für Hämatologie und Stammzelltransplantation

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Refik Pul

refik.pul@uk-essen.de

Hufelandstr 55
45147 Essen

Sponsor

Bristol-Myers Squibb GmbH & Co. KGaA

Arnulfstraße 29
80636 München

Einschlusskriterien
- Relapsing forms of Multiple Sclerosis (RMS) - Cohort 1.
i) Participants must have an Expanded Disability Status Scale (EDSS) of ≥ 3.0 and ≤ 5.5.
ii) Participants must have a diagnosis of Multiple Sclerosis (MS) with relapsed/refractory MS or conversion to active secondary progressive multiple sclerosis (aSPMS), and worsening of disease within 12 months prior to Screening and while on treatment with a high-efficacy DMT for at least 6 months.
- Progressive forms of MS - Cohort 2.
i) Participants must have an EDSS ≥ 3.0 and ≤ 6.0.
ii) Participants must have a diagnosis of primary progressive multiple sclerosis (PPMS) that is treatment-resistant or diagnosis of inactive secondary progressive multiple sclerosis (iSPMS).

Ausschlusskriterien
- Participants that cannot complete the 9-Hole Peg Test (9-HPT) for each hand in <240 seconds.
- Participants that cannot perform a Timed 25-Foot Walk Test (T25FWT) in < 150 seconds.
- Participants must not have MS lesions or symptoms that may place patients at increased risk of neurotoxicity, including, but not limited to, tumefactive lesion (3 cm or greater within 5 years prior to Screening) or decreased level of consciousness, and/or presence of active, clinically significant concomitant central nervous system pathology other than MS that may confound the ability to interpret study results or complicate identification or evaluation of neurotoxicity.
- Other protocol-defined Inclusion/Exclusion criteria apply.

Studienteilnehmende Mindestalter
18 Jahr(e)

Studienteilnehmende Höchstalter
60 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
MS - Multiple Sklerose, Phase I Studie

Medizinischer Befund
Multiple Sclerosis (RMS)\nProgressive Forms of Multiple Sclerosis (PMS)

Institute
Klinik für Hämatologie und Stammzelltransplantation, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Bastian von Tresckow

+49 (0)201 723-82530
bastian.vontresckow@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

F. Hoffmann-La Roche AG

Einschlusskriterien
* Previously untreated participants with CD20-positive LBCL
* Confirmed availability of tumor tissue
* International prognostic index (IPI) score 2-5
* Eastern cooperative oncology group (ECOG) performance status of 0, 1, or 2
* At least one bi-dimensionally measurable lesion, defined as > 1.5 cm in its longest dimension as measured by CT or MRI
* Left ventricular ejection fraction (LVEF) >/=50% on cardiac multiple-gated acquisition (MUGA) scan or cardiac echocardiogram (ECHO)
* Adequate hematologic function
* Negative HIV test at screening with exceptions as defined by the protocol
* Negative SARS-CoV-2 antigen or PCR test

Ausschlusskriterien
* Contraindication to any of the individual components of Pola-R-CHP or glofitamab, including prior receipt of anthracyclines, or history of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies, or known sensitivity or allergy to murine products
* Prior solid organ transplantation
* Current Grade > 1 peripheral neuropathy by clinical examination or demyelinating form of Charcot-Marie-Tooth disease
* History of indolent lymphoma
* Current diagnosis of the following: Follicular lymphoma grade 3B; transformations of indolent B-cell lymphomas (e.g., de novo transformed follicular lymphoma); mediastinal grey zone lymphoma; primary mediastinal (thymic) large B-cell lymphoma; Burkitt lymphoma; primary large B-cell lymphoma of immune-privileged sites; primary effusion DLBCL; and primary cutaneous DLBCL
* Prior treatment with systemic immunotherapeutic agents
* Prior use of any monoclonal antibody for the purposes of treating cancer within 3 months of the start of Cycle 1
* Any investigational therapy for the purposes of treating cancer within 28 days prior to the start of Cycle 1
* Prior radiotherapy to the mediastinal/pericardial region
* Prior therapy for LBCL, with the exception of corticosteriods
* Corticosteroid use > 50 mg/day of prednisone or equivalent, for purposes other than lymphoma symptom control
* History of other malignancy that could affect compliance with the protocol or interpretation of results
* Significant or extensive history of cardiovascular disease
* Recent major surgery (within 4 weeks prior to the start of Cycle 1), other than for diagnosis
* Current or past history of central nervous system (CNS) disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease
* History of treatment-emergent immune-related adverse events associated with prior immunotherapeutic agents
* Active autoimmune disease which is not well controlled by therapy
* Clinically significant liver disease
* Live, attenuated vaccine within 4 weeks before study treatment infusion on Day 1 of Cycle 1 or anticipation that such a live, attenuated vaccine will be required during the study. Live vaccines during the study and until participants B cells recover are prohibited
* Any active infection within 7 days prior to Cycle 1 Day 1 that would impact participant safety
* Suspected active or latent tuberculosis
* Positive test results for chronic hepatitis B infection, hepatitis C, or the human T-lymphotropic virus type 1 (HTLV-1)
* History of progressive multifocal leukoencephalopathy

Studienteilnehmende Mindestalter
18 Jahr(e)

Studienteilnehmende Höchstalter
80 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
DLBCL - Diffuses großzelliges B-Zell-Lymphom

Medizinischer Befund
Large B-Cell Lymphoma