Studien

Institute
Neurologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Ulrike Schara-Schmidt

+49 (0)201 723-2356
ulrike.schara@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

German Cancer Research Center, Heidelberg

Einschlusskriterien
- Age ? 18 years, smoking or non-smoking, of any ethnic origin and gender
- Patients present with unequivocal first, second or third recurrence of a histologically confirmed IDH1R132H-mutated glioma WHO grade II, III or IV progressive after radiotherapy and chemotherapy
- Absence of chromosomal 1p/19q co-deletion in the primary tumor tissue and/or
- Loss of nuclear ATRX expression in the primary tumor tissue (partial loss allowed)
- Availability of tumor tissue for analysis (FFPE bulk tissue)
- Patients have received radiotherapy (54 - 60 Gy) and at least six months of alkylating chemotherapy
- Patients are at least three months off radiotherapy
- Patients must be candidates for re-resection and the re-resection must be postponable for seven weeks
- Patients should be immunocompetent (i.e. no concomitant treatment with dexamethasone (or equivalent), or receive stable/decreasing steroid levels not exceeding 2 mg/day dexamethasone (or equivalent) during the last 3 days prior to clinical screening; no severe lymphopenia)
- Karnofsky Performance Status ? 70
- Estimated creatinine clearance ? 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method)
- Ability of patient to understand character and individual consequences of the clinical trial
- Evidence of informed consent document personally signed and dated by the patient (or a witness in case the patient is unable to write) and indicating that the patient has been informed of all pertinent aspects of the study and that the patient consents to participate in the trial
- Women of child-bearing potential (WOCBP; i.e. those who have not undergone a hysterectomy, bilateral salpingectomy and bilateral oophorectomy or who have not been post-menopausal for at least 24 consecutive months) must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of the investigational medicinal product(s) (IMPs).
- WOCBP must be using an effective method of birth control to avoid pregnancy throughout the study and for 3 months after the last dose of the IMP. This includes two different forms of effective contraception (e.g. hormonal contraceptive and condom, IUD/IUS and condom) or sterilization, resulting in a failure rate less than 1% per year.
- Men must be willing and able to use an effective method of birth control throughout the study for up to 3 months after the last dose of the IMP(s), if their sexual partners are WOCBP (acceptable methods see above).
- Availability of pre-study MRT (magnetic resonance tomography) of latest tumor recurrence
- Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

Ausschlusskriterien
- Current use of immunosuppressive medication, EXCEPT for the following:
1. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection);
2. Systemic corticosteroids at physiologic doses = 10 mg/day of prednisone or equivalent;
3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
- Pregnancy or lactation
- Previous or concurrent experimental treatment for the tumor other than radiotherapy and alkylating chemotherapy. This includes local therapies such as interstitial radiotherapy or local chemotherapy (i.e. BCNU wafers), loco-regional hyperthermia, electric fields, and antiangiogenic therapy (such as Bevacizumab).
- Abnormal (= Grade 2 CTCAE v4.03) laboratory values for thyroid gland: free T4 and TSH
- Abnormal (= Grade 2 CTCAE v4.03) laboratory values for hematology, liver and renal function (serum creatinine). In detail, the following values apply as exclusion criteria:
1. Hemoglobin < 9 g/dL (5.59 mmol/L)
2. White blood cell count (WBC) decrease ( 10.0 x 109/L)
3. Absolute neutrophil count (ANC) decrease (< 1.5 x 109/L)
4. Platelet count decrease (< 100 x 109/L)
5. Bilirubin > 1.5 x ULN (upper limit of normal according to the performing lab´s reference range)
6. ALT > 2,5 x ULN
7. AST > 2,5 x ULN
8. GGT > 2.5 x ULN
9. Serum creatinine increase (> 1.5 x ULN)
- Patients with history or presence of HIV and/or HBV/HCV positivity (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)
- Patients with history or known presence of tuberculosis (positive QuantiFERON®-TB Gold test (or equivalent) or tuberculin skin test). Patients with an indeterminate result of the QuantiFERON®-TB Gold test (or equivalent) are not eligible unless additional testing demonstrates a negative result (tuberculin skin test or repeated QuantiFERON®-TB Gold test/or equivalent). If a tuberculin skin test is performed, an induration of > 6 mm is "positive" for a patient with history of BCG vaccine, while an induration of > 10 mm is "positive" for a patient without history of BCG vaccine. If necessary, a QuantiFERON®-TB Gold or equivalent test might be complemented by additional specific diagnostic tests as per standard procedures.
- Patients with severe infection(s) or signs/symptoms of infection within 2 weeks prior to the first administration of the study drug(s)
- Active infection requiring systemic therapy
- Patients who have received a live, attenuated vaccine within 4 weeks prior to the first administration of the study drug(s)
- Patients with a prior solid organ transplantation or haematopoietic stem cell transplantation
- Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible.
- Clinically significant (i.e., active) cardiovascular disease: Cerebral vascular accident/stroke (< 6 months prior to enrolment), myocardial infarction (< 6 months prior to enrolment), unstable angina, congestive heart failure (= New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.
- Persisting toxicity related to prior therapy (NCI CTCAE v.4.03 Grade >1); however, alopecia, sensory neuropathy Grade = 2, or other persisting toxicities Grade = 2 not constituting a safety risk based on investigator´s judgement is acceptable.
- Other severe acute or chronic medical conditions including colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment 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.
- History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v4.03 Grade = 3).
- Participation in other clinical trials or their observation period during the last 30 days before the first administration of the IMP(s).

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
NONKO - Neuroonkostudien

Medizinischer Befund
Malignant Glioma

Institute
Urologie, Westdeutsches Tumorzentrum

Sponsor

Universitätsklinikum Jena

Einschlusskriterien
- Written informed consent
- Males ?18 years of age
- Histologically or cytologically confirmed adenocarcinoma of prostate
- Investigator assessed metastatic disease documented either by a positive bone scan, or for soft tissue or visceral metastases, either by contrast-enhanced abdominal/pelvic/chest computed tomography (CT) or magnetic resonance imaging (MRI) scan assessed. Metastatic disease is defined as either malignant lesions in bone scan or soft tissue/visceral lesions according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1. Lymph nodes are measurable if the short axis diameter is ?15 mm, soft tissue/visceral lesions are measurable if the long axis diameter is ?10 mm.
- Subjects with lymph node metastases only (either below the aortic bifurcation (N1) or above the aortic bifurcation (M1a)) will not be eligible for the study.
- Subjects must be candidates for ADT, docetaxel and darolutamide therapy per Investigator's judgment
- Started ADT (LHRH agonist/antagonist or orchiectomy) with or without first generation anti-androgen, but no longer than 12 weeks before randomization. For subjects receiving LHRH agonists, treatment in combination with a first generation anti-androgen for at least 4 weeks, prior to randomization is recommended. First generation anti-androgen has to be stopped prior to randomization.
- An Eastern Cooperative Oncology Group performance status of 0 or 1
- Blood counts at Screening: hemoglobin ?9.0 g/dL, absolute neutrophil count ?1.5x109/L, platelet count ?100x109/L (subject must not have received any growth factor within 4 weeks or a blood transfusion within 7 days of the hematology laboratory sample obtained at Screening)
- Screening values of serum alanine aminotransferase and/or aspartate transaminase ?1.5x upper limit of normal (ULN), total bilirubin ?ULN, creatinine ?2.0x ULN
Sexually active male subjects must agree to use condoms as an effective barrier method and refrain from sperm donation, and/or their female partners of reproductive potential to use a method of effective birth control, during the treatment with darolutamide and for 3 months after the end of the treatment with darolutamide and 6 months after treatment with docetaxel.

Ausschlusskriterien
- Prior treatment with:
- LHRH agonist/antagonists started more than 12 weeks before randomization Second-generation androgen receptor (AR) inhibitors such as enzalutamide, apalutamide, darolutamide, other investigational AR inhibitors
- Cytochrome P 17 enzyme inhibitor such as abiraterone acetate or oral ketoconazole as antineoplastic treatment for prostate cancer
- Chemotherapy, immunotherapy, radium or other therapeutic radiopharmaceuticals for prostate cancer (e.g. Lutetium177-PSMA) prior to randomization
- Treatment with radiotherapy (external beam radiation therapy, brachytherapy) within 2 weeks before randomization
- Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation of the study drugs
- Contraindication to both CT and MRI contrast agent
- Had any of the following within 6 months before randomization: stroke, myocardial infarction, severe/unstable angina pectoris,coronary/peripheral artery bypass graft, congestive heart failure (New York Heart Association Class III or IV)
- Uncontrolled hypertension as indicated by a resting systolic blood pressure (BP) =160 mmHg or diastolic BP =100 mmHg despite medical management
- Had a prior malignancy. Adequately treated basal cell or squamous cell carcinoma of skin or superficial bladder cancer that has not spread behind the connective tissue layer (i.e., pTis, pTa, and pT1) is allowed, as well as any other cancer for which treatment has been completed =5 years before randomization and from which the subject has been disease-free
- A gastrointestinal disorder or procedure which is expected to interfere significantly with absorption of study drug
- An active viral hepatitis, known human immunodeficiency virus infection with detectable viral load, or chronic liver disease with a need for treatment
- Previous (within 28 days before the start of study drug or 5 half-lives of the investigational treatment of the previous study, whichever is longer) or concomitant participation in another clinical study with investigational medicinal product(s)
- Any other serious or unstable illness, or medical, social, or psychological condition, that could jeopardize the safety of the subject and/or his/her compliance with study procedures, or may interfere with the subject's participation in the study or evaluation of the study results
- Inability to swallow oral medications
- Previous assignment to treatment in this study

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich

Indikation
Urogenitale Tumore

Medizinischer Befund
Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)

Institute
Urologie, Westdeutsches Tumorzentrum, Westdeutsches Tumorzentrum Münster

Sponsor

Merck Serono GmbH, Darmstadt

Einschlusskriterien
For inclusion in the study, all of the following inclusion criteria must be fulfilled:
• Adult patients, aged ? 18 years of age at the time of signing the informed consent form (ICF)
• Patients with locally advanced or metastatic urothelial cancer of any histological subtype
• Patients who have completed first-line platinum-based chemotherapy with no evidence of disease progression
• Patients who are treatment naive for Avelumab first-line maintenance therapy, or who have received a maximum one cycle of Avelumab first-line maintenance therapy according to the Avelumab SmPC or the respective local label or any other regional requirements
• Patients who have provided written informed consent to participate in this study

Ausschlusskriterien
Patients are not eligible for this study if they fulfill any of the following exclusion criteria:
• Patients with contraindications for Avelumab according to the Avelumab SmPC or the respective local label or any other regional requirements
• Patients who have participated in any interventional clinical trial of a drug or device within 28 days prior to the start of Avelumab maintenance therapy

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
Urogenitale Tumore

Medizinischer Befund
urothelial cancer

Institute
Urologie, Westdeutsches Tumorzentrum, Westdeutsches Tumorzentrum Münster

Sponsor

Merck Healthcare KGaA, Darmstadt

Einschlusskriterien
- Participants with the Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
- Participants with a histologically confirmed diagnosis of RCC with any histological origin
- Participants with a locally advanced/metastatic disease (that is [ie], newly diagnosed Stage 4 RCC per American Joint Committee on Cancer) or has recurrent disease
- Participants has received 1 or 2 cycles of Avelumab plus Axitinib treatment as a first-line therapy according to the approved Summary of Product Characteristics (SmPC)
- Participants willing to sign the written informed consent form (ICF) to participate in this study

Ausschlusskriterien
- Participants with contraindications for Avelumab or Axitinib according to the approved SmPC
- Participants who have participated in any interventional clinical study of a drug or device within 28 days prior to the start of Avelumab plus Axitinib

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Urogenitale Tumore

Medizinischer Befund
Carcinoma, Renal Cell

Institute
Med.Klinik Hämatologie, Neurologie

Prüfarzt (AMG) / Studienleitung (BO)

Kontakt Italfarmaco S.p.A.

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)

Geschlecht
Divers, Männlich, Weiblich

Indikation
MS - Multiple Sklerose, Phase I Studie

Medizinischer Befund
Relapsing Multiple Sclerosis (RMS)\nMyasthenia gravis (MG)\nProgressive Multiple Sclerosis (PMS)

MedDRA Term
Relapsing multiple sclerosis, Myasthenia gravis, Multiple sclerosis, Progressive multiple sclerosis

Institut
Neurologie

Einschlusskriterien
Erwachsene Patienten mit erstmaligem akutem (bis 48 Stunden nach Symptombeginn) ischämischem Schlaganfall

Ausschlusskriterien
- Vorherige Infarkte
- subakute oder chronische Infarkte (>48 Stunden nach Symptombeginn)
- hämorrhagische Infarkte
- nicht erfolgte Einwilligung

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
STROKE  - Schlaganfall

Medizinischer Befund
ischemic stroke

Institut
Neurologie

Sponsor

University Medicine Essen Clinician Scientist Academy (UMEA)

Einschlusskriterien
- Betroffene mit SCA3 oder SCA6 oder neurologisch gesunde Teilnehmer
- Mindestalter von 18 Jahren

Ausschlusskriterien
- Drogen- oder Alkoholabhängigkeit
- Einnahme von zentral-wirksamen Medikamenten
- Vorliegen von neurologischen oder psychiatrischen Erkrankungen ausgenommen SCA3 oder SCA6

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
CEREBELLUM - Kleinhirn / Ataxie

Medizinischer Befund
Spinozerebelläre Ataxie Typ 3 (SCA3) und Spinozerebelläre Ataxie Typ 6 (SCA6)

Institut
Neurologie

Prüfarzt (AMG) / Studienleitung (BO)

Kontakt Italfarmaco S.p.A.

Sponsor

Merck KGaA

+49 (0)6151 720
service@merckgroup.com

Frankfurter Straße 250
64293 Darmstadt

Einschlusskriterien
- Patienten müssen neu mit der Behandlung mit Cladribin oder Fingolimod beginnen.
- Patienten müssen eine schriftliche Einwilligungserklärung abgeben (in Ländern, in denen sowohl retrospektive als auch prospektive Daten gesammelt werden und in einigen Ländern in denen nur sekundäre Daten gesammelt werden.)

Ausschlusskriterien
- Einnahme von Fingolimod, bevor mit der Behandlung mit oralem Cladribin angefangen wird.
- Einnahme von oralem Cladribin, bevor mit der Einnahme von Fingolimod angefangen wird.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
MS - Multiple Sklerose

Medizinischer Befund
Multiple Sklerose (MS)

Institut
Neurologie

Prüfarzt (AMG) / Studienleitung (BO)

Kontakt Italfarmaco S.p.A.

Einschlusskriterien
schriftliches Einverständniserklärung für die Teilnahme am Register, nach erfolgter Aufklärung, sichere MS mit bestimmbarerer Verlaufsform oder KIS, primärer Wohnsitz in Deutschland

Ausschlusskriterien
Nicht bestimmbare MS-Verlaufsform, fehlende Einwilligungserklärung

Indikation
MS - Multiple Sklerose

Institute
Neurologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Ulrike Schara-Schmidt

+49 (0)201 723-2356
ulrike.schara@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Novocure GmbH

Einschlusskriterien
1. Histologically confirmed diagnosis of GBM according to WHO classification criteria.
2. Age ? 18 years
3. Recovered from maximal debulking surgery, if applicable (gross total resection, partial
resection and biopsy-only patients are all acceptable)
4. Planned treatment with RT/TMZ followed by TTFields and maintenance TMZ (150-200
mg/m2 daily x 5 d, q28 days)
5. Karnofsky performance status ? 70
6. Life expectancy ? least 3 months
7. Participants of childbearing age must use highly effective contraception. An effective method
of birth control is defined as one that results in a failure rate of less than 1% per year when
used consistently and correctly. The Investigator must approve the selected method, and
may consult with a gynecologist as needed.
8. All patients must understand and voluntarily sign an informed consent document prior to any
study related assessments/procedures being conducted.
9. Stable or decreasing dose of corticosteroids for the last 7 days prior to randomization, if
applicable.
10. Concomitant RT with TMZ treatment planned to start no later than 8 weeks from surgery
11. Women of childbearing potential must have a negative ?-HCG pregnancy test documented
within 14 days prior to registration
12. Is able to have MRI with contrast of the brain

Ausschlusskriterien
1. Progressive disease (per investigator’s assessment)
2. Infratentorial or leptomeningeal disease
3. Participation in another clinical treatment study during the pre-treatment and/or the treatment
phase of the study
4. Pregnancy or breast-feeding.
5. Significant co-morbidities at baseline which would preclude maintenance RT or TMZ
treatment, as determined by the investigator:
a. Thrombocytopenia (platelet count < 100 x 103/µL)
b. Neutropenia (absolute neutrophil count < 1.5 x 103/µL)
c. CTC grade 4 non-hematological Toxicity (except for alopecia, nausea, vomiting)
d. Significant liver function impairment - AST or ALT > 3 times the upper limit of normal
e. Total bilirubin > 1.5 x upper limit of normal
f. Significant renal impairment (serum creatinine > 1.7 mg/dL, or > 150 µmol/l)
g. History of any psychiatric condition that might impair patient’s ability to understand or
comply with the requirements of the study or to provide consent
6. Implanted pacemaker, defibrillator, deep brain stimulator, other implanted electronic devices
in the brain, or documented clinically significant arrhythmias.
7. Evidence of increased intracranial pressure (midline shift > 5mm, clinically significant
papilledema, vomiting and nausea or reduced level of consciousness)
8. History of hypersensitivity reaction to TMZ or a history of hypersensitivity to DTIC.
9. Any other cytotoxic or biologic anti-tumor therapy received prior to enrollment will be
considered exclusion.
10. Admitted to an institution by administrative or court order.
11. Known allergies to medical adhesives or hydrogel
12. A skull defect (such as, missing bone with no replacement)
13. Prior radiation treatment to the brain for the treatment of GBM
14. Any serious surgical/post-operative condition that may risk the patient according to the
investigator
15. Standard TTFields exclusion criteria include
a. Active implanted medical devices
b. Bullet fragments
c. Skull defects

Studienteilnehmende Mindestalter
18 Jahr(e)

Indikation
NONKO - Neuroonkostudien, Glioblastom

Medizinischer Befund
Glioblastom

Institute
DKTK Translationale Neuroonkologie am WTZ, Neurologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Ulrike Schara-Schmidt

+49 (0)201 723-2356
ulrike.schara@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Novocure GmbH

Einschlusskriterien
* The participant (or legally acceptable representative) has provided documented informed consent for the study.
* Be = 18 years of age on day of providing informed consent.
* Participant with new diagnosis of GBM according to World Health Organization (WHO) 2021 Classification.
* Recovered from maximal debulking surgery (gross total resection, partial resection and biopsy-only patients are all acceptable), Gliadel wafers placement at the time of surgical resection is allowed.
* Have completed standard adjuvant chemoradiotherapy of radiotherapy (RT) according to local practice (56-64 Gy), and concomitant TMZ chemotherapy.
* Amenable to treatment with Optune concomitant with maintenance TMZ (150-200 mg/m^2 daily x 5, Q28 days).
* Have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1 assessed within 7 days before randomization.
* Stable or decreasing dose of corticosteroids (dexamethasone = 2mg or equivalent) for the last 7 days prior to randomization, if applicable.

Ausschlusskriterien
* Has received prior therapy with an anti-Programmed Cell Death 1 (PD-1), anti- Programmed Cell Death-Ligand 1(PD-L1), or anti Programmed Cell Death-Ligand 2 (PD-L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g.Cytotoxic T-Lymphocyte-Associated protein 4 (CTLA-4), OX 40, CD137).
* Ongoing requirement for >2 mg dexamethasone (or equivalent), due to intracranial mass effect.
* Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to randomization.
* Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed.
* Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first study treatment.
* Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study medication. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
* Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
* Early progressive disease after the end of TMZ/RT. If pseudo progression is suspected, additional imaging studies should be performed to rule out true progression.
* Infratentorial or leptomeningeal disease.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
NONKO - Neuroonkostudien, Glioblastom

Medizinischer Befund
Glioblastoma

Institut
Neurologie

Prüfarzt (AMG) / Studienleitung (BO)

Kontakt Italfarmaco S.p.A.

Sponsor

Sanofi-Aventis Recherche & Développement, Frankreich

Einschlusskriterien
The participant must be 18 to 55 years of age, inclusive, at the time of signing the informed
consent form (ICF).
Type of participant and disease characteristics
I 02. The participant must have been diagnosed with RMS according to the 2017 revision of the
McDonald diagnostic criteria (19).
I 03. The participant has an EDSS score =5.5 at the first visit (Screening Visit)
I 04. The participant must have at least 1 of the following prior to screening:
• =1 documented relapse within the previous year OR
• =2 documented relapses within the previous 2 years, OR
• =1 documented Gd enhancing lesion on an MRI scan within the previous year.
Note: The initial clinical demyelinating episode of MS should be counted as a relapse for the
first 2 criteria.

Ausschlusskriterien
Medical conditions
E 01. The participant has been diagnosed with primary progressive MS according to the 2017
revision of the McDonald diagnostic criteria (19) or with secondary progressive MS
without activity (22).
E 02. The participant has a history of infection or may be at risk for infection:
• A history of T-lymphocyte or T-lymphocyte-receptor vaccination, transplantation
(including solid organ, stem cell, and bone marrow transplantation), and/or antirejection
therapy.
• The participant has received any live (attenuated) vaccine (including but not limited to
varicella zoster, oral polio, and nasal influenza) within 3 months before the first treatment
visit.
• The participant has a lymphocyte count less than the lower limit of normal (LLN) at the
Screening Visit.
• A history of diagnosis of progressive multifocal leukoencephalopathy (PML) or evidence
of findings suggestive of PML on the screening MRI.
• A history of infection with human immunodeficiency virus (HIV) (eg, any known positive
HIV test or information from participant interview).
• A history of active or latent tuberculosis (TB); TB testing should be performed at
screening and again during the study, if clinically indicated, and may be repeated based on
clinical judgment, borderline results, or clinical suspicion of TB infection. Screening tests
for TB are described in Appendix 2 (Section 10.2).

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
MS - Multiple Sklerose

Medizinischer Befund
MS - Multiple Sklerose

MedDRA Term
Multiple sclerosis

Institut
Neurologie

Sponsor

Ipsen Biopharmaceuticals, Inc

Einschlusskriterien
- Participant must be aged 18 to 85 years at the time of providing informed consent
- First-ever clinical stroke, defined according to World Health Organization criteria as rapidly developing clinical signs of focal (at times global) disturbance of cerebral function lasting more than 24 hours, within the past 4 weeks;
- Confirmed paresis of the arms and/or legs which does not resolve within 1 day, according to the NIHSS score (a score of > 0 on Question 5 or 6 of the scale) within 2 weeks after the stroke
- Capable of giving informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol

Ausschlusskriterien
- Upper or lower extremity functional impairment prior to stroke per investigator judgement (e.g., modified Rankin Scale >2);
- Presence of significant/major neurological impairment that might affect muscle tone (other than limb paresis);
- Severe multi-impairment or diminished physical condition before stroke that could have caused paresis/spasticity/motor deficit per investigator judgement;
- Life expectancy of less than 12 months as a result of severity of stroke or other illnesses (e.g. cardiac disease, malignancy, etc.)
- Participation in any interventional study

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
STROKE  - Schlaganfall

Medizinischer Befund
Spasticity as Sequela of Stroke

Institut
Neurologie

Prüfarzt (AMG) / Studienleitung (BO)

Kontakt Italfarmaco S.p.A.

Indikation
MS - Multiple Sklerose

Medizinischer Befund
relapsing multiple sclerosis, primary progressive multiple sclerosis, or nonrelapsing secondary progressive multiple sclerosis

Institute
Neurologie, Strahlentherapie, Westdeutsches Tumorzentrum, WPE

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Ulrike Schara-Schmidt

+49 (0)201 723-2356
ulrike.schara@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Universitätsklinik Essen (AöR)

+49 (0)201 723-0
info@uk-essen.de

Hufelandstraße 55
45147 Essen

Einschlusskriterien
• Histologisch gesichertes WHO Grad II oder III Gliom mit Indikation zur Durchführung einer Strahlentherapie nach Beschluss der lokalen neuroonkologischen Konferenz des Studienzentrums
• Klassifikation des Tumors gemäß der WHO-Klassifikation 2016 inkl.: mutierter IDH-Status muss nachgewiesen sein, Bestimmung des 1p/19q Deletionsstatus und MGMT- Promotormethylierungsstatus muss vorliegen
• Ein Karnofsky-Index von ? 70%
• Patienten müssen ? 18 Jahre sein
• Beginn der Strahlentherapie innerhalb 6 Wochen nach Operation
• Zum Zeitpunkt des Studieneinschlusses sollte der Abstand zur letzten Operation ? 2 Wochen sein. Die Patienten müssen sich von den Folgen der Operation erholt haben
• Patient muss zustimmen und in der Lage sein eine neurokognitive Baseline-Testung noch vor Gabe der ersten Strahlendosis durchzuführen
• Der Patient muss vor Studieneinschluss die schriftliche Einwilligung zur Studienteilnahme erteilen
• Studienpatient ist in der Lage Sinn und Tragweite der Studie zu verstehen und ist gewillt den Anweisungen der klinischen Studie zu folgen und aller Voraussicht nach die geplanten Studienvisiten einzuhalten.
• Gebährfähige Patientinnen müssen einen negativen Schwangerschaftstest (aus dem Serum oder Urin) aufweisen, der nicht älter als 7 Tage ist zum Zeitpunkt der ersten Studienintervention.
• Laborwerte nicht älter als 3 Wochen vor Studieneinschluss: Absolutwert neutrophiler Granulozyten ? 1500/mm³, Thrombozytenzahl ? 100 000/mm³, Hämoglobinwert (Hb) >10 g/dL, Gesamtbilirubinwert ? 1,5-fach der oberen Normwertgrenze, Werte für Aspartat-Aminotransferase (AST) und Alanin-Aminotransferase (ALT) ? 3-fach der oberen Normwertgrenze, Kreatininwert ? 1,5-fach der oberen Normwertgrenze

Ausschlusskriterien
• Gleichzeitige Teilnahme an einer anderen klinischen Studie oder Teilnahme an einer klinischen Studie, die die Gabe eines Prüfpräparats innerhalb von 30 Tagen vor Studieneinschluss erfordert.
• Physischer oder psychischer Zustand des Patienten, der, im Ermessen des Studienarzts, den Patienten gefährden könnte, die Studienergebnisse verfälschen könnte oder der die Teilnahme des Patienten an der klinischen Studie negativ beeinflussen könnte.
• Bekannter oder anhaltender Missbrauch von Drogen, Alkohol oder Medikamenten.

Indikationsspezifische Ausschlusskriterien:
• Vorausgegangene Strahlentherapie am Kopf oder im Gesichts-Halsbereich
• Vorausgegangene Chemotherapie aufgrund einer ZNS Neoplasie
• Schwere Komorbidtät, die eine Compliance mit den Studienvorgaben limitiert
• Bösartige invasive Tumorerkrankung mit einer Tumorfreiheit von < 3 Jahren
• Hinweise für eine leptomeningeale Dissiminierung
• Spinale oder infratentorielle Tumorlokalisation
• Patienten mit bekannter Infektion mit dem humanen Immundefizienz-Virus (HIV) und unter laufender retroviraler Therapie.
• Patienten mit neuerlich diagnostizierter Hepatitis-Infektion oder - nach Ermessen des zuständigen Studienarztes - erheblichem Risiko einer Reaktivierung

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
NONKO - Neuroonkostudien

Medizinischer Befund
Gliom

Institute
Neurologie, Strahlentherapie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Ulrike Schara-Schmidt

+49 (0)201 723-2356
ulrike.schara@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

NOXXON Pharma AG, Berlin

Einschlusskriterien
1. Written informed consent
2. Age =18 years
3. Patient agreement to diagnostic and scientific work-up of glioblastoma tissue obtained during the preceding surgery or biopsy
4. Patient agrees to subcutaneous port implantation
5. Newly diagnosed, histologically confirmed, supratentorial WHO grade IV glioblastoma
6. Status post biopsy or incomplete resection
7. Unmethylated MGMT promoter status
8. Maximum Eastern Cooperative Oncology Group (ECOG) score 2
9. Estimated minimum life expectancy 3 months
10. Stable or decreasing dose of corticosteroids during the week prior to inclusion
11. The following laboratory parameters should be within the ranges specified:
- Total bilirubin = 1.5 x upper limit normal (ULN)
- Creatinine = 1.5 x ULN or glomerular filtration rate = 60 mL/min/1.73m²
- ALT (alanine transaminase) = 3 x ULN
- AST (aspartate transaminase) = 3 x ULN
12. Female patients of child-bearing potential must have a negative serum pregnancy test within 21 days prior to enrollment and agree to use a highly effective method of birth control (failure rate less than 1% per year when used consistently and correctly such as contraceptive implants, vaginal rings, sterilization, or sexual abstinence)" during and for 3 months following last dose of drug (more frequent pregnancy tests may be conducted if required per local regulations)
13. Male patients must use an effective barrier method of contraception during study and for 3 months following the last dose if sexually active with a FCBP

Ausschlusskriterien
1. Inability to understand and collaborate throughout the study or inability or unwillingness to comply with study requirements
2. Participation in any clinical research study with administration of an investigational drug or therapy within 30 days from screening visit or observation period of competing studies
3. Contra-indication or known hypersensitivity to MRI contrast agents, olaptesed pegol or polyethylene glycol
4. Cytostatic therapy (chemotherapy) within the past 5 years
5. History of other cancers (except for adequately treated basal or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the patient was disease-free for = 5 years)
6. Clinically significant or uncontrolled cardiovascular disease
7. Prior radiotherapy to the head
8. Any other previous or concomitant experimental glioblastoma treatments
9. Placement of Gliadel® wafer, seeds, or ferromagnetic nanoparticles
10. Pregnancy or lactation
11. Uncontrolled intercurrent illness; patients must be free of any clinically relevant disease (other than glioma) that would, in the treating investigator's opinion, interfere with the conduct of the study or study evaluations
12. Treatment not initiated within 6 weeks after first biopsy or surgery of glioblastoma
13. Prior enrolment into this study

Exclusion Criteria Expansion Group Arms A and B:
1. Inability to understand and collaborate throughout the study or inability or unwillingness to comply with study requirements
2. Participation in any clinical research study with administration of an investigational drug or therapy within 30 days from screening visit or observation period of competing studies
3. Contra-indication or known hypersensitivity to MRI contrast agents, bevacizumab (Arm A only) olaptesed pegol or polyethylene glycol
4. Planned hypofractionated radiotherapy
5. Cytostatic therapy (chemotherapy) within the past 5 years
6. History of other cancers (except for adequately treated basal or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the patient was disease-free for = 5 years)
7. Secondary malignancy which is currently active
8. Clinically significant or uncontrolled cardiovascular disease, including
- Myocardial infarction in the previous 12 months
- Uncontrolled angina
- Congestive heart failure (New York Heart Association functional classification of =2)
- Diagnosed or suspected congenital long QT syndrome
- QTc prolongation on an electrocardiogram prior to entry (>470 ms)
- Uncontrolled hypertension (blood pressure = 160/95 mmHg)
- Heart rate <50/min on the baseline electrocardiogram
- History of ventricular arrhythmias of any clinically significant type (such as ventricular tachycardia, ventricular fibrillation or torsades de pointes)
- Cerebrovascular accident
9. Prior radiotherapy to the head
10. Any other previous or concomitant experimental glioblastoma treatments
11. Placement of Gliadel® wafer, seeds, or ferromagnetic nanoparticles
12. Patients with a history of arterial or venous thrombosis (or any other disease) requiring permanent intake of anticoagulants (Arm A only)
13. Pregnancy or lactation
14. Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, chronic liver disease (e.g., cirrhosis, hepatitis), diabetes mellitus, or subjects with either of the following: fasting blood glucose (FBG defined as fasting for at least 8 hours) = 200 mg/dL (7.0 mmol/L), or HbA1c = 8%, chronic renal disease, pancreatitis, chronic pulmonary disease, auto-immune diseases, or psychiatric illness/social situations that would limit compliance with study requirements. Patients must be free of any clinically relevant disease (other than glioma) that would, in the treating investigator's opinion, interfere with the conduct of the study or study evaluations
15. Prolongation of coagulation factors = 2.5 x ULN (Arm A only)
16. Treatment not initiated within 6 weeks after first biopsy or surgery of glioblastoma
17. Prior enrolment into this study

Exclusion Criteria Expansion Group Arms C:
1. Inability to understand and collaborate throughout the study or inability or unwillingness to comply with study requirements
2. Participation in any clinical research study with administration of an investigational drug or therapy within 30 days from screening visit or observation period of competing studies
3. Contra-indication or known hypersensitivity to MRI contrast agents olaptesed pegol or polyethylene glycol or pembrolizumab (= Grade 3)
4. Biopsy-only of GBM with less than 20% of tumor removed
5. Presence of extracranial metastatic or leptomeningeal disease
6. Severe hypersensitivity (= Grade 3) to other monoclonal antibodies
7. Receiving immunosuppressive therapy
8. Previous or current treatment with an anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PDL2 agent
9. Planned hypofractionated radiotherapy
10. Cytostatic therapy (chemotherapy) within the past 5 years
11. History of other cancers or secondary malignancy which is currently active (except for adequately treated basal or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the patient was disease-free for = 5 years)
12. Clinically significant or uncontrolled cardiovascular disease, including
- Myocardial infarction in the previous 12 months
- Uncontrolled angina
- Congestive heart failure (New York Heart Association functional classification of =2)
- Diagnosed or suspected congenital long QT syndrome
- QTc prolongation on an electrocardiogram prior to entry (>470 ms)
- Uncontrolled hypertension (blood pressure = 160/95 mmHg)
- Heart rate <50/min on the baseline electrocardiogram
- History of ventricular arrhythmias of any clinically significant type (such as ventricular tachycardia, ventricular fibrillation or torsades de pointes)
- Cerebrovascular accident
13. Prior radiotherapy to the head
14. Evidence of acute intracranial / intra-tumoral hemorrhage
15. Any other previous or concomitant experimental glioblastoma treatments
16. Placement of Gliadel® wafer, seeds, or ferromagnetic nanoparticles
17. Pregnancy or lactation
18. Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, chronic liver disease (e.g., cirrhosis, hepatitis), diabetes mellitus, or subjects with either of the following: fasting blood glucose (FBG defined as fasting for at least 8 hours) = 200 mg/dL (7.0 mmol/L), or HbA1c = 8%, chronic renal disease, pancreatitis, chronic pulmonary disease, auto-immune diseases or psychiatric illness/social situations that would limit compliance with study requirements. Patients must be free of any clinically relevant disease (other than glioma) that would, in the treating investigator's opinion, interfere with the conduct of the study or study evaluations.
19. Received a live vaccine within 30 days prior to the first dose of study drug.
20. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Previously treated brain metastases may participate provided these remain stable
21. Known history of HIV infection, hepatitis B or hepatitis C infection
22. Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs)
23. History of (non-infectious) pneumonitis / interstitial lung disease that required steroids or current pneumonitis / interstitial lung disease
24. Immunodeficiency diagnosis or receiving chronic systemic steroid therapy (exceeding 10 mg daily of prednisone) or any other form of immunosuppressive therapy
25. High dose of corticosteroids (> 4mg/day of dexamethasone or equivalent for at least 3 consecutive days) within two weeks prior to the first dose of study drug
26. Treatment not initiated within 6 weeks after first biopsy or surgery of glioblastoma
27. Prior enrolment into this study

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
NONKO - Neuroonkostudien, Glioblastom

Medizinischer Befund
Glioblastoma

MedDRA Term
Glioblastoma

Institute
Urologie, Westdeutsches Tumorzentrum

Sponsor

Universitätsklinik Essen (AöR)

+49 (0)201 723-0
info@uk-essen.de

Hufelandstraße 55
45147 Essen

Einschlusskriterien
1 Must be =18 years of age
2 Signed an informed consent form (ICF) indicating that the participant understands the purpose of and procedures required for the study and is willing to participate in the study; participants must be willing and able to adhere to the prohibitions and restrictions specified in this protocol
3 Histologically confirmed adenocarcinoma of the prostate including following criteria: Very High-risk defined by a total Gleason-Score =4+4 (ISUP-GG 4+5) and clinical stage cT3 (digital rectal examination or imaging based) plus clinical nodal status cN+ or Serum-PSA level >20ng/ml
4 Exclusion of metastases (M0) on conventional imaging and maximum oligometastatic status on PSMA PET imaging
5 Treatment naïve patients
6 Eastern Cooperative Oncology Group ECOG 0-1
7 Candidate for radical prostatectomy with pelvic lymph node dissection as per the investigator
8 Patients must be PSMA Positron Emission Tomography (PET) scan positive with a prostatic SUVmax > 12 (PRIMARY Score: 5) .
9 Following laboratory criteria must be obtained within 14 days prior to randomization:
o Bone Marrow reserve
• White blood cells, WBC = 2000/µL
• Neutrophils = 1500/µL
• Platelets = 100 x103/µL
• Hemoglobin = 9.0 g/dL
o Hepatic
• AST/ALT = 3 x ULN
• Total Bilirubin = 1.5 x ULN (except participants with Gilbert Syndrome, who may have total bilirubin < 3.0 mg/dL)
o Renal
• Serum creatinine = 1.5xULN
o Endocrine
• TSH 0,4 - 4,0 mU/l = 0,4 - 4,0 µU/ml
o If TSH is not in normal range, fT3 and fT4 must be determined
o fT3 2,3 - 4,5 pg/ml = 3,5 - 7,0 pmol/l
o fT4 0,8 - 1,8 ng/dl = 8 - 18 ng/l = 10 - 23 pmol/l
o Albumin >3.0 g/dL (3.0 g/dL is equivalent to 30 g/L)
o Electrolytes:
• Potassium: 3.5-5 mmol/L
• Sodium: 135-145 mmol/L
o Pancreatic:
• amylase, lipase = 3 x ULN
o alkaline phosphatase (range to be assessed in context of oligometastatic disease)
o blood sugar < 200 mg/dL (11.1 mmol/L)
10 Sexually active patients must use a condom to prevent them from fathering a child and to prevent delivery of study treatment via seminal fluid to their partner for at least 14 weeks after the last dose of [177Lu]Lu-PSMA-617
11 Tumor tissue of both prostate biopsy and radical prostatectomy specimen available for local histology review and reference pathology by (...)

Ausschlusskriterien
1 Distant metastasis (clinical stage M1) on conventional imaging. Oligometastatic patients on exclusively PSMA PET imaging will not be excluded. Patients with PSA values below 20ng/ml and no evidence of nodal disease are excluded
2 Prior treatment with androgen receptor antagonists. Treatment with GnRH analogs prior to ICF signature
3 Bilateral orchiectomy
4 History of prior systemic or local therapy for prostate cancer, including pelvic radiation for prostate cancer
5 Use of any investigational agent ?4 weeks prior to randomization or any therapeutic procedure for prostate cancer at any time
6 Major surgery ?4 weeks prior to randomization
7 Prior therapy with CTLA4 antibodies
8 Previous treatment with any of the following within 6 months of randomization:
• Strontium?89, Samarium?153, Rhenium?186, Rhenium?188, Radium?223,
• Previous PSMA?targeted radioligand therapy
9 Any immunosuppressive therapy given within the past 30 days prior to study drug administration (excluding physiologic steroid hormone replacement and / or steroid therapy up to a maximum dose of 10 mg prednisone or equivalent per day)
10 Other concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, or investigational therapy
11 Lack of availability for clinical follow?up assessments
12 Other potential life?threatening malignancies within the past five years requiring treatment
13 Serious cardiac, gastrointestinal, hepatic or pulmonary disease reducing life expectancy to less than five years
14 Patients with serious intercurrent illness, requiring hospitalization
15 Other serious illnesses, e.g., serious infections requiring antibiotics or bleeding disorders
16 Patients carrying organ transplants and/or receiving continuous immunosuppressive medication (other than steroid therapy of up to 10 mg prednisone per day)
17 The patient is known to be positive for Human Immunodeficiency Virus (HIV) or other chronic infections (HBV, HCV) or has another confirmed or suspected immunosuppressive or immunodeficient condition
18 Known hypersensitivity reaction to any of the components of study treatment
20 Participation in another clinical study and use of any investigational or non?registered product (drug or vaccine) other than the study treatment within the 30 days before registration
21 Significant disease or condition which, in the investigator’s opinion, would exclude the patient from the study
22 Legal incapacity or limited legal capacity

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich

Indikation
Urogenitale Tumore

Medizinischer Befund
High risk localized or Locally advanced prostate cancer

Institute
Neurologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Ulrike Schara-Schmidt

+49 (0)201 723-2356
ulrike.schara@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Rheinische Friedrich-Wilhelms-Universität Bonn

Einschlusskriterien
1. First relapse after first-line therapy with radiotherapy (RT) and alkylating chemotherapy, > 3 months after last chemotherapy application and >6 months after end of RT. Drug therapy and/or radiothera-py for first relapse treatment not yet started.
2. Tumor progression according to RANO criteria
3. Written informed consent
4. Cognitive state to understand rationale and necessity of study therapy and procedures
5. MGMT promotor-methylated (MGMTmeth), IDH wildtype glioblastoma (GBM) or gliosarcoma con-firmed with histology of the primary resection
6. age > 18 years
7. Karnofsky performance score (KPS) ?60%;
8. Life expectancy > 6 months
9. Adequate bone marrow reserve (WBC >3 G/nl, platelets >100 G/nl)
10. Adequate liver function (bilirubin <1.5 x ULN; ASAT /ALAT <3 x ULN, creatinine < 1.5 x ULN)
11. Patient compliance and geographic proximity that allow adequate follow up
12. Male and female patients with reproductive potential must use an approved contraceptive method during and for 3 months after the trial (Pearl index <1%)
13. Pre-menopausal female patients with childbearing potential: a negative serum pregnancy test (beta-HCG) must be obtained prior to treatment start
Additional inclusion criterion ONLY for phase I:
14. Resection at first relapse not yet performed; according to the local treating neurosurgeon and the documented decision of local neurooncological tumor board, reresection of the tumor is clinically indicated and can be safely de-ferred until day 7-10 after initiation of MFA/TMZ therapy.

Ausschlusskriterien
1. Indication for hematotoxicity in first-line therapy not allowing TMZ starting dose 150 mg/m2/d
2. Skin or liver toxicity >CTCAE5 grade 1 in first-line therapy
3. History of gastrointestinal bleeding or gastroduodenal ulcer, active gastritis
4. History of asthma, urticaria or allergic-type skin reactions to NSAID
5. Prior malignancy other than glioma
6. History of confirmed or suspected hypersensitivity (delayed type and immediate type, inclusive of anaphylactic reaction) to any background/ standard TMZ drug product or one of its ingredients of the chosen product, or to cyclooxygenase inhibitors (“NSAIDs”), or to any ingredient of meclofenamate drug product
7. History of disease with poor prognosis
8. Severe coronary heart disease (esp. after coronary artery bypass graft or history of myocardial infarction), severe heart failure
9. Known HIV infection, active hepatitis B or C
10. Breastfeeding or pregnant
11. Unable to undergo contrast-enhanced MRI (i.e. contrast allergy, implants, etc).
12. Treatment in another clinical trial with therapeutic medical intervention or use of any other investiga-tional agent during the trial or within the 30 days before enrollment
13. Medication with a drug that is not allowed in conjunction with MFA intake and cannot be discontin-ued: i.e. lithium, methotrexate, etc.
14. Patients with active bleeding, bleeding diathesis, antiplatelet therapy or anticoagulant therapy except for the following anticoagulants which are permitted for low-dose thrombosis prophylaxis up to the dosage specified here: unfractionated heparin 7,500 IU BID or 5,000 IU TID; low molecular weight heparin e. g. enoxa-parin 40 mg/d; fondaparinux 2.5 mg/d; danaparoid sodium 750 IU BID; argatroban IV route throm-bin time < 70 s; vitamin-K-antagonist INR < 1.8; dabigatran 150 mg BID; rivaroxaban 10 mg/d; edoxaban 30 mg/d; epixaban 2.5 mg BID This restriction is due to a potentially increased risk of GI ulcers with subsequent bleeding under MFA therapy
15. Patients with medically diagnosed hereditary Galactose Intolerance, complete lactase deficiency or confirmed Glucose-Galactose-Malabsortion
16. Medical History of gastrointestinal Resection of any kind that may potentially alter the absorption of the investigational study drug, according to investigators judgement
17. The presence of any other concomitant severe, progressive, or uncontrolled renal, hepatic, hematological, endocrine, pulmonary, cardiac (including coronary artery bypass graft), or psychiatric disease, or signs and symptoms thereof, that may affect the subjects participation in the study, according to investigators judgement

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
NONKO - Neuroonkostudien, Glioblastom

Medizinischer Befund
Adult patients with IDHwt, MGMT promotor methylated glioblastoma at first relapse

MedDRA Term
Glioblastoma

Institute
Urologie, Westdeutsches Tumorzentrum

Sponsor

MSD Merck Sharp & Dohme LLC

Einschlusskriterien
- For Cohorts A, B, C, D, E, G: Has histologically- or cytologically-confirmed adenocarcinoma of the prostate without small cell histology
-- For Cohorts F, H, I: Has t-NE or de novo metastatic prostate cancer defined by ?1% neuroendocrine cells that are located in discrete regions of a recent biopsy specimen from a metastasis as determined by the investigational site and confirmed by central histology review prior to enrollment
- Is able to provide tumor tissue from a site not previously irradiated as follows: Cohorts A, E, and G: must provide a core or excisional biopsy from soft tissue or bone biopsy within 1 year of screening and after developing mCRPC; Cohort B: must provide an archival tumor tissue sample or tumor tissue from a newly obtained core or excisional biopsy from soft tissue if the lesion is clinically accessible; Cohorts C and D with soft tissue disease: must provide a core or excisional biopsy from a soft tissue lesion if clinically accessible within 1 year of screening and after developing mCRPC and an archival specimen if available; and Cohorts F, H, and I must provide a core or excisional biopsy from soft tissue or a bone biopsy. For de novo metastatic neuroendocrine prostate participants, biopsies must be performed within 1 year of screening. Participants with bone metastasis only must provide an archival tumor tissue specimen.
- Has prostate cancer progression within 6 months prior to screening, as determined by the investigator, by means of one of the following: PSA progression as defined by a minimum of 2 rising PSA levels with an interval of ?1 week between each assessment where the PSA value at screening should be ?2 ng/mL; radiographic disease progression in soft tissue based on Response Evaluation Criteria In Solid Tumors Version 1.1 criteria with or without PSA progression; radiographic disease progression in bone defined as the appearance of 2 or more new bone lesions on bone scan with or without PSA progression. Participants with de novo neuroendocrine prostate cancer will not need to provide evidence of progression within 6 months
- Has ongoing androgen deprivation with serum testosterone <50 ng/dL (<2.0 nM). Treatment with luteinizing hormone-releasing hormone agonists or antagonists for all cohorts must have been initiated ?4 weeks prior to first dose of study therapy and must be continued throughout the study. Participants with de novo metastatic NE prostate cancer will not be required to have been previously treated with androgen deprivation therapy (ADT). ADT must be started in these participants by the time of treatment allocation/randomization
- Participants receiving bone resorptive therapy (including, but not limited to bisphosphonate or receptor activator of nuclear factor kappa-? ligand inhibitor) must be on stable doses for ?4 weeks prior to first dose of study therapy
- Must be abstinent from heterosexual intercourse, refrain from donating sperm, or agree to use contraception (unless confirmed to be azoospermic) during the intervention period starting with the first dose of study therapy. The length of time required to continue contraception after the last dose of study intervention for each study intervention is as follows: 7 days for abiraterone acetate and lenvatinib; 30 days for enzalutamide; and 95 days for olaparib, docetaxel, and carboplatin/etoposide. No contraception measures are required during and after the intervention period for pembrolizumab/vibostolimab coformulation.
- Has a performance status of 0, 1, or 2 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale for Cohorts A and C and a performance status of 0 or 1 for Cohorts B, D, E, F, G, H, and I within 10 days of study start
- For Cohort A: Has received docetaxel for mCRPC. Prior treatment with 1 other chemotherapy for mCRPC is allowed. Up to 2 second-generation hormonal manipulations (e.g., abiraterone acetate and/or enzalutamide) are allowed. Prior docetaxel for metastatic hormone-sensitive prostate cancer is allowed if ?4 weeks have elapsed from the last dose of docetaxel prior to day 1 of Cycle 1
- For Cohort B: Has received prior treatment with either abiraterone acetate or enzalutamide (but not both) in the prechemotherapy mCRPC state. Participants in Cohort B must have received at least 4 weeks of either abiraterone or enzalutamide treatment (but not both) who failed treatment or became intolerant of the drug
- For Cohort C: Has received prior treatment with abiraterone acetate in the pre-chemotherapy mCRPC state without prior enzalutamide. Participants in Cohort C must have received at least 4 weeks of abiraterone treatment who failed treatment or become intolerant of the drug. Participants who received abiraterone acetate in the hormone-sensitive state will not be eligible
- For Cohort D: Has not received chemotherapy for mCRPC and has either not had prior second generation hormonal manipulation for mCRPC OR has previously been treated with enzalutamide for mCRPC and failed treatment or has become intolerant of the drug. Prior docetaxel for metastatic hormone-sensitive prostate cancer is allowed if ?4 weeks have elapsed from the last dose of docetaxel. Prior treatment with abiraterone acetate in the hormone-sensitive metastatic setting is allowed as long as there was no progression on this agent and abiraterone acetate was not discontinued due to adverse events (AEs)
- For Cohorts E and G: Has received docetaxel for mCRPC. Prior treatment with 1 other chemotherapy for mCRPC is allowed. Up to 2 second-generation hormonal manipulations (eg, abiraterone acetate, enzalutamide, apalutamide, darolutamide or other next-generation hormonal agents [NHA]) are allowed. Participants who received prior ketoconazole for metastatic disease may be enrolled. If docetaxel chemotherapy is used more than once (eg, once for metastatic hormone-sensitive and once for mCRPC), it will be considered as 1 therapy. Prior docetaxel for metastatic hormone-sensitive prostate cancer (mHSPC) is allowed if ?4 weeks have elapsed from the last dose of docetaxel prior to Day 1 of Cycle 1
- For Cohort F, H, and I: Participants must have received prior treatment with androgen deprivation therapy (ADT) for metastatic disease. Participants must also have received prior treatment with an NHA (eg, abiraterone acetate, apalutamide, darolutamide, enzalutamide, or other NHA) or docetaxel for mHSPC or mCRPC. Prior treatment with up to a total of 2 chemotherapies for mCRPC is allowed, as well as up to 2 second-generation hormonal manipulations for mCRPC. Participants who received prior ketoconazole for metastatic disease may be enrolled. Docetaxel for mHSPC is allowed in addition to docetaxel for mCRPC. If docetaxel chemotherapy is used more than once (eg, once for metastatic hormone-sensitive and once for mCRPC), it will be considered as 1 therapy.

Ausschlusskriterien
- Has had a prior anticancer monoclonal antibody (mAb) within 4 weeks prior to first dose study therapy or who has not recovered (i.e., Grade =1 or at baseline) from AEs due to mAbs administered >4 weeks earlier
- Has had prior chemotherapy, targeted small molecule therapy abiraterone treatment, enzalutamide treatment, or radiation therapy within 2 weeks prior to first dose of study therapy or who has not recovered (ie, Grade =1 or at baseline) from AEs due to a previously administered agent
- Is currently participating in and receiving study therapy or has participated in a study of an investigational agent and received study drug or used an investigational device within 4 weeks of treatment allocation/randomization
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to treatment allocation/randomization
- Has had prior treatment with therapeutic radiopharmaceuticals for prostate cancer, such as Radium-223 or Leutitium-177, within 4 weeks prior to the first dose of trial treatment
- Has an active autoimmune disease that has required systemic treatment in past 2 years
- Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or current pneumonitis/interstitial lung disease
- Has previously participated in any other pembrolizumab trial, or received prior therapy with an anti-programmed cell death 1 (anti-PD-1), anti-programmed cell death ligand 1 (anti-PD-L1), and anti-programmed cell death ligand 1 (anti-PD-L2)
- Has a known history of Human Immunodeficiency Virus (HIV)
- Has known active Hepatitis B or Hepatitis C
- Has received a live vaccine or live-attenuated vaccine within 30 days of the first dose of study therapy. 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, adenoviral vaccines, or inactivated vaccines. These vaccines will be treated just as any other concomitant therapy. Investigational vaccines (ie, those not licensed or approved for emergency use) are not allowed
- Has known active central nervous system metastases and/or carcinomatous meningitis
- Has a "superscan" bone scan defined as an intense symmetric activity in the bones and diminished renal parenchymal activity on baseline bone scan such that the presence of additional metastases in the future could not be evaluated
- Has had prior solid, organ or bone marrow transplant
- For Cohort A: Has experienced a seizure or seizures within 6 months of study start or is currently being treated with cytochrome P450 enzyme (CYP) inducing anti-epileptic drugs for seizures
- For Cohort A: Is currently receiving strong or moderate inhibitors of CYP3A4 including azole antifungals; macrolide antibiotics; or protease inhibitors
- For Cohort A: Is currently receiving strong or moderate inducers of CYP3A4
- For Cohort A: Has myelodysplastic syndrome
- For Cohort A: Has symptomatic congestive heart failure (New York Heart Association Class III or IV heart disease), unstable angina pectoris, cardiac arrhythmia, or uncontrolled hypertension
- For Cohort B: Has received prior treatment with docetaxel or another chemotherapy agent for metastatic prostate cancer
- For Cohort B: Has peripheral neuropathy Common Terminology Criteria for Adverse Events =2 except due to trauma
- For Cohort B: Has ascites and/or clinically significant pleural effusion
- For Cohort B: Has symptomatic congestive heart failure (New York Heart Association Class III or IV heart disease)
- For Cohort B: Is currently receiving any of the following classes of inhibitors of CYP3A4: azole antifungals; macrolide antibiotics; or protease inhibitors
- For Cohort C: Has received prior chemotherapy for mCRPC. Prior docetaxel for metastatic hormone-sensitive prostate cancer is allowed if =4 weeks elapsed from last dose of docetaxel. Participants who received abiraterone acetate in the hormone-sensitive state will not be eligible
- For Cohort C: Has a history of seizure or any condition that may predispose to seizure (including, but not limited to prior cerebrovascular accident, transient ischemic attack, or brain arteriovenous malformation; or intracranial masses such as a schwannoma or meningioma that is causing edema or mass effect)
- For Cohort C: Has known or suspected brain metastasis or leptomeningeal carcinomatosis
- For Cohort C: Has a history of loss of consciousness within 12 months of the screening visit
- For Cohort C: Has hypotension (systolic blood pressure 170 mmHg or diastolic blood pressure >105 mmHg) at the screening visit
- For Cohort C: Has received treatment with 5-a reductase inhibitors (e.g., finasteride, dutasteride), estrogens, and/or cyproterone within 4 weeks prior to Cycle 1
- For Cohort C: Has a history of prostate cancer progression on ketoconazole
- For Cohort D: Has received prior treatment with docetaxel or another chemotherapy agent for metastatic prostate cancer
- For Cohort D: Has progressed on prior abiraterone acetate for treatment of castration sensitive or resistant metastatic prostate cancer
- For Cohort D: Has discontinued prior treatment with abiraterone acetate due to AEs
- For Cohort D: Has previously been treated with ketoconazole for prostate cancer for >7 days
- For Cohort D: Has received prior systemic treatment with an azole drug (eg, fluconazole, itraconazole) within 4 weeks of Cycle 1, Day 1
- For Cohort D: Has uncontrolled hypertension (systolic BP = 160 mm Hg or diastolic BP = 95 mm Hg)
- For Cohort D: Has a history of pituitary or adrenal dysfunction
- For Cohort D: Has clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association Class II-IV heart disease or cardiac ejection fraction measurement of <50% at baseline
- For Cohort D: Has atrial fibrillation, or other cardiac arrhythmia requiring therapy
- For Cohort D: Has a history of chronic liver disease
- For Cohort D: Is currently receiving strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) during abiraterone acetate treatment, CYP2D6 substrates with a narrow therapeutic index (for example thioridazine), or CYP2C8 substrates with a narrow therapeutic index (for example pioglitazone)
- For Cohorts E and F: Has a left ventricular ejection fraction (LVEF) below the institutional (or local laboratory) normal range, as determined by multigated acquisition (MUGA) or echocardiogram (ECHO)
- For Cohorts E and F: Has radiographic evidence of encasement or invasion of a major blood vessel, or of intratumoral cavitation
- For Cohorts E and F: Has prolongation of QT interval by Fredericia (QTcF) interval to >480 milliseconds
- For Cohorts E and F: Has had major surgery within 3 weeks prior to first dose of study interventions
- For Cohorts E and F: Has pre-existing =Grade 3 gastrointestinal or non-gastrointestinal fistula
- For Cohorts E and F: Has had significant cardiovascular impairment within 12 months of the first dose of study intervention, such as history of New York Heart Association >Class II congestive heart failure, unstable angina, myocardial infarction, or cerebrovascular accident (CVA)/stroke, cardiac revascularization procedure, or cardiac arrhythmia associated with hemodynamic instability
- For Cohorts E and F: Has active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of lenvatinib
- For Cohorts E and F: Has gastrointestinal malabsorption or any other condition that might affect the absorption of lenvatinib
- For Cohorts G, H, and I: Has had a severe hypersensitivity reaction to treatment with another monoclonal antibody
- For Cohorts G, H, and I: Has symptomatic ascites or pleural effusion
- For Cohort I: Has clinically active diverticulitis, intra-abdominal abscess, gastrointestinal obstruction, and/or abdominal carcinomatosis
- For Cohort I: Has received previous treatment for prostate cancer with platinum-containing compoundsHas had a prior anticancer monoclonal antibody (mAb) within 4 weeks prior to first dose study therapy or who has not recovered (i.e., Grade =1 or at baseline) from AEs due to mAbs administered >4 weeks earlier

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich

Indikation
Urogenitale Tumore

Medizinischer Befund
Metastatic Castration-Resistant Prostate Cancer

MedDRA Term
Castration-resistant prostate cancer

Institute
Urologie, Westdeutsches Tumorzentrum

Sponsor

MSD Merck Sharp & Dohme LLC

Einschlusskriterien
1. Has a histologically or cytologically confirmed diagnosis of RCC with clear cell component per AJCC (8th Edition), with or without sarcomatoid features.
2. Has intermediate-high risk, high risk, or M1 NED RCC as defined by the following pathological tumor-node metastasis and tumor grading:
a) Intermediate-high risk RCC:
• pT2, Grade 4 or sarcomatoid, N0, M0
• pT3, any grade, N0, M0
b) High-risk RCC:
• pT4, any grade, N0, M0
• pT, any stage, any grade, N+, M0
c) M1 NED RCC participants who present not only with the primary kidney tumor, but also solid, isolated, soft tissue metastases that can be completely resected at 1 of the following:
• the time of nephrectomy (synchronous), or
• ?2 years from nephrectomy (metachronous)
3. Has undergone complete resection of the primary tumor (partial or radical nephrectomy) and complete resection of solid, isolated, soft tissue metastatic lesion(s) in M1 NED participants.
4. Must have undergone a nephrectomy and/or metastasectomy ?12 weeks prior to randomization.
5. Must be tumor-free before randomization as assessed by the investigator and verified by BICR by either CT or MRI scan of the brain and CAP (?28 days from randomization) and a bone scan (?42 days from randomization).
6. Must have provided tissue per any of the following:
• Nephrectomy only: tissue from nephrectomy (required).
• Synchronous M1 NED: tissue from nephrectomy (required) and tissue from metastasectomy (if available).
• Metachronous M1 NED: tissue from metastasectomy (required) and tissue from nephrectomy (if available).
7. Is male or female, at least 18 years of age, at the time of signing the informed consent.
8. Has ECOG performance status of 0 to 1 within 10 days before randomization.
9. Agrees to the following during the intervention period and for at least the time needed to eliminate the study intervention after the last dose of study intervention. The length of time required to continue contraception for the study intervention is as follows:
- Belzutifan/placebo – at least 7 days after the last dose
• Abstains from heterosexual intercourse as their preferred and usual lifestyle and agree to remain abstinent OR
• Uses contraception unless confirmed to be azoospermic as detailed below:
- Uses a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant.
- Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions is more stringent than the requirements above, the local label requirements are to be followed.
10. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
• Not a WOCBP
OR
• A WOCBP and:
- Uses a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle, during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception for each study intervention is as follows:
- At least 120 days after the last dose of pembrolizumab or
- At least 30 days after last dose of belzutifan/placebo, whichever occurs last
• The investigator should evaluate the potential for contraceptive method failure in relationship to the first dose of study intervention. Contraceptive use by female should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions is more stringent than the requirements above, the local label requirements are to be followed.
• A WOCBP must have a negative highly sensitive pregnancy test within 24 hours for urine test or 72 hours for serum test before the first dose of study intervention. If a urine test cannot be confirmed as negative, a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
- At least 120 days after the last dose of pembrolizumab or
- At least 30 days after last dose of belzutifan/placebo, whichever occurs last
• Medical history, menstrual history, and recent sexual activity has been reviewed by the investigator to decrease the risk for inclusion of a female with an early undetected pregnancy
11. The participant has provided documented informed consent/assent for the study. The participant may also provide consent/assent for FBR. However, the participant may participate in the study without participating in FBR.
12. Has adequate organ function.

Ausschlusskriterien
1. Has had a major surgery, other than nephrectomy plus resection of preexisting metastases for M1 NED participants, within 4 weeks prior to randomization.
2. Has residual thrombus post nephrectomy in the vena renalis or vena cava.
3. Has any of the following:
• Pulse oximeter reading <92% at rest, or
• Requires intermittent supplemental oxygen, or
• Requires chronic supplemental oxygen.
4. Has clinically significant cardiovascular disease within 6 months from first dose of study intervention, including NYHA III or IV congestive heart failure, unstable angina, myocardial infarction, cerebrovascular accident, undergone CABG or PTCA, or cardiac arrhythmia.
5. Has other clinically significant disorders such as:
• Serious active nonhealing wound/ulcer/bone fracture
• Requirement for hemodialysis or peritoneal dialysis
6. Has preexisting brain or bone metastatic lesions.
7. Has received colony-stimulating factors (eg, G-CSF, GM-CSF) or recombinant EPO or transfusion within 28 days before study intervention initiation.
8. Is unable to swallow orally administered medication or has a history or current evidence of a GI condition (eg, inflammatory bowel disease, Crohn’s disease, ulcerative colitis) or impaired liver function or diseases that in the opinion of the investigator may significantly alter the absorption or metabolism of oral study intervention.
9. Has a severe hypersensitivity (Grade =3) reaction to belzutifan/placebo or pembrolizumab and/or any of their excipients.
10. Has received prior systemic therapy for RCC
11. Has received prior radiotherapy for RCC.
12. Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed.
13. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study intervention.
14. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study intervention.
15. Has a known additional malignancy (other than RCC treated with nephrectomy and/or metastasectomy) that is progressing or has required active treatment within the past 3 years.
16. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
17. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
18. Has an active infection, requiring systemic therapy.
19. Has a known history of HIV infection, a known history of Hepatitis B (defined as HbsAg reactive), or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
20. Has a history or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound the results of the study, interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator.
21. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.
22. Has had an allogenic tissue/solid organ transplant.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Urogenitale Tumore

Medizinischer Befund
Clear Cell Renal Cell Carcinoma (ccRCC)

MedDRA Term
Renal cell carcinoma

Institute
Urologie, Westdeutsches Tumorzentrum

Sponsor

Merck Healthcare KGaA, Darmstadt

Einschlusskriterien
Participants with histologically confirmed, unresectable locally advanced or metastatic urothelial carcinoma. Both transitional cell and mixed transitional/non- transitional cell histologies are allowed, but transitional cell carcinoma must be the predominant histology
Participants has documented Stage IIIA/IIIB with N1-N3, or Stage IV disease (per American Joint Committee on Cancer/International Union for Cancer Control Tumor Node Metastasis system, 8th edition) at the start of first line chemotherapy.
The last dose of first line chemotherapy must have been received no less than 4 weeks, and no more than 10 weeks, prior to randomization in the present study
Estimated life expectancy of at least 3 months
Participants without progressive disease as per RECIST v1.1 guidelines following completion of 4 to 6 cycles of 1L chemotherapy. Eligibility based on this criterion will be determined by Investigator review of pre chemotherapy and post chemotherapy radiological assessments (CT/MRI scans).
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
Adequate hematological, hepatic, and renal function as defined in the protocol
Other protocol defined inclusion criteria could apply

Ausschlusskriterien
Participants with prior immunotherapy with Interleukin-2 (IL-2), IL-15, interferon alfa (IFN-a), or an anti programmed death receptor-1 (PD-1), anti programmed death-ligand 1 (PD-L1), anti PD-L2, anti CD137, or cytotoxic T cell lymphocyte-4 (CTLA-4) antibody (including ipilimumab), anti TROP2, any other antibody or drug specifically targeting T cell costimulation or immune checkpoint pathways, or any of the investigational drugs used in combination with avelumab.
Participants with active infection 48 hours before randomization requiring systemic therapy
Participants with known prior or suspected hypersensitivity to study drugs or any component in their formulations
Participants with prior adjuvant or neoadjuvant systemic therapy within 12 months of randomization
Participants with vaccination within 4 weeks of the first dose of study treatment and while on trial is prohibited except for administration of inactivated vaccines (for example, inactivated influenza vaccines) and replication-deficient coronavirus vaccines approved or authorized by local Health Authorities
Other protocol defined exclusion criteria could apply

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Urogenitale Tumore

Medizinischer Befund
Advanced or Metastatic Urothelial Carcinoma

Institute
Neurologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Ulrike Schara-Schmidt

+49 (0)201 723-2356
ulrike.schara@uk-essen.de

Hufelandstraße 55
45147 Essen

Einschlusskriterien
o Alter mindestens 18 Jahre
o Neudiagnose eines primären Glioblastoms (IDH-Wildtyp)
o Nie zuvor Radio- oder Chemotherapie erhalten
o Karnofsky Index >=70 %
o Keine Schädel-Hirntraumata in der Vergangenheit, die zu einem Aufsuchen des Arztes geführt haben
o Keine Infektionszeichen im Sinne eines respiratorischen Infekts bei Einschluss (Hinweis: Einschluss möglich, wenn erhöhter CRP/PCT Wert ohne Anzeichen eines respiratorischen Infekts)
o Keine signifikante Aphasie: ausgeprägte Verständigungsprobleme, die eine Teilnahme an und/oder das Verständnis von einer oder mehrerer geplanter Untersuchungen behindert; Bei V.a. relevante Sprachstörung ist zur Bestätigung und Analyse eine logopädische Testung geplant (modifizierter Aachener Aphasie Test, Aachener Aphasie Bedside Test und Aphasie Check Liste)

Ausschlusskriterien
o Vorhandensein folgender Erkrankungen, die zur Riechfunktion führen können:
-Neurodegenerative Erkrankungen (z.B. Parkinsonerkrankungen, Morbus Alzheimer, Chorea Huntington, Korsakowsyndrom, Morbus Pick, Shy-Drager
Syndrom)
-Tumore oder Operationen im Kopf- oder Halsbereich mit Ausnahme eines Hirntumors oder der Operation an einem Hirntumor
-Respiratorischer Infektion insbesondere der oberen Atemwege
-Zustand nach Infekten, die zur dauerhaften Beeinträchtigung der Riechfunktion geführt haben (z.B. Influenza, Corona ect.)
o Erkrankungen, die im Ermessen des Untersuchers die Durchführung der Studie beeinträchtigen (z.B. Schizophrenie)

Studienteilnehmende Mindestalter
18 Jahr(e)

Indikation
NONKO - Neuroonkostudien, Glioblastom

Medizinischer Befund
Glioblastom

Institute
Urologie, Westdeutsches Tumorzentrum

Sponsor

Janssen-Cilag International NV (BE)

Einschlusskriterien
1. Must be ?18 years of age
2. Signed an informed consent form (ICF) indicating that the subject understands the purpose of and procedures required for the study and is willing to participate in the study; subjects must be willing and able to adhere to the prohibitions and restrictions specified in this protocol (Section 4.3)
3. Histologically confirmed adenocarcinoma of the prostate
4. Criterion modified per Amendment 1
4.1. Criterion modified per Amendment 2
4.2 High risk disease defined by a total Gleason Sum Score ?4+3 (=Grade Groups [GG] 3 5) and ?1 of the following 4 criteria:
• Any combination of Gleason Score 4+3 (=GG 3) and Gleason Score 8 (4+4 or 5+3) in ?6 systematic cores (with ?1 core Gleason Score 8 [4+4 or 5+3] included);
• Any combination of Gleason Score 4+3 (=GG 3) and Gleason Score 8 (4+4 or 5+3) in ?3 systematic cores and PSA ?20 ng/mL (with ?1 core Gleason Score 8 [4+4 or 5+3] included);
• Gleason Score ?9 (=GG 5) in at least 1 systematic or targeted core; or
• At least 2 systematic or targeted cores with continuous Gleason Score ?8 (=GG 4), each with ?80% involvement
5. Criterion modified per Amendment 1
5.1. Candidate for RP with pLND as per the investigator
6. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1
7. Criterion modified per Amendment 1
7.1. Criterion modified per Amendment 2
7.2. Adequate organ function determined by the following central laboratory values:
a. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin within normal limits, ie, ? the upper limit of normal ([ULN]; note that in subjects with Gilbert's syndrome, if total bilirubin is >1.5 X ULN, measure direct and indirect bilirubin. If direct bilirubin is ? 1.5 X ULN, the subject may be eligible);
b. Serum creatinine <1.8 mg/dL;
c. Platelets ?75,000/microliter, without transfusion and/or growth factors within 1 month prior to randomization;
d. Hemoglobin ?12.0 g/dL (7.4 mmol), without transfusion and/or growth factors within 1 month prior to randomization
8. Criterion modified per Amendment 4
8.1. Able to receive ADT for at least 13 months, based on cardiovascular risk assessment and the investigator's assessment
9. Criterion modified per Amendment 1
9.1. Be able to swallow whole study drug tablets
10. Criterion modified per Amendment 1
10.1. Criterion modified per Amendment 2
10.2. Criterion modified per Amendment 7
10.3. Contraceptive use by male subjects (and female partners of male subjects enrolled in the study who are of childbearing potential or are pregnant) should be consistent with local regulations regarding the use of contraceptive methods for subjects participating in clinical studies.

Ausschlusskriterien
1. Distant metastasis based on conventional imaging (clinical stage M1). Nodal disease below the iliac bifurcation (clinical stage N1) is not an exclusion. Diagnosis of distant metastasis (clinical M stage; M0 versus M1a, M1b, M1c) and pelvic nodal disease (clinical N stage; N1 versus N0) will be assessed by central radiological review. Patients are considered eligible only if the central radiological review confirms clinical stage M0
2. Criterion modified per Amendment 2
2.1. (a) Prior treatment with androgen receptor antagonists.
(b) Treatment with GnRHa analogs prior to ICF signature.
3. Criterion deleted per Amendment 1
4. Criterion deleted per Amendment 1
5. Bilateral orchiectomy
6. Criterion modified per Amendment 1
6.1. Criterion modified per Amendment 2
6.2. History of prior systemic or local therapy for prostate cancer, including pelvic radiation for prostate cancer
7. Criterion modified per Amendment 1
7.1. Use of any investigational agent =4 weeks prior to randomization or any therapeutic procedure for prostate cancer at any time
8. Major surgery =4 weeks prior to randomization
9. Criterion modified per Amendment 4
9.1. Any of the following within 12 months prior to first dose of study drug: severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (eg, pulmonary embolism, cerebrovascular accident including transient ischemic attacks), or clinically significant ventricular arrhythmias or New York Heart Association Class II to IV heart disease; uncomplicated deep vein thrombosis is not considered exclusionary
10. Human immunodeficiency virus-positive subjects with 1 or more of the following:
a. Not receiving highly active antiretroviral therapy
b. Had a change in antiretroviral therapy within 6 months of the start of screening
c. Receiving antiretroviral therapy that may interfere with study drug (consult sponsor for review of medication prior to enrollment)
d. CD4 count <350 at screening
e. AIDS-defining opportunistic infection within 6 months of start of screening
11. Active or symptomatic viral hepatitis or chronic liver disease; ascites or bleeding disorders secondary to hepatic dysfunction
12. Criterion modified per Amendment 2
12.1. History of seizure; any condition that may predispose to seizure (including, but not limited to, prior stroke, transient ischemic attack, or loss of consciousness =1 year prior to randomization); presence of brain arteriovenous malformation; or intracranial masses such as schwannomas and meningiomas that are causing edema or mass effect
13. Treatment with drugs known to lower the seizure threshold within 4 weeks prior to randomization
14. Gastrointestinal conditions affecting absorption
15. Criterion modified per Amendment 1
15.1. Known or suspected contraindications or hypersensitivity to apalutamide, GnRHa analogues or any of the components of the formulations
16. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject
17. Criterion modified per Amendment 2
17.1. Active malignancies (ie, progressing or requiring treatment or treatment change in the last 24 months) other than prostate cancer. The only allowed exceptions are: non-muscle invasive bladder cancer (NMIBC); skin cancer (non-melanoma or melanoma) treated within the last 24 months that is considered completely cured; breast cancer (adequately treated lobular carcinoma in situ or ductal carcinoma in situ, or history of localized breast cancer and receiving antihormonal agents and considered to have a very low risk of recurrence); malignancy that is considered cured with minimal risk of recurrence.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich

Indikation
Urogenitale Tumore

Medizinischer Befund
High-risk localized or locally advanced prostate cancer

MedDRA Term
Prostate cancer

Institut
Neurologie

Prüfarzt (AMG) / Studienleitung (BO)

Kontakt Italfarmaco S.p.A.

Sponsor

Genzyme Corporation, USA

Binney Street 50
02142 Cambridge

Einschlusskriterien
- 18 to 55 years of age inclusive
- Diagnosis of PPMS according to the 2017 McDonald criteria
- Expanded disability status scale (EDSS) score between 2.0 to 6.5 points, at screening inclusive
- Positive cerebrospinal fluid oligoclonal bands and/or elevated Immunoglobulin G (IgG) index either during screening or documented previous history.
- Contraceptive use consistent with local regulations for individuals participating in clinical studies
Participant is eligible to participate if she is not pregnant or
breastfeeding, and at least one of the following conditions applies:
- Is not a woman of child bearing potential (WOCBP)
OR
- Is a WOCBP and agrees to use an acceptable contraceptive method

Ausschlusskriterien
- Participant has conditions that would adversely affect study participation such as short life expectancy.
- History of organ transplant.
- Evidence of infection with human immunodeficiency virus (HIV), progressive multifocal leukoencephalopathy (PML), active hepatitis B or C, active or latent tuberculosis or other active infection that would adversely affect study participation.
- History of malignancy within 5 years prior to screening.
- History of alchohol or drug abuse within 1 year prior to Screening.
- Hospitalized for psychiatric disease within 2 years prior to Screening.
- Clinically significant laboratory abnormalities (including evidence of liver injury) or electrocardiogram abnormalities at Screening.
- Bleeding disorder, known platelet dysfunction or platelet count <150 000/µL at Screening or history of significant bleeding event within 6 months prior to Screening.
- Lymphocyte count below the lower limit of normal at Screening.
- Recent live (attenuated) vaccine within 2 months before the first treatment visit.
- Recent major surgery (within 4 weeks of Screening) or planned major surgery during the study.
- The participant has received medications/treatments for MS within a specified time frame.
- Receiving strong inducers or inhibitors of cytochrome P450 3A (CYP3A) or CYP2C8 hepatic enzymes.
- Receiving anticoagulant or antiplatelet therapy (such as aspirin, clopidogrel, warfarin).
- Contraindications to magnetic resonance imaging (MRI).
NOTE: Other Inclusion/Exclusion criteria may apply

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
MS - Multiple Sklerose

Medizinischer Befund
Primary Progressive Multiple Sclerosis

MedDRA Term
Primary progressive multiple sclerosis

Institute
Klinik für Kinderheilkunde II, Neurologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Ulrike Schara-Schmidt

+49 (0)201 723-2356
ulrike.schara@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

European Organisation for Research and Treatment of Cancer (EORTC), Belgien

Einschlusskriterien
• Newly diagnosed, histologically proven, genetically classified, centrally confirmed medulloblastoma (WNT M0-1, SHH (p53wt) M0-1, Group 4 M0-1)
• Molecular subtype: medulloblastoma, SHH-activated and TP53-wildtype, M0-1; medulloblastoma, WNT-activated, M0-1; medulloblastoma, Group 4, M0-1
• Histologic subtype: medulloblastoma, classic (CMB); medulloblastoma, desmoplastic/nodular (DNMB); medulloblastoma, with extensive nodularity (MBEN); medulloblastoma, large cell/anaplastic (LCA)
• Adults (? 18 years) in WNT-activated and Group 4 medulloblastoma
• Post-pubertal patients (<18y of age), or adults (18 y of age and above) in SHH-activated and TP53-wildtype medulloblastoma
Non-SHH dependent patients under age 18 should be transferred to a paediatric site for inclusion in the PNET5 trial in countries where PNET5 is open. SHH-activated patients under age 18 with M1 disease or above should be transferred to a paediatric site for inclusion in the HRMB trial in countries where HRMB is open.
• For patients with SHH activated tumours: exclusion of germline alteration of TP53, PTCH, SUFU, BRCA2 and PALB2 if known before randomization or enrollment
• Clinical status within 2 weeks of randomization/enrollment: Karnofsky 50-100. NANO-score 0 to 9 (allowing full-blown cerebellar symptoms)
• Clinically standard-risk (centrally assessed MRI review) defined as: total or near total surgical resection with less than or equal to 1.5 cm2 (measured in axial plane) of residual tumour on early post-operative MRI, without and with contrast; no CNS metastasis on MRI (cranial and spinal); Chang stage M0-1 with no clinical evidence of extra-CNS metastasis
• Full recovery from surgery or any post-surgical complication (e.g. bleeding, infections etc.)
• Post-surgery (within 72h) MRI available (pre-surgery MRI upload is encouraged if available)
• Baseline brain MRI and spinal MRI for uploading available within 2 weeks of randomization/enrollment
• Normal liver, renal and haematological function within 2 weeks of randomization/enrollment.
• WBC ? 3×10^9/L
• ANC ? 1.5×10^9/L
• Platelet count of ? 100×10^9/L independent of transfusion
• Hemoglobin ? 10 g/dl
• Total Bilirubin ? 1.5 × ULN
• ALT (SGPT), AST (SGOT), alkaline phosphatase (ALP) ? 2.5 × ULN
• Serum creatinine 30 mL/min (using the Cockcroft-Gault formula)
• Negative serum or urine pregnancy test within 7 days before randomization/enrollment for WOCBP
• Patients of childbearing / reproductive potential (WOCBP) must use two methods of adequate birth control, including a highly effective method and a barrier method during the study treatment period and for at least 20 months after the last study treatment is mandatory for the patients that received sonidegib, for all other patients this period is at least 6 months after the last study treatment. A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly. Male patients even those who have had a vasectomy must always use a condom during treatment and for 6 months after last treatment. Men should not donate semen during treatment and for at least 6 months after ending treatment (donation of semen for the semen analyses in the 1 b fertility project is allowed)
• Female subjects who are breast feeding must discontinue nursing prior to the first dose of study treatment and until 20 months after the last study treatment
• Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations. For patients less than 18 years of age, consent has to be obtained from the parent(s) or legal representative.

Ausschlusskriterien
• Prior treatment for medulloblastoma
• Unavailability of central review pathology results
• Known prognostic markers (MYC/MYCN amplification, MYC/MYCN mutation)
• Inability to start radiotherapy within 43 days after surgery
• Significant sensorineural hearing deficit as defined by pure tone audiometry with bone conduction or air conduction and normal tympanogram showing impairment = 20 dB at 1-3 kHz
• Any medical contraindication to radiotherapy or chemotherapy
• Hypersensitivity to contrast medium for MRI
• Hypersensitivity towards the active substance of any of study drugs or their excipients
• Prior or current use of mitoxantrone, methotrexate, topotecan, imatinib, irinotecan or statins
• Concurrent severe or uncontrolled medical disease (e.g., active systemic infection, diabetes, psychiatric disorder) that, in the opinion of the investigator, would compromise the safety of the patient or compromise the ability of the patient to complete the study
• Prior or second invasive malignancy, except non-melanoma skin cancer, completely resected cervical carcinoma in situ, low risk prostate cancer (cT1-2a N0 and Gleason score = 6 and PSA < 10 ng/mL), either totally resected or irradiated with curative intent (with PSA of less than or equal to 0.1 ng/mL) or under active surveillance as per ESMO guidelines. Other cancers for which the subject has completed potentially curative treatment more than 5 years prior to diagnosis of medulloblastoma study entry are allowed
• Known history or current evidence of active Hepatitis B (e.g., positive HBV surface antigen) or C (e.g., HCV RNA [qualitative] is detected)
• Known or current evidence of Human Immunodeficiency Virus (HIV) infection (positive HIV-1/2 antibodies)
• Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
NONKO - Neuroonkostudien

Medizinischer Befund
Newly Diagnosed Medulloblastoma

MedDRA Term
Medulloblastoma

Institute
Urologie, Westdeutsches Tumorzentrum

Sponsor

Janssen-Cilag International NV (BE)

Einschlusskriterien
- Histologically confirmed adenocarcinoma of the prostate
- Previously treated with radical prostatectomy with or without lymph node dissection and either: a) for biochemical recurrence after radical prostatectomy (RP): any post-operative prostate-specific antigen (PSA) measurement of less than (=) 0.1 ng/mL within the 4 to 8-week period after RP or b) for persistent PSA after RP: PSA >=0.1 ng/mL within the 4 to 8-week period after RP, confirmed by additional measurement at least 3 weeks later
- Be able to swallow whole the study drug tablets or follow the instructions for admixing with apple sauce
- Results of the Prostate specific membrane antigen-positron emission tomography (PSMA-PET) at screening as determined by blinded independent, central review (BICR), must be: PSMA-PET-negative for any prostate cancer lesions (that is, no loco-regional lesion and no distant lesions); or PSMA-PET-positive for at least one loco-regional (pelvic) lesion without distant extra-pelvic lesion; or PSMA PET- positive for at least one loco--regional (pelvic) lesion with extra-pelvic lesion(s).
- High risk of developing metastasis defined as; a) for biochemical recurrence after RP: pathological Gleason score greater than or equal to (>=) 8 evaluated from prostate tissue specimen at radical prostatectomy, or prostate-specific antigen doubling time (PSADT) less than or equal to (=8, evaluated from prostate tissue specimen at radical prostatectomy
- Participants with evidence of distant metastasis on screening PSMA-PET scan must have no evidence of prostate cancer metastases on screening CT/MRI of the chest/abdomen/pelvis, Technetium 99m [99mTc] whole-body bone scan. Participants with a single bone lesion on 99mTc whole-body bone scan should have confirmatory imaging by CT or MRI; if the confirmatory scan confirms the bone lesion, the participant should be excluded from the study. Conventional images (99mTc-bone scan and CT/MRI) from the screening will be evaluated locally before randomization
- Eastern Cooperative Oncology Group Performance Status Grade 0 or 1

Ausschlusskriterien
- History of pelvic radiation for malignancy
- Previous treatment with androgen deprivation therapy (ADT) for prostate cancer
- Previously treated for biochemical recurrence (BCR) or persistent PSA after RP (previous surgical treatment of one or more loco-regional lesions is allowed)
- Prior treatment with a CYP17 inhibitor (example, oral ketoconazole, orteronel, abiraterone acetate, galeterone) or any androgen receptor (AR) antagonist including bicalutamide, flutamide, nilutamide, apalutamide, enzalutamide or darolutamide and any other medications that may lower androgen levels (estrogens, progestins, aminoglutethimide, etc.), including bilateral orchiectomy
- Known or suspected contraindications or hypersensitivity to apalutamide, Luteinizing Hormone-Releasing Hormone (LHRH) agonist or any of the components of the formulations
- Prior chemotherapy for prostate cancer
- Any evidence of prostate cancer metastasis on computed tomography/magnetic resonance imaging (CT/MRI) of the chest/abdomen/pelvis or 99mTc whole-body bone scan, at any time prior to screening

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich

Indikation
Urogenitale Tumore

Medizinischer Befund
High risk recurrent prostate cancer previously treated with radical prostatectomy\nProstatic Neoplasms

MedDRA Term
Prostate cancer recurrent

Institute
Urologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

PD Dr. med. Wilfried Eberhardt

wilfried.eberhardt@uk-essen.de

Hufelandstr. 55
45147 Essen

Sponsor

Saving Patients' Lives Medical BV

+49 171 1735476
jurgen.feuerstein@splmed.com

Transistorweg 5
6534 Nijmegen

Einschlusskriterien
1) Voluntarily given and written informed consent.
2) Male ?18 years of age.
3) Histologically newly-confirmed adenocarcinoma of the prostate.
4) Risk for lymph node metastases of 20-60%, based on Briganti nomogram [Briganti et al., 2012, or Gandaglia et al., 2018]
5) Patients scheduled for radical prostatectomy (RP) with extended lymph node dissection (ePLND) between Day 7 and Day 42 after Ferrotran®-enhanced MRI.
6) Consent to practice contraception until end of study, including female partners of childbearing potential. Effective contraceptive measures include hormonal oral, injected or implanted female contraceptives, male condom, vaginal diaphragm, cervical cap, intrauterine device.
7) Preoperative PSA, clinical T-stage, primary Gleason grade, secondary Gleason grade, positive core % (according the Briganti nomogram 2012; Briganti et al., 2012 ), or respectively preoperative PSA, clinical stage at multiparametric magnetic resonance imaging (mpMRI), maximum lesion diameter at mpMRI, biopsy Gleason grade group at MRI-targeted biopsy, percentage of cores with clinically significant PCA at systematic biopsy (Briganti nomogram; Gandaglia et al., 2018)

Ausschlusskriterien
1) Any contraindication to MRI, as per standard criteria.
2) Prior radiation therapy for prostate cancer.
3) Any radiotherapy or systemic antiproliferative (chemo-, immuno, or hormonal) therapy for prostate cancer (Lupron, Taxotere, Casodex, Eulexin, Zoladex, etc.) prior to screening and until after post-surgery FUP MRI.
4) Known hypersensitivity to Ferrotran® or its components such as dextran
5) Known hypersensitivity to other parenteral iron products.
6) Acute allergy, including drug allergies and allergic asthma.
7) Evidence of iron overload or disturbances in the utilisation of iron (e.g., haemochromatosis, haemosiderosis, chronic haemolytic anaemia with frequent blood transfusions).
8) Presence of liver dysfunction.
9) Any other investigational medicinal product within 30 days prior to receiving study medication until end of study visit.
10) Simultaneous participation in any other clinical trial.
11) Abnormal safety laboratory values at screening or baseline that are assessed by the principal investigator as clinically relevant.
12) Patients not able to declare meaningful informed consent on their own (e.g. with legal guardian for mental disorders), or other vulnerable patients (e.g. under arrest).

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich

Indikation
Urogenitale Tumore

Medizinischer Befund
newly-diagnosed prostate cancer (PCA)

MedDRA Term
Prostate cancer

Institute
Urologie, Westdeutsches Tumorzentrum, Westdeutsches Tumorzentrum Münster

Sponsor

Janssen Research & Development, LLC

Einschlusskriterien
- Ineligible for or have elected not to undergo radical cystectomy
- All adverse events associated with any prior surgery and/or intravesical therapy must have resolved to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 Grade less than (<) 2 prior to randomization
- Eastern Cooperative Oncology Group (ECOG) performance status Grade 0, 1, or 2
- Thyroid function tests within normal range or stable on hormone supplementation per investigator assessment.
- Adequate bone marrow, liver, and renal function: Bone marrow function (without the support of cytokines or erythropoiesis-stimulating agent in preceding two weeks): Absolute neutrophil count (ANC) greater than or equal to (>=) 1,500/cubic millimeters (mm^3); Platelet count >=80,000/mm^3; Hemoglobin >=9.0 grams per deciliter (g/dL); Liver function: (Total bilirubin less than or equal to (<=) 1.5 * upper limit of normal (ULN) or direct bilirubin )1.5*ULN (except participants with Gilbert's Syndrome, who must have a total bilirubin < 3.0 mg/dL), and Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to (40 mL/min using the Cockcroft-Gault formula

Ausschlusskriterien
- Must not have had urothelial carcinoma or histological variant at any site outside of the urinary bladder. Ta/T1/Carcinoma in situ (CIS) of the upper urinary tract (including renal pelvis and ureter) is allowable if treated with complete nephrouretrectomy more than 24 months prior to initiating study
- Must not have diffuse CIS based on cystoscopy and biopsy. Diffuse, or multi-focal, CIS is defined as the presence of at least 4 distinct CIS lesions in the bladder at the time of the Screening re-TURBT
- Participants must not have evidence of cT4b, or N1-3, or M1 disease based on local radiology staging (chest, abdomen, and pelvis must be performed using Computed tomography [CT] or Magnetic resonance imaging [MRI]) within 42 days prior to randomization
- Presence of any bladder or urethral anatomic feature that, in the opinion of the investigator, may prevent the safe placement, indwelling use, or removal of TAR 200
- Evidence of bladder perforation during diagnostic cystoscopy

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Urogenitale Tumore

Medizinischer Befund
Muscle-Invasive Urothelial Carcinoma (MIBC) of the Bladder

MedDRA Term
Urothelial carcinoma bladder stage IV, Urothelial carcinoma bladder stage III, Urothelial carcinoma bladder stage II, Urothelial carcinoma bladder

Institute
Urologie, Westdeutsches Tumorzentrum

Sponsor

Janssen-Cilag International NV (BE)

Einschlusskriterien
-High grade papillary Ta or T1 or CIS
-BCG naïve (or stopped BCG >3 years before enrolment)

Ausschlusskriterien
- Muscle invasive, locally advanced, non-resectable or metastatic urothelial carcinoma
- Concurrent extra-vesical nonmuscle invasive transitional cell carcinoma of the urothelium

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Urogenitale Tumore

Medizinischer Befund
BCG-naïve High-Risk Non-Muscle Invasive Bladder Cancer

MedDRA Term
Urothelial carcinoma bladder

Institute
Neurologie, Westdeutsches Tumorzentrum

Prüfarzt (AMG) / Studienleitung (BO)

Prof. Dr. med. Ulrike Schara-Schmidt

+49 (0)201 723-2356
ulrike.schara@uk-essen.de

Hufelandstraße 55
45147 Essen

Sponsor

Novocure GmbH

Einschlusskriterien
- ? 18 years of age
- Newly diagnosed, histologically confirmed GBM (WHO Grade IV)
- Patient after completion of radiochemotherapy but within first 3 cycles of first-line tumor-specific mainte-nance chemotherapy
- Clinical indication of treatment with NovoTTF-200A System (Optune®) according to IFU and medical guidelines
- Signed informed consent

Ausschlusskriterien
- Any foreseeable deviation from the IFU of NovoTTF-200A System (Optune®)

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
NONKO - Neuroonkostudien, Glioblastom

Medizinischer Befund
Glioblastom

Institute
Urologie, Westdeutsches Tumorzentrum

Sponsor

Exelixis, Inc., USA

Einschlusskriterien
- Cytologically or histologically confirmed solid tumor that is unresectable, locally advanced or metastatic.
- Dose-Escalation Cohorts: Subjects with a solid tumor that is unresectable or metastatic and for which life-prolonging therapies do not exist or available therapies are intolerable or no longer effective.
- Expansion Cohort 1 (ccRCC): Subjects with unresectable advanced or metastatic RCC with a clear cell component who have not received prior systemic therapy.
-- Note: Prior non-VEGF targeted adjuvant or neoadjuvant is allowed if disease recurrence occurred 6 months after the last dose.
- Expansion Cohort 2 (ccRCC): Subjects with unresectable advanced or metastatic RCC with a clear cell component.
-- Must have radiographically progressed after a combination therapy consisting of a PD-1/PD-L1 targeting mAb with a VEGFR-TKI or a PD-1 targeting mAb with a CTLA-4 mAb as the preceding line of therapy.
- Expansion Cohort 3 (mCRPC): Men with metastatic adenocarcinoma of the prostate.
-- Must have progressed after one NHT given for castration-sensitive locally advanced (T3 or T4) or metastatic castration-sensitive prostate cancer (CSPC), M0 CRPC, or mCRPC.
- Expansion Cohort 4 (UC, ICI-naive): Subjects with histologically confirmed unresectable, locally advanced or metastatic transitional cell carcinoma of the urothelium (including the renal pelvis, ureter, urinary bladder, or urethra).
-- Must have progressed during or after prior first-line platinum-based combination therapy, including subjects who received prior neoadjuvant or adjuvant platinum-containing therapy with disease recurrence < 12 months from the end of last therapy.
- Expansion Cohort 5 (UC, ICI-experienced): Subjects with histologically confirmed unresectable, locally advanced or metastatic transitional cell carcinoma of the urothelium (including the renal pelvis, ureter, urinary bladder, or urethra).
-- Must have progressed during or after prior PD-1/PD-L1 targeting ICI therapy given as monotherapy, combination therapy, or maintenance therapy.
- Expansion Cohort 6 (nccRCC): Subjects with unresectable advanced or metastatic nccRCC of the following subtypes: Papillary RCC (any type), unclassified RCC, sarcomatoid RCC (? 50% of the tumor has sarcomatoid features).
-- No prior systemic anticancer therapy is allowed except adjuvant or neoadjuvant therapy if disease recurrence occurred at least 6 months after the last dose.
- Expansion Cohorts 1, 2, 4, 5, 6: Measurable disease per RECIST 1.1 as determined by the Investigator.
- For expansion cohorts only: Archival tumor tissue material, if available, or fresh tumor tissue if it can be safely obtained.
- Recovery to baseline or ? Grade 1 CTCAE v5 from AE(s) related to any prior treatments unless AE(s) are deemed clinically nonsignificant by the Investigator and/or stable on supportive therapy.
- Karnofsky Performance Status (KPS) ? 70%.
- Adequate organ and marrow function.
- Sexually active fertile subjects and their partners must agree to use highly effective methods of contraception.
- Female subjects of childbearing potential must not be pregnant at screening

Ausschlusskriterien
- Prior treatment with XL092, nivolumab, ipilimumab, or agents targeting the IL-2 pathway such as bempegaldesleukin.
- For Cohorts 2 (ccRCC), 3 (mCRPC), 4 and 5 (UC): Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before first dose of study treatment.
- For Cohort 3 (mCRPC): Receipt of abiraterone within 1 week; cyproterone within 10 days; or receipt of flutamide, nilutamide, bicalutamide, enzalutamide, or other androgen receptor inhibitors within 2 weeks before first dose of study treatment.
- For Cohorts 2 (ccRCC), 3 (mCRPC), 4 and 5 (UC): Receipt of any type of anticancer antibody or systemic chemotherapy within 3 weeks before first dose of study treatment.
- Prior external radiation therapy within 2 weeks and prior radium-223 therapy within 6 weeks before first dose of study treatment.
- Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy (including radiosurgery) or surgically removed and stable for at least 4 weeks before first dose of study treatment.
- Concomitant anticoagulation with oral anticoagulants and platelet inhibitors.
- Uncontrolled, significant intercurrent or recent illness.
- Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms per electrocardiogram (ECG) within 14 days before first dose of study treatment.
- Pregnant or lactating females.
- Any other active malignancy within two years before first dose of study treatment, except for locally curable cancers that have been apparently cured such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
Note: Additional Inclusion and Exclusion criteria may apply.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
Urogenitale Tumore

Medizinischer Befund
Renal Cell Carcinoma\nMetastatic Castration-resistant Prostate Cancer\nUrothelial Carcinoma\nSolid Tumor

MedDRA Term
Castration-resistant prostate cancer, Urothelial carcinoma ureter metastatic, Malignant solid tumor, Urothelial carcinoma urethra metastatic, Urothelial carcinoma bladder stage IV, Solid tumor, Urothelial carcinoma, Clear cell renal cell carcinoma metastatic

Institute
Urologie, Westdeutsches Tumorzentrum

Sponsor

Janssen-Cilag International NV (BE)

Einschlusskriterien
1. ?18 years (or the legal age of consent in the jurisdiction in which the study is taking place) at the time of informed consent
2. Histologically proven, cT2-T4a N0, M0 infiltrating urothelial carcinoma of the bladder. Diagnosis must have been within 90 days of randomization date. Participants with variant histologic subtypes (e.g. squamous cell carcinoma) are allowed if urothelial (transitional cell) differentiation is predominant (e.g. 20% variant histologic subtype). However, the presence of any neuroendocrine, micropapillary, signet ring cell, plasmacytoid, or sarcomatoid features will make a participant ineligible
3. Ineligible for or have elected not to undergo radical cystectomy.
4. All adverse events associated with any prior surgery and/or intravesical therapy must have resolved to CTCAE version 5.0 Grade ? 2 prior to randomization
5. Eastern Cooperative Oncology Group (ECOG) performance status Grade 0, 1, or 2
6. Thyroid function tests within normal range or stable on hormone supplementation per investigator assessment.
7. Adequate bone marrow, liver, and renal function:
a. Bone marrow function (without the support of cytokines or erythropoiesis-stimulating agent in preceding two weeks):
i. Absolute neutrophil count (ANC) ? 1,000/mm^3
ii. Platelet count ?75,000/mm^3
iii. Hemoglobin ?8.0 g/dL
b. Liver function:
i. Total bilirubin ?1.5 x ULN OR direct bilirubin ?ULN for participants with total bilirubin levels >1.5xULN (except participants with Gilbert’s Syndrome, who must have a total bilirubin < 3.0 mg/dL),
ii. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ?2.5x institutional ULN
c. Renal function:
- Creatinine clearance >40 mL/min either directly measured via 24-hour urine collection, calculation using the Cockcroft-Gault formula, or calculation for the Modification of Diet in Renal Disease for adult participants.
8. Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for participants participating in clinical studies.
a.) For women of childbearing potential (defined as: fertile, following menarche and until becoming postmenopausal unless permanently sterile):
- Highly effective method of contraception (failure rate of <1% per year when used consistently and correctly).
- Permanent sterilization methods (for the purposes of this study) include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.
Examples of highly effective contraceptives include:
- user-independent methods: implantable progestogen-only hormone contraception associated with inhibition of ovulation; intrauterine device; intrauterine hormone-releasing system; vasectomized partner; sexual abstinence: true abstinence when this is in line with the preferred and usual lifestyle of the participant (Note: periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods], declaration of abstinence for the duration of exposure to study drug, and withdrawal are not acceptable methods of contraception.)
- user-dependent methods: combined (estrogen- and progestogencontaining) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, and transdermal; progestogen-only hormone contraception associated with inhibition of ovulation: oral and injectable
- agrees to remain on a highly effective method of contraception during the study and for at least 6 months after the last dose of study drug.
- agrees to not donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for at least 6 months after the last dose of study drug.
- not breastfeeding and not planning to become pregnant during the study and for at least 6 months after the last dose of study drug
b. For men who are sexually active with women of childbearing potential:
- agrees to use a condom with spermicidal foam/gel/film/cream/suppository
- agrees to not donate sperm during the study and for at least 6 months after the last dose of study drug
- not planning to father a child during the study or within 6 months after the last dose of study drug
9. A woman of childbearing potential must have a negative highly sensitive serum (beta-human chorionic gonadotropin [beta-hCG]) within the Screening Period prior to the first dose of study drug
10. Must sign an Informed Consent Form indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study and agree to store samples when applicable

Ausschlusskriterien
1. Active malignancies other than the disease being treated under study.
2. Must not have had urothelial carcinoma or histological variant at any site outside of the urinary bladder.
3. Must not have diffuse carcinoma in situ based on cystoscopy and biopsy. Diffuse, or multi-focal, CIS is defined as the presence of at least 4 distinct CIS lesions in the bladder at the time of the Screening re-TURBT.
4. Participants must not have evidence of cT4b, or N1-3, or M1 disease based on local radiology staging within 42 days prior to randomization.
5. Presence of any bladder or urethral anatomic feature that, in the opinion of the investigator, may prevent the safe placement, indwelling use, or removal of TAR-200.
6. Evidence of bladder perforation during diagnostic cystoscopy.
7. Bladder post-void residual volume >350 mL at screening after second voided urine.
8. History of clinically significant polyuria with recorded 24-hour urine volumes greater than 4,000-mL.
9. Currently participating or has participated in a study of an investigational agent and received study therapy or investigational device within 4 weeks prior to randomization.
10. Received intervening intravesical chemotherapy or immunotherapy from the time of most recent cystoscopy/Transurethral Resection of Bladder Tumor to starting study treatment.
11. Prior therapy with an anti-programmed cell death 1, anti-PD-ligand 2 agent, or with an agent directed to another co-inhibitory T-cell receptor.
12. Participants with a history of Grade =3 toxic effects when using anti-TNF or anti-IL-6 agents.
13. Received prior systemic chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to starting study treatment or not recovered from adverse events due to a previously administered agent.
14. An active, known or suspected autoimmune disease.
15. Received a live virus vaccine within 30 days prior to planned start of study treatment.
16. Active infection requiring systemic therapy within 14 days prior to randomization.
17. Has had an allogeneic tissue/solid organ transplant.
18. A pyeloureteral tube externalized to the skin is exclusionary. Unilateral nephrostomy tube or ureteral stent is permitted if it does not interfere with placement or retention of TAR-200 in the bladder. Participants with unilateral hydronephrosis are permitted; however, participants with bilateral hydronephrosis are excluded.
19. Indwelling urinary catheters are not permitted; however, intermittent catheterization is acceptable.
20. Participants who require immunosuppressive medications including but not limited to systemic corticosteroid at doses >10 mg/day of prednisone or its equivalence, methotrexate, cyclosporine, azathioprine, and TNF-alpha blockers. Use of immunosuppressive medications for the management of immune related adverse events, infusion related reactions, or in participants with contrast allergies is acceptable. Use of inhaled, topical, and intranasal corticosteroids are permitted.
21. Must not have clinically significant liver disease that precludes participant treatment regimens prescribed on the study
22. Known human immunodeficiency virus (HIV) infection, unless the participant has been on a stable anti-retroviral therapy regimen for the last 6 months or more and has had no opportunistic infections and a CD4 count of >350 in the last 6 months.
23. Known evidence of active hepatitis B or C infection
24. Concurrent urinary tract infection
25. History of allergy to protein-based therapies and participants with a history of any significant drug allergy.
26. Known hypersensitivity to any component of the drug formulation for cetrelimab, gemcitabine (or other drug excipients) or chemically-related drugs.
27. Known hypersensitivity to gemcitabine (or other drug excipients) or chemically-related drugs.
28. Known hypersensitivity to the device constituent or the Inserter materials.
29. Evidence of interstitial lung disease or active non-infectious pneumonitis.
30. Must not have active tuberculosis.
31. History of uncontrolled cardiovascular disease including any of the following in the preceding 3 months: unstable angina, myocardial infarction, ventricular fibrillation, Torsades de Pointes, cardiac arrest, or known congestive New York Heart Association Class III-IV heart failure, cerebrovascular accident, or transient ischemic attack; pulmonary embolism or other venous thromboembolism within the preceding 2 months.
32. Impaired wound healing capacity defined as skin/decubitus ulcers, chronic leg ulcers, known gastric ulcers, or unhealed incisions.
33. Major surgery within 4 weeks before first dose (TURBT is not considered major surgery).
34. Must not have tumors larger than 3-cm in greatest diameter following screening re- TURBT.

Studienteilnehmende Mindestalter
18 Jahr(e)

Geschlecht
Divers, Männlich, Weiblich

Indikation
Urogenitale Tumore

Medizinischer Befund
Muscle-Invasive Urothelial Carcinoma (MIBC) of the Bladder

MedDRA Term
Urothelial carcinoma bladder stage IV, Urothelial carcinoma bladder stage III, Urothelial carcinoma bladder stage II, Urothelial carcinoma bladder

Institute
Urologie, Westdeutsches Tumorzentrum

Sponsor

Janssen-Cilag International NV (BE)

Einschlusskriterien
1. Male, 18 years of age or older (or the legal age of consent in the country in which the study is taking place).
2 Signed an Informed Consent Form (ICF) indicating that the participant understands the purpose of, and procedures required for the study and is willing to participate in the study; participants must be willing and able to adhere to the prohibitions and restrictions specified in this protocol.
3. Histologically confirmed adenocarcinoma of the prostate.
4. Criterion changed per Amendment 1.
4.1 Previously treated with radical prostatectomy with lymph node dissection and first post-operative PSA measurement of <0.1 ng/mL between Week 6 and Week 13.
5. Any pathologic stage at initial diagnosis: pTany, pNany, M0 (on CT/MRI and 99mTc bone scan).
6. Criterion changed per Amendment 1.
6.1 Biochemically recurrent prostate cancer after RP with a high risk of developing metastasis defined as
- pathological Gleason score ?8 at diagnosis or time of surgery, OR
- PSADT ?12 months at the time of screening using at least 3 consecutive values ?0.1 ng/mL, from time of BCR, estimated using the Memorial Sloan Kettering Cancer Center online calculator.
7. Criterion changed per Amendment 1.
7.1 PSMA-PET must be performed at screening:
- Patients who are PSMA-PET-positive for at least one loco-regional (pelvic) lesion with or without distant (extra pelvic) lesions at screening, as determined by BICR, will be eligible to be randomized to either arm of the Interventional Cohort. The investigators will be blinded to the location of the PSMA-PET lesions after randomization.
- Patients who are PSMA-PET-negative for any prostate cancer lesions (ie, no loco regional lesion and no distant lesions) at screening, as determined by BICR, will be eligible for inclusion in the Observational Cohort.
8. Criterion changed per Amendment 1.
8.1 No evidence of metastases on screening CT/MRI of the chest/abdomen/pelvis, 99m Tc whole-body bone scan. Participants with a single bone lesion on 99mTc whole-body bone scan should have confirmatory imaging by CT or MRI; if the confirmatory scan confirms the bone lesion, the patient should be excluded from the study.
10. Criterion changed per Amendment 1.
10.1 Adequate organ function as defined by the following criteria:
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 X upper limit of normal (ULN) and total bilirubin ?1.5 x ULN.
- Serum creatinine <1.8 mg/dL.
- Platelets ?75,000/?L, without transfusion and/or growth factors within 1 month prior to randomization.
- Hemoglobin ?10.0 g/dL (6.21 mmol/L), without transfusion and/or growth factors within 1 month prior to randomization.
11. Criterion changed per Amendment 1.
11.1 Be able to swallow whole the study drug tablets or follow the instructions for admixing with apple sauce.
12. Criterion changed per Amendment 1.
12.1 If the participant engages in sexual activity with a woman of childbearing potential, a condom must be used together with another highly effective method of contraception during the Treatment Period and for 3 months after the last dose of study intervention.
13. The participant must agree not to donate sperm for the purpose of reproduction during the Treatment Phase and for a minimum 3 months after receiving the last dose of study intervention.
14. Criterion added per Amendment 1.
Participants receiving bone-loss prevention treatment with bone-sparing agents indicated for the treatment of osteoporosis at doses and dosing schedules appropriate for the treatment of osteoporosis (eg, denosumab [Prolia®], zoledronic acid [Reclast®]) must be on stable doses for at least 4 weeks before randomization.

Ausschlusskriterien
1. History of pelvic radiation for malignancy.
2. Criterion deleted per Amendment 1.
3. Previous treatment with ADT for prostate cancer.
4. Previously treated for BCR prostate cancer.
5. Prior treatment with a CYP17 inhibitor (eg, oral ketoconazole, orteronel, abiraterone acetate, galeterone) or any AR antagonist including bicalutamide, flutamide, nilutamide, apalutamide, enzalutamide or darolutamide and any other medications that may lower androgen levels (estrogens, progestins, aminoglutethimide, etc.), including bilateral orchiectomy.
6. Pathological finding consistent with small cell, or neuroendocrine carcinoma of the prostate.
7. Any of the following within 6 months prior to first dose of study intervention: severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (eg, pulmonary embolism, cerebrovascular accident including transient ischemic attacks), or clinically significant ventricular arrhythmias or New York Heart Association Class II to IV heart disease; uncomplicated deep vein thrombosis is not considered exclusionary
8. Use of 5-alpha-reductase inhibitor =4 weeks prior to randomization.
9. Use of investigational agent =4 weeks prior to randomization.
10. Prior chemotherapy for prostate cancer.
11. Active malignancies (ie, progressing or requiring treatment change in the last 24 months) other than the disease being treated under study. The only allowed exceptions are:
- Non-muscle invasive bladder cancer.
- Skin cancer (non-melanoma or melanoma) treated within the last 24 months that is considered completely cured.
- Breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ, or history of localized breast cancer and considered to have a very low risk of recurrence.
- Malignancy that is considered cured with minimal risk of recurrence.
12. Human immunodeficiency virus-positive participants with 1 or more of the following:
- Not receiving highly active antiretroviral therapy
- Had a change in antiretroviral therapy within 6 months of the start of screening
- Receiving antiretroviral therapy that may interfere with study intervention (consult Sponsor for review of medication prior to enrollment)
- CD4 count <350 at screening
- AIDS-defining opportunistic infection within 6 months of start of screening
13. Chronic, active or symptomatic viral hepatitis or chronic liver disease; ascites or bleeding disorders secondary to hepatic dysfunction.
14. History of seizure or any condition that may predispose to seizure (including, but not limited to, prior stroke, transient ischemic attack, or loss of consciousness =1 year prior to randomization; brain arteriovenous malformation; or intracranial masses such as schwannomas and meningiomas that are causing edema or mass effect).
15. Treatment with drugs known to lower the seizure threshold within 4 weeks prior to randomization.
16. Known or suspected contraindications or hypersensitivity to apalutamide, LHRH agonist or any of the components of the formulations.
17. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant.
Plans to father a child while enrolled in this study or within 4 weeks after the last dose of study intervention.
18. Criterion deleted per Amendment 1.

Studienteilnehmende Mindestalter
18 Jahr(e)

Indikation
Urogenitale Tumore

Medizinischer Befund
Prostate cancer recurrent

MedDRA Term
Prostate cancer recurrent

Institut
Neurologie

Sponsor

Janssen-Cilag International NV (BE)

Einschlusskriterien
- Ischemic Stroke: a neurological deficit attributable to an acute brain infarction and national institute of health stroke score scale (NIHSS) score less than or equal to (=) 6
- Participants will be randomized as soon as possible after determining eligibility and within 48 hours of onset of event.
- Current or planned antiplatelet treatment per international and/or local guidelines. If acetyl salicylic acid (ASA) is used, it will be limited to low dose (75 to 100 milligrams (mg)/day). Loading dose of antiplatelet agents (including ASA) are allowed per standard-of-care
- A female participant must agree not to be pregnant, breastfeeding, or planning to become pregnant until 4 days (5 half lives) after the last dose of study intervention
- Willing and able to adhere to the lifestyle restrictions specified in this protocol

Ausschlusskriterien
- Prior history of intracranial hemorrhage except subarachnoid hemorrhage greater than (>) 1 year prior with adequate treatment
- The index stroke or TIA is considered to have a cardio-embolic etiology based on local standard-of-care investigations and for which guidelines recommend anticoagulation
- The index stroke or TIA considered to have another known cause, not related to athero-thrombotic sources (treatment of acute stroke trial [TOAST] Other Determined Etiology), based on local standard-of-care investigations
- Increased risk of bleeding, including clinically significant bleeding within the previous 3 months or known bleeding diathesis or known activated partial thromboplastin time (aPTT) prolongation or spinal cord hemorrhage or retinal hemorrhage
- Current active liver disease, eg, acute hepatitis, known cirrhosis, including participants receiving antiviral treatment for hepatitis
- Known allergies, hypersensitivity, or intolerance to milvexian or its excipients

Studienteilnehmende Mindestalter
40 Jahr(e)

Geschlecht
Männlich, Weiblich

Indikation
STROKE  - Schlaganfall

Medizinischer Befund
Ischemic Stroke\nTransient Ischemic Attack