Primary objective is to evaluate the efficacy of the combination of durvalumab with chemotherapy and RFA. Corresponding endpoint • Overall survival rate after 12 months (OS@12months) defined as proportion of patients alive 12 months after enrollment

Secondary objectives are: a) To further characterize the efficacy of the combination of durvalumab with chemotherapy and RFA. Corresponding endpoints • Progression-free survival (PFS) defined as time from enrollment to the date of disease progression or death from any cause • Overall survival (OS) Defined as time from enrollment to the date of death from any cause b) To evaluate the safety and tolerability of the combination of durvalumab with chemotherapy and RFA. Corresponding endpoint • Assessment of safety of the treatment as determined by the incidence, nature, causality, frequency, timing and severity of adverse events using NCI CTCAE 5.0 • Time to cholangitis Defined as time from enrollment to the date of confirmed cholangitis (see 3.2.2 for definition) c) To assess quality of life (QoL) data from patients using EORTC QLQ-C30 and EORTC QLQ-BIL21

Patient* has given written informed consent. 2. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up. 3. Patient is ≥ 18 years of age at time of signing the written informed consent. 4. Patient has been diagnosed with histologically or cytologically confirmed a. cholangiocarcinoma as adenocarcinoma of pancreatobiliary type b. unresectable perihilar and/or ductal cholangiocarcinoma with indication for bile duct stenting and palliative systemic therapy as determined by the local multidisciplinary team (MDT) and already resolved cholestasis due to RFA + stent 5. Patient tolerated RFA prior to inclusion and is eligible for repeat RFA during the study (does not have any contraindications) as determined by investigator. 6. Patient is eligible for palliative systemic therapy based on clinical and laboratory parameters (except hyperbilirubinemia) as determined by the local MDT 7. Patient has a ECOG ≤ 1. 8. Patient has life expectancy of ≥ 12 weeks 9. Patient has body weight > 30 kg 10. Adequate blood count, liver-enzymes, and renal function: a. ANC > 1,500 cells/μL without the use of hematopoietic growth factors b. Platelet count ≥ 100 x 109/L (>100,000 cells/μL) c. Hemoglobin ≥ 9 g/dL d. Serum total bilirubin ≤ 3 x upper normal limit (ULN) (biliary drainage is allowed for biliary obstruction; elevated bilirubin should be caused by obstruction not impaired liver function as assessed by albumin and INR values) e. Albumin levels ≥ 2.8 g/dL f. Patients not receiving therapeutic anticoagulation must have an INR < 2.0 x ULN and PTT < 1.5 x ULN within 7 days prior to enrollment. The use of full dose anticoagulants is allowed as long as the INR or PTT is within therapeutic limits (according to the medical standard in the institution) and the patient has been on a stable dose for anticoagulants for at least three weeks at the time of inclusion g. AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional ULN unless liver metastases are present, in which case it must be ≤ 5 x ULN h. Serum Creatinine ≤ 1.5 x ULN and a calculated creatinine clearance rate ≥ 60 mL /min 11. Female patients defined as women of childbearing potential (WOCBP) or male patients with WOCBP partners must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of <1% per year during the treatment period and for at least 6 months after the last dose of chemotherapy or for at least 3 months after last dose of durvalumab, whatever happens last. Male patients must refrain from donating sperm during this same period. Male patients with a pregnant partner must agree to remain abstinent or to use a condom for the duration of the pregnancy. * There are no data that indicate special gender distribution. Therefore, patients will be enrolled in the study gender-independently

1. Patient received previous or simultaneous endobiliary treatment other than RFA (e.g. PDT or brachytherapy) 2. Patient received previous systemic therapy with a PD-1, PD-L1 inhibitor (including durvalumab) or CTLA4 inhibitor or classical chemotherapy agents like platinum, fluoropyrimidine or gemcitabine based regimens in palliative intent. 3. Patient receives any concurrent chemotherapy, investigational product or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer related conditions (e.g., hormone replace therapy) is acceptable. 4. Patient has known hypersensitivity to any component of the durvalumab formulation as well as a known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion protein and/or any known contraindication (including hypersensitivity) to gemcitabine or cisplatin. 5. Patient has history of active primary immunodeficiency. 6. Patient has stage B cirrhosis according to Child-Pugh criteria (or worse) or cirrhosis (of any grade) with a history of hepatic encephalopathy or clinically significant ascites resulting from cirrhosis. Clinically significant ascites is defined as ascites resulting from cirrhosis requiring diuretics or paracentesis. 7. Patient has any unresolved NCI CTCAE grade ≥ 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and laboratory values defined in the inclusion criteria a. Patients with grade ≥ 2 neuropathy will be evaluated on a case-by-case basis after consultation with the Lead Investigator b. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Lead Investigator. 8. Patient had a prior allogeneic bone marrow or stem cell transplantation or prior solid organ transplantation. 9. Patient has active or history of autoimmune or inflammatory disorders (including, but not limited to, inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis]). The following are exceptions: a. Patients with vitiligo or alopecia b. Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement c. Patients with any chronic skin condition that does not require systemic therapy d. Patients with celiac disease controlled by diet alone e. Patients without active disease in the last 5 years may be included but only after consultation with the Lead Investigator 10. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent 11. Patient has active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (defined as having a positive hepatitis B surface antigen [HBsAg], HBV core antibody [anti-HBc], or HCV antibody test prior to enrollment) NOTE: Patients with resolved HBV infection (defined as negative HBsAg and a positive anti-HBc test) are eligible. Patients positive for HCV antibody are eligible only if polymerase chain reaction testing is negative for HCV RNA 12. Patient is known to have tested positive for human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies) or active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice). 13. Patient received an administration of a live attenuated vaccine within 30 days prior to start of study treatment, or anticipation that such a live attenuated vaccine will be required during the study or within 90 days after the last dose of durvalumab. 14. Patient had a treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin-2) within four weeks or five half-lives of the drug, whichever is longer, prior to study enrollment. 15. Patient has current or prior treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 weeks prior to initiation of study treatment. The following are exceptions: a. Intranasal, inhaled, topical steroids or local steroid injections (e.g. intra articular injection) b. Systemic corticosteroids at physiologic dose not to exceed 10mg/day of prednisone or its equivalent c. Steroids as premedication for hypersensitivity reactions (e.g. CT premedication) 16. Patient has history of leptomeningeal carcinomatosis 17. Patient has a history of malignancy other than CCA except for: a. Malignancy treated with curative intent and with no known active disease ≥ 5 years before the first dose of study treatment and of low potential risk for recurrence b. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease c. Adequately treated carcinoma in situ without evidence of disease 18. Patient underwent major surgical procedure other than for diagnosis within 4 weeks prior to initiation of study treatment. Note: Local RFA plus stent implantation is acceptable. 19. Patient has active disseminated intravascular coagulation 20. Patient has any other serious concomitant or medical condition that, in the opinion of the investigator, presents a high risk of complications to the patient or reduces the likelihood of clinical effect. 21. Patient participated in another interventional clinical study within 28 days prior to study enrollment or participation in a clinical study at the same time as this study, unless it is an observational/ non-interventional study or during the follow-up period of an interventional study. 22. Patient has taken an investigational drug within 28 days prior to initiation of study drug. 23. Female patients, who are pregnant or breast feeding or planning to become pregnant within and 6 months after the end of treatment. Female patients of childbearing potential must have a negative serum pregnancy test result within 7 days prior to initiation of study treatment

Gesamtüberleben (Overall survival; OS) Progressionsfreies Überleben (PS)

Therapieassoziierte Komplikationen Parameter der Lebensqualität (ECOG, BMI, Fragebögen) Parameter der im Rahmen der klinischen Routine durchgeführten Untersuchungen

Generelle Einschlusskriterien: - Alter ≥ 18 J - Schriftlich dokumentierte Einwilligung zur Registerteilnahme Indikationsspezifische Einschlusskriterien: - Histopathologisch gesicherte neuroendokrine Neoplasie

Patient ist nicht in der Lage den Umfang, die Bedeutung und die Konsequenzen dieser klinischen Prüfung zu verstehen

RFS (Recurrence free survival, defined as time from treatment randomization to the earliest date of assessment of first relapse or death by any cause)

1. Written informed consent and obtained from the subject prior to performing any protocol-related procedures, including screening evaluations. 2. Female patient, age ≥ 18 years. 3. FIGO Stage III-IV high-grade ovarian cancer (all histological types, except mucinous histology) 4. Complete primary debulked patients (without any macroscopic residuals), confirmed by CT-Scan postoperatively. 5. Patients must have formalin-fixed, paraffin-embedded tumor samples available from the primary cancer for central NGS analysis and must be HRDpositive defined as BRCAmut independent of NOGGO GIS Score OR NOGGO GIS Score >83 independent of BRCA status, based on these results 6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 7. Patients must be able to take oral medications. 8. Synchronous and secondary malignancies are allowed if the prognosis of the ovarian cancer is not affected. The investigator must contact the medical monitoring team before enrolling the patient in the clinical trial. 9. Patients must have normal organ and bone marrow function: a. Hemoglobin ≥ 10.0 g/dL independent of transfusion ≤ 14 days prior to screening hemoglobin assessment b. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L c. Platelet count ≥ 100 x 109/L d. Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN); < 2 × ULN if hyperbilirubinemia is due to Gilbert's syndrome e. Aspartate aminotransferase /Serum Glutamic Oxaloacetic Transaminase (ASAT/SGOT)) and Alanine aminotransferase /Serum Glutamic Pyruvate Transaminase (ALAT/SGPT)) ≤ 2,5 x ULN f. Serum creatinine ≤ 1.5 x institutional ULN and creatinine clearance > 30 mL/min. 10. Postmenopausal or evidence of non-childbearing status for women of childbearing potential prior to the first dose of study treatment. Female patients of childbearing potential must have a negative serum pregnancy test result ≤3 days prior to administration of the first dose of study treatment. Patients are considered to be of childbearing potential unless 1 of the following applies: a. Considered to be permanently sterile. Permanent sterilization includes hysterectomy, bilateral salpingectomy, and/or bilateral oophorectomy; or b. Is postmenopausal, defined as no menses for at least 12 months without an alternative medical cause. A high follicle-stimulating hormone (FSH) level consistently in the postmenopausal range (30 mIU/mL or higher) may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy; however, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to confirm a postmenopausal state. Female patients of reproductive potential must practice highly effective methods (failure rate < 1% per year) of contraception with their partners, if of reproductive potential, during treatment and for 6 months following the last dose of chemotherapy or the last dose of niraparib, whichever occurs later, or longer if requested by local authorities. Highly effective contraception includes: Ongoing use of progesterone only injectable or implantable contraceptives; Placement of an intrauterine device (IUD) or intrauterine system (IUS); Bilateral tubal occlusion; Sexual abstinence as defined as complete or true abstinence, acceptable only when it is the usual and preferred lifestyle of the patient; periodic abstinence (e.g., calendar, symptothermal, post-ovulation methods) is not acceptable; or Sterilization of the male partner, with appropriate post-vasectomy documentation of absence of sperm in ejaculate.

1. Non-epithelial origin of the ovary, the fallopian tube or the peritoneum (i.e., germ cell tumors) and Ovarian tumors of low malignant potential (e.g., borderline tumors), or mucinous carcinoma of the ovary. 2. Low-grade ovarian, fallopian tube or peritoneal cancer. 3. Has known hypersensitivity to any of the study drugs or any of the excipients of any of the study drugs. 4. Has known hypersensitivity to platin-containing compounds other than carboplatin. 5. Patients posttransplant, including previous allogeneic bone marrow transplant.6. Has undergone interval debulking of the tumor. 7. Has received any anti-cancer therapy for ovarian cancer other than primary surgery. 8. Administration of other simultaneous chemotherapy drugs, any other anti-cancer therapy or anti-neoplastic hormonal therapy, or simultaneous radiotherapy during the trial treatment period (hormonal replacement therapy is permitted as are steroidal antiemetics). 9. Has received prior treatment with a PARP inhibitor or has participated in a trial where any treatment arm included the administration of a PARP inhibitor. 10. Bevacizumab is planned to be given together with first line chemotherapy or as maintenance. 11. Clinically significant cardiovascular disease: a. Cerebrovascular accident or myocardial infarction or unstable angina ≤6 months before start of study treatment b. Severe cardiac arrhythmia (recent event or active or uncontrolled) c. New York Heart Association grade ≥2 congestive heart failure d. Uncontrolled hypertension (defined as systolic blood pressure >140 mmHg and/or diastolic blood pressure >90 mmHg), or history of hypertensive crisis, or hypertensive encephalopathy or posterior reversible encephalopathy syndrome e. History of stroke or transient ischemic attack ≤6 months before start of study treatment f. Coronary/peripheral artery bypass graft ≤6 months before start of study treatment g. Deep vein thrombosis or thromboembolic events ≤1 month before start of study treatment 12. History or evidence of brain metastases or spinal cord compression. 13. Known history of MDS or a pre-treatment cytogenetic testing result at risk for a diagnosis of MDS/AML. 14. Current, clinically relevant bowel obstruction at the time of randomization.15. Patients with gastrointestinal disorders likely to interfere with absorption of the study medication. 16. Pregnant or lactating women, women of child-bearing potential who do not agree to the usage of highly effective contraception methods (see inclusion criteria) starting with the screening visit through at least 6 months after the last dose of chemotherapy treatment or through at least 1 month after the last dose of niraparib, whichever occurs later. 17. Participation in another clinical study with an investigational product immediately prior to randomization. Earliest time point for randomization is after the time required for the investigational product to undergo 5 half-lives has passed. 18. Has a known history of Human Immunodeficiency Virus (HIV) infection (known HIV1/HIV2 antibodies positive) or acquired immunodeficiency syndrome (AIDS) related illness. 19. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] has been detected) infection. 20. Has active infection with SARS-CoV-2 (antigen test). 21. Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of chemotherapy treatment and while and 28 days after the last dose of trial treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. Administration of inactivated vaccines is allowed. 22. Patient has contraindications listed in the most recent SmPC. 23. Patient who might be dependent on the sponsor, CRO, site or the investigator. 24. In Germany: Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40a S. 1 Nr. 2 AMG.

The primary objective of this NIS is to evaluate quality of life (QoL) in adults with grade 2 astrocytoma and oligodendroglioma in a real-world setting. Further patient-relevant endpoints include seizure burden, effectiveness including PFS, ORR, safety and tolerability, treatment reality including time to start therapy after surgery as well as factors affecting treatment decision making.

• Age ≥18 years • WHO grade 2 astrocytoma or oligodendroglioma • Presence of IDH1- or IDH2-mutation • Surgical intervention • No immediate need of radiotherapy or chemotherapy according to the treating physician • Decision for treatment with vorasidenib as per current SmPC • Signed written informed consent • Willingness to participate in Patient-Reported Outcome (PRO) assessment in German language

• Participation in an interventional clinical trial • Patient unable to consent

To confirm the superiority of OSE2101 versus docetaxel on Overall Survival (OS)

To confirm the clinical benefit of OSE2101 versus docetaxel including Patient Reported Outcomes (PROs)

1. Patients expressing HLA-A2 phenotype in blood by pre-screening central laboratory 2. Patients with histologically or cytologically squamous or non-squamous documented NSCLC, metastatic stage at study entry, not eligible for definite surgery or radiation, without EGFR, ALK and ROS1 gene alterations eligible for targeted therapy; other sensitizing mutations known to be immunosensitive are eligible in case of lack of local access to targeted therapy (i.e.; KRAS G12C and BRAF mutations) after Sponsor' agreement 3. Patients who progressed after ≥ 24 weeks of first-line CT-ICI, including ≥12 weeks of anti-PD(L)1 as monotherapy or in combination with another ICI prior to randomization (i.e.; ICI secondary resistance); a radiological tumor assessment by the Investigator at 24 weeks (± 2 weeks) after the start of ICI is needed to exclude PD; induction treatment with first-line CT-ICI should contain at least 2 cycles of platinum-based CT except if contraindication to platinum

1. Small-cell lung cancer/mixed NSCLC with small cell component or other neuroendocrine lung cancers (typical and atypical carcinoids, large-cell neuroendocrine carcinomas) 2. Patients with known hypersensitivity to the active substances or to any of the excipients of OSE2101 or docetaxel 3. Patients with PD during induction first-line CT-ICI (to exclude hyper progression and fast progression to CT-ICI) or with PD within 24 weeks of ICI; chemotherapy, other cytotoxic agent or antiangiogenics in combination with ICI within 12 weeks prior to randomization are not authorized; patients who stopped ICI due to toxicity or other reason than PD are not eligible

Untersuchung der klinischen Leistungsfähigkeit multimodaler Biomarker-Tests hinsichtlich der Quantifizierbarkeit der Tumorlast und deren Änderung unter Therapie bei Patient*innen mit maligner Erkrankung

Patienten mit neu diagnostizierter, rezidivierter oder metastasierter Maligner Erkrankung Alter ≥18 Jahre Unterschriebene Einverständniserklärung

Unzureichende Einwilligungsfähigkeit Kein Einverständnis für die Registrierung, Lagerung und Handhabung der personenbezogenen Krankheitsdaten und des Verlaufes sowie Information des Hausarztes über die Studienteilnahme kein Einverständnis für die Asservierung biologischer Proben

Objektive Erfassung kognitiver Veränderung, insbesondere bezüglich exekutiver Funktionen bei Epilepsie erkrankten Kindern und Jugendlichen, anhand eines parallelen Einsatzes von Eye-Tracking-Technologie während der Durchführung des EpiTrack Juniors. Erforschung, ob Augenbewegungen zur frühzeitigen und spezifischen Erkennung von ASM- und Epilepsieeffekte auf die Kognition beitragen können. Für die Kohorte mit erstem unprovozierten epileptischen Anfall soll dies im Längsschnitt vor und nach Beginn einer anfallssuppressiven Dauertherapie überprüft werden.

Erfassung möglicher Zusammenhänge zwischen abgeleiteten Parametern der Eye-Tracking-Daten und den Ergebnissen der Untertests Zahlen verbinden, Zahlen-Punkte verbinden und figurales Gedächtnis. Insbesondere soll folgendes untersucht werden: Korrelationen zwischen Eye-Tracking-Daten, abgeleiteten Größen und Testergebnissen; mögliche Vorhersagen zu Testergebnissen anhand der Eye-Tracking-Daten; mögliche Klassifizierung der Patienten anhand der Analysen.

1. Für die klinische Stichprobe: Kinder und Jugendliche mit Epilepsie oder einem ersten, unprovozierten epileptischen Anfall 2. Für die Kontrollgruppe: alle gesunden Kinder und Jugendlichen 3. Alter zwischen 6 und 18 Jahren 4. Unterschriebene Einverständniserklärung eines Sorgeberechtigten

1. Mangelnde Kooperationsfähigkeit und Testdurchführbarkeit (klinische Einschätzung durch einen Prüfer) 2. Mangelnde Deutschkenntnisse 3. Für klinische Stichprobe: Patienten mit bekannten tonischen oder atonen Sturzanfällen (Sicherheitsaspekt der Brille) 4. Für gesunde Kontrollgruppe: neurologische Erkrankungen oder chronische Erkrankungen mit ZNS Beteiligung

Overall survival (OS) in randomized participants with PD-L1 1% to 49%

OS in randomized participants with PD-L1 ≥ 1% Progression-free survival (PFS) as assessed by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) per blinded independent central review (BICR) Overall response rate (ORR)

AUSWAHL: Participants must have histologically confirmed Stage IV or recurrent Non-small Cell Lung Cancer (NSCLC) of non-squamous (NSQ) histology with no prior systemic anti-cancer therapy given as primary therapy for advanced or metastatic disease. Participants must have measurable PD-L1 ≥ 1% Tumor Cell (TC) score by the investigational PD-L1 immunohistochemistry (IHC) assay VENTANA PD-L1 (SP263) CDx Assay conducted by central laboratory during the screening period prior to randomization. Participants must have measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST v1.1 criteria. Participants must have an Easter Cooperative Oncology Group (ECOG) performance status of ≤ 1 at screening. Participants must have a life expectancy of at least 3 months at the time of randomization.

AUSWAHL: Participants with epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or ROS-1 mutations that are sensitive to available targeted inhibitor therapy. Participants with unknown EGFR, ALK, or ROS-1 status are excluded. Participants with known BRAFV600E mutations, that are sensitive to available targeted inhibitor therapy; participants with known activating rearranged during transfection (RET) mutations or neurotrophic tyrosine receptor kinase (NTRK) fusion gene alterations are excluded. Participants with unknown or indeterminate BRAF mutation, activating RET mutations or NTRK fusion gene alterations are eligible. Participants must not have untreated central nervous system (CNS) metastases. Participants must not have leptomeningeal metastases (carcinomatous meningitis). Participants must not have concurrent malignancy requiring treatment. Participants must not have an active autoimmune disease. Participants must not have history of interstitial lung disease or pneumonitis that required oral or intravenous (IV) glucocorticoids to assist with management. Participants must not have a history of myocarditis. Participants must not have had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or other antibody or drug targeting T-cell co-stimulation or checkpoint pathways.

Niedriggradige Gliome (LGG) sind eine heterogene Gruppe WHO Grad I und II Hirntumore mit 10-Jahres-Übeleben von 94% und einem 10-Jahre progressionsfreiem Überleben mit einer Standardchemotherapie von 44%. Die Mehrzahl der Patienten mit einem LGG außerhalb der Fossa cranii posterior werden nach initialer Diagnosestellung bzw. nach primärer Tumorresektion lediglich engmaschig nachbeobachtet. Jedoch ist in 1 von 3 Patienten das LGG nicht oder nicht vollständig resezierbar, zeigt klinische Symptome und/oder ist radiologisch progredient. Diese Patienten benötigen eine zusätzliche medizinische Behandlung. Das übergeordnete Ziel der LOGGIC Core BioClinical Datenbank ("LOGGIC Core") ist die Einrichtung einer molekularen und klinischen Datenbank für pädiatrische niedriggradige Gliome (LGG). Die Daten werden verwendet, um das Verständnis der Tumorbiologie der Erkrankung zu verbessern, aber auch, um molekulare Untergruppen von LGG mit dem klinischen Ergebnis zu korrelieren. Ziele mehr über die genetischen Strukturen von LGGs zu erfahren, besonders häufige und für Therapien nutzbare Angriffspunkte zu identifizieren Medikamenten-Empfindlichkeiten und Resistenzen zu erkennen Biomarker zu identifizieren, die den Krankheitsverlauf genauer vorhersagen können diese Therapien dann in einer anschließenden klinischen Studie genauer auf deren Nutzen und auch mögliche Risiken prüfen zu können.

To demonstrate the efficacy of rilvegostomig in combination with tremelimumab and bevacizumab (Arm A) relative to atezolizumab and bevacizumab (Arm C) by assessment of OS in participants with advanced HCC

To demonstrate the efficacy of rilvegostomig and bevacizumab (Arm B) relative to atezolizumab and bevacizumab (Arm C) by assessment of OS in participants with advanced HCC

Age 1 Participant must be 18 or the legal age of consent in the jurisdiction in which the study is taking place, at the time of signing the informed consent. Type of Par ticipant and Disease Charac teristics 2 Locally advanced or metastatic and/or unresectable HCC with diagnosis confirmed by histopathology/ cytology or clinically by AASLD criteria in cirrhotic patients. (a) Participants without cirrhosis require histological confirmation of diagnosis. 3 WHO/ECOG performance status of 0 or 1 with no deterioration over 2 weeks prior to baseline at screening and prior to randomisation. 4 Must not have received prior systemic therapy for intermediate, advanced, or metastatic HCC. 5 Disease that is not amenable to curative surgical and/or locoregional therapies. Participants with recurrent/progressive disease after surgical and/or locoregional therapies are eligible. Participants who have received approved adjuvant therapy (including immune checkpoint inhibitor treatment) must have a minimum interval of 6 months between the completion of such therapy and the documented diagnosis of recurrent or metastatic disease. For participants who received locoregional therapy for HCC, locoregional therapy must have been completed ≥ 28 days prior to the baseline scan for the current study. 6 BCLC stage B (that is not eligible for locoregional therapy) or stage C. 7 Child-Pugh Score class A with no deterioration over the previous 2 weeks prior to baseline at screening and prior to randomisation. 8 For randomised period, mandatory provision of an FFPE tumour tissue sample (newly acquired or archival ≤12 months old prior to screening) in a quantity sufficient to allow for central PD-L1 testing before randomisation. 9 At least one measurable target lesion, not previously treated with local therapy, that can be accurately measured at baseline and suitable for accurate repeated measurements as per RECIST 1.1 guidelines. Lesions within the field of local therapy could be eligible if they subsequently progressed after previous treatments in accordance with RECIST 1.1. 10 Adequate organ and bone marrow function measured during the screening period (ie, Day -28 to Day -1) as defined in Table 6. 11 Participants with active HBV infection (as characterized by positive HBsAg and/or anti-HBc with detectable HBV DNA [≥10 IU/mL or above the limit of detection per local laboratory]) must receive antiviral therapy for a minimum of 14 days prior to randomisation per institutional practice to show evidence of HBV stabilization or signs of viral response (eg, reduction HBV DNA levels) prior to enrolment. Participants must remain on antiviral therapy for the study duration and for 6 months after the last dose of study treatment. Participants with active co-infection of HBV and HDV are not eligible (active HBV infection is indicated by the presence of HBsAg and/or anti-HBcAb with detectable HBV DNA; active HDV infection is indicated by detectable HDV-RNA with/without the presence of anti-HDV antibodies). 12 Participants with active HCV infection must be well-controlled per local institutional practice for the study determined by investigators. Participants with active HCV infection must have a confirmed diagnosis of HCV characterized by the presence of detectable HCV RNA with/without anti-HCV antibody upon enrolment. Participants co-infected with HBV and HCV are not eligible (HCV-positive infection is indicated by the presence of anti-HCV antibodies). 13 Participants must have a life expectancy of at least 12 weeks at the time of screening. Weight 14 Participants must be ≥ 35 kg. Sex and Contr aceptive/Bar rier Requirements 15 Male and female. Contraceptive use by males or females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies; see Appendix G for further details. (a) Male participants: • Non-sterilized male participants who intend to be sexually active with a WOCBP must use an acceptable method of contraception (see Appendix G) from enrolment to 180 days after last dose of tremelimumab, atezolizumab and bevacizumab, 90 days after last dose of rilvegostomig (b) Female participants: • Females not of child-bearing potential, see Appendix G for definition. • Females receiving HRT and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods outlined for WOCBP if they wish to continue using HRT during the study. Otherwise, HRT must be discontinued to allow confirmation of post-menopausal status prior to randomisation; see Appendix G for further details. • Female participants of child-bearing potential who are not totally sexually abstinent and intend to be sexually active with a non-sterilized male partner must use at least one highly effective form of contraception from enrolment throughout study and until at least 180 days after last dose of tremelimumab, atezolizumab and bevacizumab, 90 days after last dose of rilvegostomig ; see Appendix G for further details. All WOCBP must have a negative serum pregnancy test result at Cycle 1 Day 1; must not breastfeed and must not donate, or retrieve for their own use, ova from screening to at least 180 days after last dose of tremelimumab, atezolizumab and bevacizumab, 90 days after last dose of rilvegostomig. (c) Pregnancy test: • All WOCBP must have negative pregnancy test at screening and prior to each administration of investigational product. In formed Consent 16 Capable of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the ICF and in this protocol. 17 Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports the Genomic Initiative (see Appendix D 2)

Medical Conditions 1. As judged by the investigator, any evidence of uncontrolled intercurrent diseases (such as severe or uncontrolled systemic diseases, including, but not limited to, active ILD or pneumonitis, serious chronic gastrointestinal conditions associated with diarrhoea (e.g. active inflammatory bowel disease), active non-infectious skin disease (including any grade rash, urticaria, dermatitis, ulceration, or psoriasis requiring systemic treatment) or psychiatric illness/social situations and uncontrolled tumour-related pain which, in the investigator's opinion, makes it undesirable for the participant to participate in the study or that would jeopardize compliance with the protocol. 2. History of allogeneic organ or stem cell transplantation or on the waiting list for allogeneic organ transplantation 3. Active or prior documented autoimmune or inflammatory disorders requiring chronic treatment with steroids or other immunosuppressive treatment (including but not limited to inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion: (a) Participants with vitiligo or alopecia. (b) Participants with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement. (c) Any chronic skin condition that does not require systemic therapy. (d) Participants with prior disorders who have not had an active disease in the last 5 years may be included only after consultation with the Study Physician. (e) Participants with coeliac disease controlled by diet alone. 4. History of another primary malignancy, except for: (a) Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of study treatment and of low potential risk for recurrence. (b) Adequately resected non-melanoma skin cancer or lentigo malignancy without evidence of disease. (c) Adequately treated carcinoma in situ without evidence of disease. 5. History of active primary immunodeficiency or active infection (except for HBV or HCV infection): including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), or HIV (positive HIV 1/2 antibodies). 6. Persistent toxicities caused by previous anti-cancer therapy excluding alopecia, not yet improved to Grade ≤ 1 or baseline. Note: participants may be enrolled with the following chronic, stable Grade 2 toxicities (defined as no worsening to > Grade 2 for at least 3 months prior to the first dose of study intervention and managed with SoC treatment) which the investigator deems related to previous anticancer therapy: a) Chemotherapy-induced neuropathy. b) Fatigue. c) Vitiligo. d) Endocrine disorders, that are controlled with replacement hormone therapy. e) Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention in the opinion of the investigator may be included 7. History of leptomeningeal carcinomatosis. 8. Central nervous system metastases or spinal cord compression (including asymptomatic and adequately treated disease). Participants with suspected brain metastases at screening should have an MRI (preferred) or CT scan of the brain, each preferably with iv contrast, prior to study entry. 9. Known allergy or hypersensitivity to rilvegostomig, tremelimumab, atezolizumab, bevacizumab or any of the novel agents or any of the excipients of the products. 10. Clinically meaningful ascites, pleural effusion, or pericardial effusion requiring non-pharmacologic intervention (e.g., paracentesis) to maintain symptomatic control within 6 months prior to the first scheduled dose. Participants on stable doses of diuretics for effusion for ≥ 2 months are eligible. 11. History of hepatic encephalopathy. 12. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC. 13. Disease ≥ 50% liver volume determined by investigator 14. Any of the following bleeding risks: a) History of significant bleeding disorders, vasculitis, or a significant bleeding episode from the GI tract within 6 months prior to study randomisation. History of haemoptysis (≥ 2.5 mL of bright red blood per episode) within 6 months prior to initiation of study treatment. b) Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation). c) Metastatic or involved disease that involves major airways or blood vessels, or centrally located mediastinal tumour masses < 30 mm from the carina of large volume. Participants with vascular invasion of the portal or hepatic veins may be enrolled. d) Participants with untreated or incompletely treated varices with bleeding or high-risk (red wale signs or other high risk factors) for bleeding. Participants must undergo an esophagogastroduodenoscopy (EGD), and all size of varices (small to large) must be assessed and treated per local SoC prior to enrolment. Participants who have undergone an EGD within 6 months of prior to initiation of study treatment do not need to repeat the procedure. 15. History of abdominal or trachea-oesophageal fistula, GI perforation and/or fistulae, or intraabdominal abscess within 6 months prior to initiation of study treatment. 16. History of intestinal obstruction and/or clinical signs or symptoms of GI obstruction including sub-occlusive disease or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding prior to initiation of study treatment. Participants with signs/symptoms of sub-/occlusive syndrome/intestinal obstruction at time of initial diagnosis may be enrolled if they had received definitive (surgical) treatment for symptom resolution 17. Serious or non-healing wound, active peptic ulcer, or untreated bone fracture (except asymptomatic spinal compression fractures that don't need any treatment determined by investigators) within 28 days prior to initiation of study treatment. 18. History of arterial thrombotic event, including myocardial infarction, cerebrovascular accident, or transient ischaemic attack, within 6 months prior to initiation of study treatment. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to initiation of study treatment 19. History of deep vein thrombosis, pulmonary embolism, or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered 'significant') during the 3 months prior to treatment allocation. 20. Participants with main portal vein tumour thrombosis (ie thrombosis in the main trunk of the portal vein, with or without blood flow) on baseline imaging. 21. Any history of nephrotic or nephritic syndrome. 22. Any of the following cardiac conditions: • Cardiomyopathy of any aetiology or history of myocarditis • Heart failure [as defined by New York Heart Association class III-IV] • Uncontrolled hypertension: defined as systolic BP ≥ 150 mmHg and/or diastolic BP ≥ 100 mmHg (anti-hypertensive therapy to achieve these parameters is allowed); participants with prior history of hypertensive crisis or hypertensive encephalopathy are ineligible • Unstable angina pectoris • Clinically significant coronary, carotid, or peripheral artery stenosis • Acute coronary syndrome/acute myocardial infarction and/or coronary intervention with Percutaneous coronary intervention/coronary artery bypass grafting within 12 months prior to initiation of study treatment • Prior arterial or peripheral vascular intervention within 12 months prior to initiation of study treatment • Ventricular arrhythmias requiring treatment, high degree atrioventricular (AV) block (II-III), or sinus node dysfunction with significant sinus pause, untreated with pacemaker. Note: Participants with atrial fibrillation or flutter who are clinically stable and have an optimally controlled ventricular rate (eg, mean of < 100 bpm on resting ECG or 24-hour Holter-ECG) may be eligible if all other cardiac eligibility criteria are met, and a cardiology assessment confirms suitability for study treatment. • History of QT prolongation associated with other medications that required discontinuation of that medication. • Congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives. • Planned or scheduled cardiac surgery or percutaneous coronary intervention procedure. • Planned revascularization procedure within 6 months of initiation of study Prior/Concomitant Therapy 23. Any concurrent chemotherapy, study treatment, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is acceptable. Prior treatment with anti-CTLA-4 and/or anti-TIGIT. 24. Radiotherapy within 28 days and abdominal/ pelvic radiotherapy within 60 days prior to initiation of study treatment, except palliative radiotherapy to bone lesions within 7 days prior to initiation of study treatment 25. Receipt of live attenuated vaccine within 30 days prior to the first dose of study treatment. Note that participants, if enrolled, should not receive live vaccine while receiving study treatment and within 30 days after the last dose of study treatment. COVID-19 vaccination should not be given for 72 hours prior to administration of the first dose of study treatment. 26. Receipt of treatment with herbal medications or traditional Chinese medicines with anticancer activity included in the label within 14 days prior to first dose of study treatment. These medications should be discontinued prior to consent and should be avoided during the treatment. 27. Major surgical procedure (as defined by the investigator), open biopsy, or significant traumatic injury within 28 days prior to the first dose of study treatment or anticipation of need for a major surgical procedure during the study. Abdominal surgery, abdominal interventions or significant abdominal traumatic injury within 60 days prior to initiation of study treatment or anticipation of need for major surgical procedure during the course of the study or non-recovery from side effects of any such procedure. Note that minor surgery of isolated lesions for palliative intent is acceptable if performed more than 14 days prior to the first dose of study treatment. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 3 days prior to the first dose of bevacizumab 28. Current or prior use of immunosuppressive medication within 14 days before the first dose of study treatment. The following are exceptions to this criterion: a) Intranasal, inhaled, or topical steroids or local steroid injections (eg, intra articular injection). b) Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or 2mg/day of dexamethasone or equivalent (except for the treatment of adverse events). c) Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication). 29. Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment. Participants receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study. 30. Current or recent (within 10 days of first dose of study treatment) use of aspirin (≥ 325 mg/day) or treatment with dipyridamole, ticlopidine, clopidogrel, and cilostazol 31. Current or recent (within 10 days prior to study treatment start) use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to prophylactic) purpose is ineligible; Prophylactic anticoagulation or thrombolytic agents may be used as needed upon discussion with study physician. 32. Chronic daily treatment with a NSAID. Occasional use of NSAIDs for the symptomatic relief of medical conditions such as headache or fever is allowed. Low-dose aspirin (