Patients must meet all of the following criteria to be eligible for the study:

1. Signed Informed Consent Form available

2. Patients* = 18 years of age at time of signing Informed Consent Form

3. Confirmed hepatocellular carcinoma diagnosis based on histopathological findings from tumor tissue or typical diagnostic imaging on dynamic CT or MRI according to AASLD criteria.

4. Intermediate stage HCC as defined by the following criteria:
- Disease not amenable to curative surgery, liver transplantation or curative ablation BUT disease amenable to TACE at enrollment as judged by the investigator.
- No massive multinodular pattern preventing adequate TACE
- No tumor of a diffuse infiltrative HCC type (hypovascular infiltrative tumors with ill-defined borders)
- Patent portal vein flow
- No main portal vein invasion/thrombosis on baseline/eligibility imaging. Patients with minimal invasion, (Vp1 and Vp2) may be eligible if no exclusion criteria are violated.
- No extrahepatic disease

Note: Patients with HCC beyond Milan criteria who enter a downstaging protocol may be recruited into the trial if they do not present any exclusion criteria.

5. Patients with recurrence after resection/ablation or after previous TACE are eligible, if they – according to the investigator – have an indication for (additional) TACE

6. Child-Pugh score class A or B7 without ascites requiring more than 100 mg of spironolactone/day (see exclusion criteria) at enrollment.

7. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 at enrollment.

8. Adequate organ and bone marrow function

9. Life expectancy of = 3 months

10. The following laboratory values obtained less than or equal to 7 days prior to randomization.
- Total bilirubin = 3.0 x the upper limit of normal (ULN)
- Urine dipstick for proteinuria = 2+ (within 7 days prior to randomization)
Patients discovered to have = 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate < 1 g of protein in 24 hours
- The following other laboratory values measured within 7 days prior to randomization are either normal or if abnormal do not represent a medical contraindication for TACE and
atezolizumab/bevacizumab as judged by the investigator: Platelet count, hemoglobin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum creatinine, INR or aPTT, alkaline
phosphatase, neutrophil count (ANC), and serum albumin.

11. Negative serum pregnancy test done lesser than or equal to 7 days prior to randomization, for females of childbearing potential only.

12. No presence of untreated or incompletely treated varices with bleeding or high-risk for bleeding: Availability of esophagogastroduodenoscopy (not older than 6 months) in which all size of varices (small to large) had been assessed and varices were treated per local standard of care prior to randomization.

13. Absence of other severe comorbidities

14. Resolution of any acute, clinically significant treatment-related adverse events from prior therapy/procedure to Grade = 1 prior to randomization, with the exception of alopecia.

15. For patients with active hepatitis B virus (HBV):
- HBV DNA = 2000 IU/mL obtained within 28 days prior to randomization, AND
- Anti-HBV treatment (per local standard of care; e.g., entecavir) for a minimum of 14 days prior to randomization and willingness to continue treatment for the length of the study.

16. For patients with active hepatitis C virus (HCV):
- Patients positive for hepatitis C virus (HCV) antibody are eligible, also if polymerase chain reaction testing is positive for HCV ribonucleic acid (RNA).
- However, anti-viral therapy against HCV is only allowed prior to trial but not during the trial.
- For HBV and HCV co-infection refer to exclusion criterion 11.

17. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for at least 5 months after the last dose of atezolizumab, 6 months after the last dose of bevacizumab, or 1 month after the last TACE procedure.
- A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (= 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).
- Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing
intrauterine devices, and copper intrauterine devices.
- The reliability of sexual abstinence should be evaluated in relation
to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.

18. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below:

- With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for 6 months after the last dose of bevacizumab or 1 month after the last TACE procedure. Men must refrain from donating sperm during this same period.

- With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for 6 months after the last dose of bevacizumab or 1 month after the last TACE procedure to avoid exposing the embryo.

- The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar,
ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.

*There are no data that indicate special gender distribution. Therefore, patients will be enrolled in the study gender-independently.

Patients who meet any of the following criteria will be excluded from study entry:

1. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC (only if proven by biopsy).

2. Previous treatment with atezolizumab or bevacizumab.

3. Previous treatment with a programmed death 1 (PD1), programmed death-ligand (PD-L1), or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, or any form of cancer immunotherapy for HCC.

4. Clinically meaningful ascites, defined as ascites requiring non-pharmacologic intervention (e.g. paracentesis) to maintain symptomatic control.

- Patients with ascites requiring pharmacologic intervention (e.g. diuretics) and stable for = 2 months on low doses of diuretics (spironolactone 100 mg/d or equivalent) for ascites are eligible.
Of note, diuretics for other indications such as congestive heart failure are not considered in this regard.

5. Major surgical procedure, open biopsy, or significant traumatic injury = 28 days prior to randomization or anticipation of need for major surgical procedure during the course of the study or non-recovery from side effects of any such procedure.

6. Significant cardiovascular disease, such as cardiac disease (New York Heart Association Class II or greater), myocardial infarction or cerebrovascular accident within 3 months prior to randomization, as well as unstable arrhythmias (note: beta blockers or digoxin are permitted), unstable angina, new-onset angina (begun within the last 3 months).

7. Uncontrolled hypertension defined by a systolic blood pressure (BP) = 150 mmHg or diastolic blood pressure (BP) = 100 mmHg, with or without antihypertensive medication. Prior history of hypertensive crisis or hypertensive encephalopathy. Patients with initial blood pressure (BP) elevations are eligible if initiation or adjustment of antihypertensive medication lowers pressure to meet entry criteria.

8. Current or recent (within 10 days prior to study treatment start) use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic purpose (prophylactic anticoagulation permitted, e.g. new oral anticoagulants [apixaban, dabigatran, rivaroxaban], LMW heparin, ASA up to 300 mg/qd).

9. Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism = 6 months prior to randomization.

10. With regards to eligibility for adequate TACE, patients presenting with either of the following conditions are excluded:

- Past history of bilioenteric anastomosis or biliary procedure (e.g., endoscopic papillotomy or biliary stenting) or patients with aerobilia

- Central biliary obstruction (right or left intrahepatic duct, common hepatic duct, common bile duct)

- Celiac occlusion

11. Any ongoing infection > grade 2 NCI-CTCAE version 5.0. Note on HIV, HBV, and HCV infection: also consider inclusion criteria s 15, 16, and exclusion criterion 18. Patients with co-infection for HBV and HCV are excluded, unless tested negative for HCV RNA by PCR.

12. Patients with seizure disorder requiring medication.

13. Prior allogeneic bone marrow transplantation or prior solid organ transplantation.

14. Evidence or history of bleeding diathesis or any hemorrhage or bleeding event > CTCAE grade 3 within 4 weeks prior to randomization.

15. Non-healing wound, ulcer, or bone fracture.

16. Renal failure requiring hemo- or peritoneal dialysis.

17. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation including a history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion protein; known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab or bevacizumab formulation.

18. Positive test for human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS), with the following exception: patients with a positive HIV test at screening are eligible, provided they are stable on anti retroviral therapy, have a CD4 count > 200 cells/µL, and have an undetectable viral load.

19. Active tuberculosis

20. Interstitial lung disease with ongoing signs and symptoms at the time of informed consent.

21. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, idiopathic pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest computed tomography (CT) scan

Note: History of radiation pneumonitis within the radiation field (fibrosis) is permitted.

22. Persistent proteinuria of CTCAE Grade 3 or higher (> 3.5 g/24 hrs, measured by urine protein: creatinine ratio on a random urine sample).

23. Pregnant or nursing women

24. Comorbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.

25. Active or history of autoimmune disease including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener’s granulomatosis, Sjögren syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.

Note: History of autoimmune-mediated hypothyroidism on a stable dose of thyroid replacement hormone, or controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible based on consultation with the sponsor’s medical monitor.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:

- Rash must cover < 10% of body surface area

- Disease is well controlled at baseline and requires only low-potency topical corticosteroids

- No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral corticosteroids within the previous 12 months,

26. Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-alpha agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions:

- Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study.

- Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study.

27. Use of any herbal remedies known to interfere with the liver or other major organ functions. Patients must notify the investigator of all herbal remedies used during the study.

28. Administration of a live, attenuated vaccine within four weeks prior to start of enrollment, or anticipation that such a live attenuated vaccine will be required during the study or within 5 months after the last dose of atezolizumab, 6 months after the last dose of bevacizumab, or 1 month after the last TACE procedure.

29. History of malignancy other than HCC within 3 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g. 5-year OS rate > 90%), such as adequately treated carcinoma in situ of the cervix, non melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer. Other similar cases can be considered after discussion with lead investigators and sponsor.

30. Receipt of an investigational drug within 28 days prior to initiation of study drug

31. Patient with any significant history of non-compliance to medical regimens or with inability to grant reliable informed consent or patients with substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results.

Participants are eligible to be included in the study only if all of the following criteria apply:

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 Participant 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.

Table 6 - Criteria for Adequate Organ and Bone Marrow Function

Type
Parameter: Value

Haematological
- Haemoglobin: = 9.0 g/dL (5.59 mmol/L) with no blood transfusions (packed red blood cells) within 14 days prior to first dose
- Absolute neutrophil count: = 1.5 x 10^9/L (1,500 per mm^3) in the absence of growth factor support within 14 days prior to enrolment
- Platelet count: = 75 x10^9/L (100,000 per mm^3) with no platelet transfusions within 14 days prior to first dose
- INR: = 1.6 x ULN without therapeutic anticoagulation.

Hepatic
- Albumin: = 28g/L with no albumin infusion within 14 days prior to first dose.
- Total bilirubin:
= 2.0 x the ULN in the absence of Gilbert’s syndrome
= 3 x ULN in the presence of documented Gilbert’s syndrome (unconjugated hyperbilirubinemia).
- Alanine transaminase and aspartate transaminase: = 5 x ULN

Renal
- Calculated CrCL as determined by Cockcroft Gault (using actual body weight) ((Rostoker et al 2007): = 45 mL/minute (CrCL must be = 50 mL/minute)
- Proteinuria: < 2 +
Participants having = 2+ proteinuria testing at baseline will undergo a 24-hour urine collection for quantitative assessment of proteinuria and must demonstrate < 1 g of protein in 24 hours. Participants with urine protein = 1 g per 24 hours will be ineligible.

Cardiac
- Troponin I or T: = ULN (per institutional guidelines and/or not clinically significant per investigator’s judgement).
- LVEF: = 50%.as assessed by echocardiography or multiple-gated acquisition scan
- QTcF: = 480 msec.

CrCL = creatinine clearance; ULN = upper limit of normal.

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/Barrier 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.

Informed 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)

Participants are excluded from the study if any of the following criteria apply:

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 (eg, hearing loss).

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 treatment.

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 (< 325mg/day) is permitted (Co-administration of proton pump inhibitors is strongly recommended to reduce potential GI damage)

Prior/Concurrent Clinical Study Experience

33. Previous enrolment in the present study.

34. Participation in another clinical study with a study treatment or investigational medicinal device administered in the last 4 weeks prior to first dose of study treatment or oncurrent
enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or the participant is in the follow-up period of an interventional study

Other Exclusions

35. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).

36. Judgement by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.

Note: For participants = 65 years old, use of geriatric screening tools and/or formal Geriatric Assessment (eg, CGA) should be considered, in line with local or national guidelines, prior to randomization. For participants = 80 years old, formal Geriatric Assessment (eg, CGA), if not required already by local or national guidelines, is strongly considered prior to randomisation.

37. Pregnant or lactating female, or female who intend to become pregnant during the study.

- Age equal to or greater than 18 years
- ASA I-III
- Patients undergoing elective complex robotic hepatectomies for benign or malignant lesions who meet at
least one of the following criteria: - - -
- liver resections involving segments 1, 4a, 7, or 8
- liver resections with a planned IWATE difficulty score = 6
- parenchyma-sparing non-anatomic liver resections with vessel exposure (R1-vascular resections)
- Written informed consent

- Patients requiring vascular reconstruction and/or extrahepatic resections
- Patients during pregnancy and breastfeeding
- Impaired mental state or language barrier
- Suspected lack of compliance

Geschlecht: Alle
Mindestalter: 18 Jahre
Höchstalter: kein Höchstalter

Weitere Einschlusskriterien:

- Patientinnen und Patienten mit geplanter parenchymsparender robotischer Leberresektion bei benignen oder malignen Lebererkrankungen, die alle Kriterien erfüllen:
- Atypische Leberresektion oder (Sub-)Segmentektomie
- Machbarkeit eines negativen Resektionsrandes von mindestens 10mm gemäß der präoperativen Bildgebung und keine geplante R1-vaskular Resektion

- = 18 Jahre

- Mündliche und schriftliche Einwilligungserklärung

- ASA I-III

- Patientinnen und Patienten mit Major-Leberresektion (Parenchymverlust), extrahepatischer Resektion und Gefäßrekonstruktion

- Schwangerschaft und Stillzeit

- Geistige Einschränkung, welche eine Erfassung von Wesen, Art und Umfang des Forschungsprojekt verhindert

- Fehlende Compliance

Subjects meeting all of the following criteria will be considered for admission to the clinical trial:

1. Subjects must be = 18 years at the time of screening.

2. Confirmed HCC (either by imaging in a cirrhotic liver [liver lesions that show typical features of HCC on IV contrast-enhanced CT or MRI scans, i.e., hypervascularity in the arterial phase with washout in the portal or the late venous phase] or histopathologically from biopsy specimen or surgery).

3. Disease not amenable to resection, liver transplantation or loco-regionary therapy, such as curative ablation, trans-arterial chemoembolization (TACE) or transarterial radio-embolization (TARE).

4. Eligible for therapy with Atezolizumab / Bevacizumab according to standard of care.

5. Measurable disease per RECIST 1.1.

6. Preserved liver function with a Child-Pugh score A or B (maximally 7 points).

7. Performance status ECOG 0-1.

8. Available CT scan of thorax and MRI or CT scan of abdomen with contrast agent not older than 30 days before start of treatment (A/B C1d1).

9. Documented virology status of hepatitis, as confirmed by screening HBV and
HCV serology test

10. For patients with active HBV: HBV DNA < 500 IU/ml obtained within 28 days prior to initiation of study treatment and anti-HBV treatment per local standard of care for a minimum of 14 days prior to study entry and willingness to continue treatment for the length of the study

11. For patients with active HCV infection (as characterized by the presence of de
tectable HCV RNA): must be managed per local institutional practice for the
length of the study.

12. Adequate organ and marrow function measured within 72 hours prior to randomization as follows:
a. Hemoglobin = 8 g/dL
b. Absolute neutrophil count = 1.0 x 10^9/L
c. Platelet count = 50 x 10^9/L
d. Total bilirubin = 3.0 x the upper limit of normal (ULN)
e. Alanine aminotransferase (ALT) and aspartate aminotransferase = 5 x ULN
f. International normalized ratio = 1.6.
g. Calculated creatinine clearance = 30 mL/min as determined by Cockroft Gault

13. Women of child-bearing potential (WOCBP) must agree to use, and be able to comply with, highly effective contraception (</= 1% failure rate annually, see Appendix 5: CTFG Recommendation Birth control methods) without interruption prior to starting therapy with A/B, while on treatment with A/B and for a period of 6 months after the last dose treatment with A/B.

14. WOCBP must have a negative serum pregnancy test (beta-HCG) result at screening and agree to ongoing pregnancy testing during the course of the trial.

15. Male subjects must practice true abstinence or agree to use a condom during sexual contact with WOCBP while participating in the trial.

16. Ability of subject to understand character and individual consequences of clinical trial and to comply with the study protocol and dosing regimen.

17. Written informed consent (must be available before enrolment in the clinical trial)

18. Subject willing to undergo tumor biopsy. This requires a tumor lesion accessible for a biopsy.

Subjects presenting with any of the following criteria will not be included in the clinical trial:

1. Use of immunosuppressive medication within 6 months prior to the first dose of Atezolizumab / Bevacizumab. The following are exceptions to this criterion:
a. Intranasal, inhaled, topical steroids or local steroid injections (e.g. intraarticular injection).
b. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent
c. Steroids as premedication for hypersensitivity reactions or as an antiemetic.

2. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease, diverticulitis, systemic lupus erythematosus, sarcoidosis, granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, autoimmune pneumonitis, autoimmune myocarditis, etc.).

The following are exceptions to this criterion:
a. Subjects with vitiligo or alopecia.
b. Subjects with hypothyroidism stable on hormone replacement.
c. Any chronic skin condition that does not require systemic therapy.
d. Subjects with coeliac disease controlled by diet alone.
e. Subjects without active disease in the last 5 years may be included but only after consultation with the study clinical lead.

3. Prior exposure to immune-mediated therapy including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-VEGF antibodies.

4. Known to have tested positive for human immunodeficiency virus (HIV) infection.

5. Co-infection of HBV and HCV. Subjects with a history of HCV infection but who are negative for HCV RNA by PCR will be considered non-infected with HCV.

6. Evidence by investigator assessment of varices at risk of bleeding on upper endoscopy undertaken within 12 months of randomization.

7. Refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow a formulated product, or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism or excretion of investigational product.

8. Uncontrolled arterial hypertension defined by a systolic pressure > 150 mm Hg or diastolic pressure > 90 mm Hg or other hypertensive cardiovascular complications despite standard medical treatment.

9. Any history of nephrotic or nephritic syndrome.

10. Usage of systemic antibiotic therapy within 2 weeks prior to the first dose of Atezolizumab/Bevacizumab (C1d1).

11. Usage of probiotic products/supplements within 1 week prior to the first dose of Atezolizumab/Bevacizumab (C1d1).

12. Known fibrolamellar HCC, sarcomatoid HCC, infiltrative-type HCC, or mixed cholangiocarcinoma and HCC.

13. History of another primary malignancy. Exceptions include:
a. malignancy treated with curative intent or has low potential risk for recurrence with no known active disease = 5 years before the first dose of study intervention;
b. malignancy which occurred < 5 years before the first study intervention, is not active, and not expected to recur or be clinically relevant in the next 2 years.

14. Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention.

15. Pregnancy or lactation.

16. 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.

17. Participation in other interventional clinical trials or observation period of competing clinical trials, respectively.

18. Held in an institution by legal or official order.

19. Legally incapacitated.

20. Known hypersensitivity to any component of the vancomycin, atezolizumab or bevacizumab formulation.

- Ability to understand and willingness to sign a written informed consent document.

- Histologically confirmed FL-HCC or other malignant disease that is locally advanced and inoperable or metastatic.

- Non-FL-HCC patients can be included

- in case of disease progression after therapy and fulfilling at least one of the following criteria
i. no further standard therapy is available.
ii. patient is considered unsuitable for further available standard therapy.
iii. patient is unwilling to receive treatment with available standard therapy.

- if no standard therapy exists.

- Presence of DNAJB1-PRKACA fusion transcript, assessed by RNA-based NGS or RT-PCR.

- Age = 18 years.

- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

- Patients must have measurable disease per iRECIST.

- Negative SARS-CoV-2 rapid antigen test (as long as WHO declares pandemic spread of SARS-CoV-2).

- Adequate organ function laboratory values
1. Absolute Lymphocyte Count > 500/µl
2. Platelets > 50.000/µl
3. Creatinine clearance GFR > 30 ml/min
4. Liver function Child-Pugh index class A or B7
5. Alanine aminotransferase (ALT) and aminotransferase (AST) = 5 times upper limit range
6. Bilirubin = 3 mg/dl

- Negative serological Hepatitis B test or negative PCR in case of positive serological test without evidence of an active infection, negative testing of Hepatitis C RNA, negative HIV test within 6
weeks prior to study inclusion.

- Female patients of child bearing potential (FCBP) and male patients with partners of child bearing potential, who are sexually active, must agree to the use of two effective forms (at least one
highly effective method) of contraception. This should be started from the signing of the informed consent and be continued until 5 months (both female and male patients) after last dose of an
IMP (Atezolizumab (TecentriqTM) or vaccination).

- For FCBP two negative pregnancy tests (sensitivity of at least 25 mIU/mL) prior to first application of a study drug (vaccination at visit V1), one at screening and the other one at visit V1 prior
(< 24h) to first vaccination.

- Postmenopausal or evidence of non-child-bearing status.

- Pregnant or breastfeeding.

- Unwilling or unable to follow the study schedule for any reason.

- Chemotherapy or other systemic therapy or radiotherapy, up to 14 days prior to the first dose of study drug.

- Concurrent or previous treatment within 30 days in another interventional clinical trial with an investigational anticancer therapy or any other investigational therapy, which would interfere with the study s primary and secondary endpoints.

- Major surgery within 28 days of dosing of study drug.

- Have not recovered from adverse events to grade = 2 or baseline due to previous agents administered excluding alopecia and neurotoxicity (= 2 grade).

- History of autoimmune phenomena due to treatment with immunotherapy agents (including, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA4 antibodies, etc.) (= grade 3).

- Treatment with immunotherapy agents (including, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA4 antibodies, etc.) within 28 days of dosing of study drug.

- Have received any live vaccine within 28 days prior to study treatment.

- Known sensitivity to or history of allergic reactions to any of the investigational drugs or known hypersensitivity to Chinese hamster ovary cell products.

- History of severe allergic anaphylactic reactions to chimeric, human or humanized antibodies, or fusion proteins.

- Has active autoimmune disease that requires or has required systemic immunosuppressive treatment in the past 2 years.

- Presence of any tissue or organ allograft, regardless of need for immunosuppression, including corneal allograft. Patients with a history of allogeneic hematopoietic stem cell transplant will be excluded.

- Has a diagnosis of immunodeficiency.

- Systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 7 days prior to study drug administration.

- Symptomatic interstitial lung disease.

- Active or untreated brain metastases or leptomeningeal metastases.

- Uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, symptomatic congestive heart failure, unstable angina, cardiac arrhythmia, different metastatic cancer than the one leading to study enrollment, or psychiatric illness/social situations that would limit compliance with study requirements.

Geschlecht: Alle
Mindestalter: 18 Jahre
Höchstalter: kein Höchstalter

Weitere Einschlusskriterien:

- Patienten, die sich einer elektiven Operation in kurativer Intention wegen vermuteter oder durch Biopsie nachgewiesener Malignome der Leber, der Gallenwege/Gallenblase, des periampullären Bereichs oder der Bauchspeicheldrüse unterziehen

- Alter von mindestens 18 Jahren

- Eastern Cooperative Oncology Group (ECOG) - Leistungsstatus 0 oder 1

- Fähigkeit, einen 6MWT mit einer klinisch akzeptablen Herzfrequenz und Blutdruckreaktion sicher zu absolvieren

- Freigabe zur körperlichen Betätigung auf der Grundlage eines Physical Activity Readiness Questionaire (PAR-Q) -Screenings (negatives PAR-Q oder ärztliche Freigabe bei positivem Ergebnis)

- Schriftliche Einverständniserklärung

- Geplante zwei- oder mehrzeitige Operationen innerhalb von 6 Wochen

- Patientinnen während der Schwangerschaft und Stillzeit

- Begleiterkrankungen, die nach Einschätzung des Prüfarztes die Teilnahem an einem Bewegungsprogramm ausschließen

- Vorgeschichte anderer behandelter oder unbehandelter bösartiger Tumoren in den letzten 2 Jahren

- Beeinträchtigter geistiger Zustand oder Sprachbarriere

- vermutete mangelnde Compliance

- Major abdominal surgery for confirmed or suspected gastrointestinal malignancies
- Age >= 18 years
- Written informed consent

- American Society of Anesthesiologist (ASA) classification >= 4
- Planned re-operation within 30 days after index operation
- Mental impairment that prevents an understanding of nature, type and scope of the research project
- Allergies to rosemary oil (rosemary essential oil, virgin olive oil), citrus oil (citrus essential oil, virgin olive oil), solum oil (peat extract, lavender essential oil, horse chestnut extract, horsetail extract, virgin olive oil, white petrolatum, wool wax) or melissa oil (caraway essential oil, fennel essential oil, melissa, marjoram, refined peanut oil) as used oils for the integrative nursing interventions or hypersensitivity to skincare products
- Acute skin disorders at the abdomen or legs
- Emergency Operations
- Pregnancy or breastfeeding
- Participation in another interventional trial with interference on intervention and/or outcome of this trial
- Expected lack of compliance

Einschlusskriterien zur Erfassung im Register für Lebertumoren bei Kindern und Jugendlichen:
- Alle Patienten von 0 bis 20 Jahren mit einem primären (maligne und benigne) Lebertumor, die im Bereich der GPOH diagnostiziert und behandelt werden, sollen in das Register eingeschlossen werden.
- Die schriftliche Einwilligung des Patienten bzw. des Sorgeberechtigten zur Weitergabe, Speicherung und Auswertung personenbezogener Daten muss vorliegen.
- Hinweis: Bei Behandlung eines Patienten innerhalb einer anderen GPOH Studie bzw. Register, wie z. B. Lebersarkome – CWS-Register SoTiSaR, CWS-2007-HR, Keimzelltumoren - MAKEI 96, Rhabdoidtumoren – EU-RHAB sollte dieser in der jeweiligen Studie gemeldet werden, es erfolgt keine Datenerfassung in diesem Register.

1. Patients diagnosed with cancer

2. Patients planned to undergo or undergoing neoadjuvant treatment before planned curative resection

3. Adult patients (>= 18 years of age)

4. Written informed consent

5. Ability to understand character and individual consequences of the clinical trial

Additional for the online program

6. Stable internet connection

7. Laptop of similar

8. Poultieces utensils and utensils for the other applications

9. Sports mat or similar

1. Participation in another interventional trial with interference on intervention and outcome of this trial

2. Immobility or inability to walk unaided

3. Expected lack of compliance

Alter > 18 Jahre
Zustimmung zur Studienteilnahme
Geschäftsfähigkeit
elektive Operation an Pankreas, Leber, Magen oder Ösophagus
Verlegung von einer anästhesiologischen Überwachungsstation (PACU/IMC/Intensivstation) auf Normalstation

Zurückziehen der Einwilligung
Wunsch auf Studienbeendigung
Sprachbarriere
Verletzung beider Gehörgänge, Schwerhörigkeit beidseits
Intensivstationäre Therapie aufgrund eines Organversagens vor Randomisierung
Vorliegen einer palliativen Behandlungssituation
Ablehnung durch die Patienten

- Age equal to or greater than 18 years
- Patients undergoing robotic liver surgery for benign or malignant lesions
- Written informed consent

- ASA = 4
- Patients requiring vascular reconstruction and/or extrahepatic resections
- Impaired mental state or language barrier
- Suspected lack of compliance

- Age equal to or greater than 18 years
- ASA I-III
- Patients undergoing elective complex robotic hepatectomies for benign or malignant lesions who meet at
least one of the following criteria: - - -
- liver resections involving segments 1, 4a, 7, or 8
- liver resections with a planned IWATE difficulty score = 6
- parenchyma-sparing non-anatomic liver resections with vessel exposure (R1-vascular resections)
- Written informed consent

- Patients requiring vascular reconstruction and/or extrahepatic resections
- Patients during pregnancy and breastfeeding
- Impaired mental state or language barrier
- Suspected lack of compliance