Liver Cancer Clinical Trials

• Signed Informed Consent Form available

• Patients\* ≥ 18 years of age at time of signing Informed Consent Form

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

• 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.

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

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

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

• Adequate organ and bone marrow function

• Life expectancy of ≥ 3 months

⁃ 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.

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

⁃ 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.

⁃ Absence of other severe comorbidities

⁃ 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.

⁃ 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.

⁃ 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.

⁃ 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.

⁃ 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.