The ABC-HCC Trial: Atezolizumab Plus Bevacizumab vs. Transarterial Chemoembolization (TACE) in Intermediate-stage HepatoCellular Carcinoma

This is an interventional treatment trial for Hepatocellular Carcinoma focused on measuring hepatocellular carcinoma, HCC, intermediate stage, atezolizumab, bevacizumab, TACE Read More

Inclusion Criteria:

1. Signed Informed Consent Form available
2. Patients ≥ 18 years of age at time of signing Informed Consent Form (for Taiwan: ≥ 20 years)
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. Disease not amenable to curative surgery or transplantation or curative ablation BUT disease amenable to TACE

5. Extent of disease according to the following parameters:

   • Multifocal HCC beyond Milan criteria (i.e. >3 lesions of any size OR ≥2 lesions with at least one of them being ≥ 3cm)
   • More than one untreated HCC untreated nodule > 10 mm showing arterial hyperenhancement
   • No massive multinodular pattern preventing adequate TACE
   • No tumor of a diffuse infiltrative HCC type
   • Patent portal vein flow
   • No portal vein invasion/thrombosis (even segmental) on baseline/eligibility imaging
   • No extrahepatic disease
6. Patients with recurrence after resection/ablation are eligible if initially having achieved complete response AND recurrence developed within 2 years (i.e. ≤730 days) before trial inclusion AND if ≥ 2 untreated nodules with > 10 mm with arterial enhancement are present at timepoint of trial inclusion.
7. Child-Pugh score class A without ascites requiring more than 100 mg of spironolactone/day (see exclusion criteria) at enrollment.
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 at enrollment.
9. Adequate organ and bone marrow function
10. Life expectancy of ≥ 3 months

11. The following laboratory values obtained less than or equal to 7 days prior to randomization.

    • Platelet count ≥ 75,000 per µL (75x109/L)
    • Hemoglobin ≥ 9.0 g per dL [transfusion allowed]
    • Total bilirubin ≤ 2.0 x the upper limit of normal (ULN)
    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 x ULN
    • Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCL) ≥ 50mL/min (calculated using the Cockcroft-Gault formula)
    • Urine dipstick for proteinuria ≤ 2+ (within 7 days prior to initiation of study treatment) 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
    • INR or aPTT ≤ 1.5 x ULN (therapeutic anticoagulation prohibited - see exclusion criterion #13; prophylactic anticoagulation permitted, e.g. LMW heparin, ASS up to 250mg/qd)
    • Alkaline phosphatase ≤ 2.5 x ULN
    • Absolute neutrophil count (ANC) ≥ 1.500 per µL (1.5x109/L) without granulocyte colony-stimulating factor support
    • Serum albumin ≥ 2.8 g per dL (28g/L)

12. Pre-treatment tumor tissue sample (if available)

    • If tumor tissue is available, a formalin-fixed, paraffin-embedded (FFPE) tumor specimen in a paraffin block (preferred) or approximately 10 to 15 slides containing unstained, freshly cut, serial sections should be submitted along with an associated pathology report.
    • If FFPE specimens described above are not available, any type of specimens (including fine-needle aspiration, cell pellet specimens [e.g., from pleural effusion], and lavage samples) are also acceptable. This specimen should be accompanied by the associated pathology report.
    • If tumor tissue is not available (e.g., patient has never undergone biopsy or tissue depleted because of prior diagnostic testing), patients are still eligible.
13. Negative serum pregnancy test done lesser than or equal to 7 days prior to randomization, for females of childbearing potential only.
14. 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 enrollment.
15. Absence of other severe comorbidities
16. Resolution of any acute, clinically significant treatment-related adverse events from prior therapy/procedure to Grade ≤ 1 prior to study entry, with the exception of alopecia.

17. For patients with active hepatitis B virus (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; e.g., entecavir) for a minimum of 14 days prior to study entry and willingness to continue treatment for the length of the study.

18. 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.

19. 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.

20. 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.

Exclusion Criteria:

1. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
2. Disease still amenable to curative surgery or transplantation or curative ablation.
3. Previous treatment with atezolizumab or bevacizumab.
4. 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.

5. Previous TACE or any other transarterial treatment for HCC

   • Previous RFA / MWA allowed (refer to inclusion criterion #6)
   • Other local therapies are prohibited (e.g. cryoablation, high-intensity focused ultrasound, irreversible electroporation)

6. Extent of disease too advanced:

   • Evidence of macrovascular invasion (even segmental) on baseline / eligibility imaging
   • Massive multinodular pattern preventing adequate TACE
   • Extrahepatic disease
7. Tumor of diffuse infiltrative HCC type (hypovascular infiltrative tumors with ill-defined borders)

8. Clinically meaningful ascites, defined as ascites requiring non-pharmacologic intervention (e.g. paracentesis) to maintain symptomatic control, within 6 months prior to the first scheduled dose.

   • 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.

9. Previous radiotherapy for HCC
10. 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.
11. 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).
12. Uncontrolled hypertension defined by a systolic blood pressure (BP) ≥150 mmHg or diastolic blood pressure (BP) ≥100 mmHg, with or without antihypertensive medication. Patients with initial blood pressure (BP) elevations are eligible if initiation or adjustment of antihypertensive medication lowers pressure to meet entry criteria.
13. 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.
14. History of or current pheochromocytoma.
15. 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.

16. 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
17. Ongoing infection > grade 2 NCI-CTCAE version 5.0.
18. Patients with seizure disorder requiring medication.
19. Prior allogeneic bone marrow transplantation or prior solid organ transplantation.
20. Evidence or history of bleeding diathesis or any hemorrhage or bleeding event >CTCAE grade 3 within 4 weeks prior to randomization.
21. Non-healing wound, ulcer, or bone fracture.
22. Renal failure requiring hemo- or peritoneal dialysis.
23. Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.
24. 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.
25. Positive test for human immunodeficiency virus (HIV)
26. Active tuberculosis
27. Interstitial lung disease with ongoing signs and symptoms at the time of informed consent.
28. 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.
29. Persistent proteinuria of CTC Grade 3 or higher (> 3.5 g/24 hrs, measured by urine protein: creatinine ratio on a random urine sample).
30. Any malabsorption conditions.
31. Pregnant or nursing women
32. 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.

33. 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-Barré 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
34. Pleural effusion or (thoracal/abdominal) ascites causing respiratory compromise (≥CTCAE version 4.0 Grade 2 dyspnea).

35. Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-α 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.
36. 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.
37. 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.
38. 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
39. Receipt of an investigational drug within 28 days prior to initiation of study drug
40. Patient with any significant history of non-compliance to medical regimens or with inability to grant reliable informed consent.