Phase IIIb Randomized Multicenter Open-Label Trial of Atezolizumab and Bevacizumab Versus Transarterial Chemoembolization in Intermediate-Stage Hepatocellular Carcinoma
- Trial ID
- 2024-512953-26-00
- Protocol
- ABC-HCC
Trial statistics
Diseases & Conditions
Objectives
The primary objective of the ABC-HCC Trial is to evaluate the **efficacy** and **safety** of a combination therapy of atezolizumab and bevacizumab compared to transarterial chemoembolization (TACE) in patients with intermediate-stage hepatocellular carcinoma. This is clinically relevant as it aims to determine a potentially more effective treatment option for this stage of liver cancer, which could improve patient outcomes and provide an alternative to existing therapies.
Secondary objectives include:
- Further characterizing the responses obtained with the respective therapeutic strategy.
- Assessing the impact of each therapeutic strategy on liver function over time.
- Evaluating the safety and tolerability of each therapeutic strategy and their respective impact on Quality of Life.
- Identifying prognostic and predictive angiogenic and immune-related biomarkers (tissue and circulating) for study endpoints.
- Assessing expression of Programmed Death-Ligand 1 (PD-L1) protein expression by immunohistochemistry on available FFPE biopsy tissue samples collected.
Participants
The clinical trial involves a total of **85 participants** diagnosed with **intermediate-stage hepatocellular carcinoma**. The study population includes both male and female subjects, aged 18 years and older, with no specific gender distribution indicated. Participants were selected based on their confirmed diagnosis of hepatocellular carcinoma, as well as their eligibility for transarterial chemoembolization (TACE) as determined by the investigator. The trial includes individuals with a Child-Pugh score class A or B7, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and a life expectancy of at least 3 months. Participants are required to have adequate organ and bone marrow function and must not have severe comorbidities. The study does not specify particular lifestyle considerations such as diet or physical activity. The trial population includes a vulnerable population, and both male and female subjects are required to adhere to specific contraceptive measures during the study period. The sponsor has not provided additional information regarding the general health status or lifestyle habits of the participants.
Plans and Procedures
The clinical trial is a **randomized**, multicenter, open-label, phase IIIb study designed to evaluate the efficacy and safety of **atezolizumab** in combination with **bevacizumab** compared to transarterial chemoembolization (TACE) in patients with intermediate-stage **hepatocellular carcinoma**. The trial is expected to run from October 2021 to October 2027, with a maximum treatment period of 96 weeks for participants. The study involves intravenous administration of the investigational products, Avastin and Tecentriq, both formulated as solutions for infusion.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as laboratory values and medical history. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety. These visits will include assessments of primary and secondary endpoints, such as time to failure of treatment strategy, overall survival, and progression-free survival. The end-of-study visit will conclude the participant's involvement, assessing the final outcomes and any long-term effects of the treatment.
Participant involvement is expected to last up to 96 weeks, depending on individual response and tolerance to the treatment. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The trial aims to provide comprehensive data on the comparative effectiveness of the treatment regimens, contributing valuable insights into the management of intermediate-stage hepatocellular carcinoma.
Treatment
The clinical trial involves the administration of two experimental medications: **Avastin** and **Tecentriq**. **Avastin** (bevacizumab) is provided as a 25 mg/ml concentrate for solution for infusion. It is administered intravenously. The maximum daily dose is 15 mg/m², with a total maximum dose of 480 mg/m² over the treatment period. The treatment duration is set for a maximum of 96 weeks. **Bevacizumab** is a protein-based therapeutic agent, specifically classified under the ATC code L01FG01, and is manufactured by Roche Registration GmbH.
**Tecentriq** (atezolizumab) is supplied as a 1,200 mg concentrate for solution for infusion. This medication is also administered intravenously. The maximum daily dose is 1,200 mg, with a total maximum dose of 38,400 mg over the treatment period. The treatment duration is similarly set for a maximum of 96 weeks. **Atezolizumab** is a protein-based therapeutic agent, classified under the ATC code L01FF05, and is also manufactured by Roche Registration GmbH.
Both medications are used in combination to evaluate their efficacy and safety compared to transarterial chemoembolization (TACE) in patients with intermediate-stage hepatocellular carcinoma. The trial does not include any non-experimental treatments such as standard-of-care therapy or placebo. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol.
Efficacy
The efficacy of the clinical trial will be assessed using a combination of primary and secondary endpoints. The primary endpoint is the **Time to Failure of Treatment Strategy (TTFS)**. Secondary endpoints include Overall Survival (OS), Overall Survival Rate at 24 months (OS@24), Objective Response Rate (ORR), Time to Progression (TTP), Time to Loss of Systemic Treatment Options (TTSYS), Progression-Free Survival (PFS), Duration of Treatment, Duration of Response (DOR), Time to Deterioration of Liver Function, Safety, Quality of Life (QoL) as measured by Patient Reported Outcomes (PRO), and Baseline PD-L1 protein expression in FFPE tumor tissue.
The trial is designed to compare the efficacy and safety of atezolizumab in combination with bevacizumab versus transarterial chemoembolization (TACE) in patients with intermediate-stage hepatocellular carcinoma. Efficacy parameters will be collected and analyzed at various timepoints throughout the study, with specific attention to the progression and response of the disease, as well as the overall survival of the participants. The study is expected to conclude by October 21, 2027, with recruitment having started on October 22, 2021.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Signed Informed Consent Form available
- Patients* ≥ 18 years of age at time of signing Informed Consent Form. *There are no data that indicate special gender distribution. Therefore, patients will be enrolled in the study gender-independently
- 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
Exclusion Criteria
- Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC (only if proven by biopsy).
- Previous treatment with atezolizumab or bevacizumab
- 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.
- 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
- 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
- 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).
- 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
- 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).
- Arterial or venous thrombotic or embolic events such as cerebro-vascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism ≤6 months prior to randomization
- 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
- 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
- Patients with seizure disorder requiring medication
- Prior allogeneic bone marrow transplantation or prior solid organ transplantation
- Evidence or history of bleeding diathesis or any hemorrhage or bleeding event > CTCAE grade 3 within 4 weeks prior to randomization
- Non-healing wound, ulcer, or bone fracture.
- Renal failure requiring hemo- or peritoneal dialysis
- 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
- 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
- Active tuberculosis
- Interstitial lung disease with ongoing signs and symptoms at the time of informed consent
- 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.
- Persistent proteinuria of CTCAE Grade 3 or higher (> 3.5 g/24 hrs, measured by urine protein: creatinine ratio on a random urine sample
- Pregnant or nursing women
- 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
- 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.
- 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.
- 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.
- 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.
- 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.
- Receipt of an investigational drug within 28 days prior to initiation of study drug
- 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Recruiting | 22 Oct 2021 | 25 |
 France | Recruiting | 22 Oct 2021 | 49 |
 Germany | Recruiting | 22 Oct 2021 | 180 |
 Italy | Recruiting | 22 Oct 2021 | 15 |
 Spain | Recruiting | 22 Oct 2021 | 25 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Avastin 25 mg/ml concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 15 | 96 | PRD389577 |
Tecentriq 1 200 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 1200 | 96 | PRD5434943 |