Clinical trial NCT04803994: The ABC-HCC Trial: Atezolizumab Plus Bevacizumab vs. Transarterial Chemoembolization (TACE) in Intermediate-stage HepatoCellular Carcinoma
Official title: The ABC-HCC Trial: A Phase IIIb, Randomized, Multicenter, Open-label Trial of Atezolizumab Plus Bevacizumab Versus Transarterial Chemoembolization (TACE) in Intermediate-stage HepatoCellular Carcinoma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Hepatocellular Carcinoma
Keywords: hepatocellular carcinoma
HCC
intermediate stage
atezolizumab
bevacizumab
TACE
Lead sponsor: Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
Sponsor class: OTHER
First posted: 2021-03-18
Enrollment: 434
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Clinical trial with two study arms:

Experimental arm A: 50% of the patients will receive a combination therapy (systemic) of the monoclonal antibodies atezolizumab and bevacizumab.

Control arm B: 50% of the patients will receive TACE therapy (locoregional).
Primary purpose: TREATMENT

Brief summary: The ABC-HCC trial is a Phase IIIb, randomised, multicenter, open-label study designed to evaluate the safety and efficacy of atezolizumab plus bevacizumab versus TACE in patients with intermediate-stage HCC. Approximately 434 patients in two arms of treatment will be enrolled.

Detailed description: The main purpose of this phase IIIb study is to test the efficacy and safety of atezolizumab in combination with bevacizumab compared to TACE in patients with intermediate stage liver cancer.

Primary efficacy objective is to assess the efficacy of atezolizumab in combination with bevacizumab compared to TACE in patients with intermediate stage liver cancer.

The secondary efficacy objective is to further characterize the responses obtained with the respective therapeutic strategy and to assess the impact of each therapeutic strategy on liver function over time.

Furthermore the objective is to evaluate the safety and tolerability of each therapeutic strategy and their respective impact on Quality of Life and to identify prognostic and predictive angiogenic and immune related biomarkers (tissue and circulating) for study endpoints.

This is a Phase IIIb, randomised, multicenter, open-label study. Approximately 434 patients suffering from intermediate-stage hepatocellular carcinoma will be enrolled in this trial. Patients will be recruited from up to 60 sites in 10 different countries.

Eligibility criteria: Inclusion Criteria:

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.

Exclusion Criteria:

1. 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 cerebro-vascular 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-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.
26. 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.
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.

Primary outcomes:
measure: Time to failure of treatment strategy
timeFrame: 48 months - assessed every 8 weeks (±7days)
Secondary outcomes:
measure: Overall survival (OS)
timeFrame: 48 months
measure: Overall Survival Rate at 24 months (OS@24)
timeFrame: 24 months
measure: Objective Response Rate (ORR)
timeFrame: 48 months
measure: Time to Progression (TTP)
timeFrame: 48 months
measure: Time to loss of systemic treatment options (TTSYS)
timeFrame: 24 months
measure: Progression free survival (PFS)
timeFrame: 48 months
measure: Duration of Treatment
timeFrame: 24 months
measure: Duration of Response (DOR)
timeFrame: 48 months
measure: Time to deterioration of liver function
timeFrame: 48 months
measure: Treatment-related and -unrelated toxicities (AEs, SAEs) according to NCI CTCAE v5.0
timeFrame: 48 months
measure: QoL (EORTC QLQ-C30 and HCC18 sub-questionnaire)
timeFrame: 48 months
Other outcomes:
measure: Exploratory endpoint - Correlation of biomarkers for study endpoints
timeFrame: 48 months
measure: Exploratory endpoint - PD-L1 expression
timeFrame: 48 months
Locations:
city: Graz
country: Austria
facility: LKH - Univ. Klinikum Graz
city: Innsbruck
country: Austria
facility: Medzinische Universität Innsbruck
city: Klagenfurt
country: Austria
facility: Klinikum Klagenfurt am Wörthersee
city: Linz
country: Austria
facility: Ordensklinikum Linz
city: St. Pölten
country: Austria
facility: Universitätsklinikum St. Pölten
city: Wien
country: Austria
facility: Medizinische Universität Wien
city: Avignon
country: France
facility: Institut Sainte-Catherine
city: Bobigny
country: France
facility: Hôpital Jean-Verdier Avicenne
city: Bordeaux
country: France
facility: CHU Bordeaux
city: Clermont-Ferrand
country: France
facility: CHU Clermont-Ferrand CHU Estaing
city: Clichy
country: France
facility: Beaujon Hospital
city: Grenoble
country: France
facility: CHU Grenoble
city: Lyon
country: France
facility: Croix-Rousse Hopital
city: Marseille
country: France
facility: Saint Joseph Hopital - Marseille
city: Paris
country: France
facility: Hôpital Universitaire Pitié Salpêtrière
city: Villejuif
country: France
facility: Centre Hépato-biliaire Paul Brousse
city: Aachen
country: Germany
facility: University Hospital RWTH Aachen
city: Amberg
country: Germany
facility: Klinikum St. Marien Amberg
city: Berlin
country: Germany
facility: Vivantes Klinikum Neukölln
city: Bochum
country: Germany
facility: Universitätsklinikum Bochum
city: Dresden
country: Germany
facility: Universitätsklinikum Dresden
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen
city: Esslingen
country: Germany
facility: Klinikum Esslingen
city: Frankfurt am Main
country: Germany
facility: Krankenhaus Nordwest
city: Frankfurt
country: Germany
facility: Universitätsklinikum Frankfurt
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg
city: Göttingen
country: Germany
facility: Universitätsmedizin Göttingen
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Konstanz
country: Germany
facility: Klinikum Konstanz
city: Krefeld
country: Germany
facility: Krankenhaus Maria-Hilf Krefeld
city: Köln
country: Germany
facility: Uniklinik Köln
city: Lübeck
country: Germany
facility: Universitätsklinikum Schleswig-Holstein
city: Mainz
country: Germany
facility: Universitätsmedizin Mainz
city: Mannheim
country: Germany
facility: Universitätsklinikum Mannheim
city: Marburg
country: Germany
facility: Universitätsklinikum Marburg
city: München
country: Germany
facility: Klinikum rechts der Isar München
city: Trier
country: Germany
facility: Klinikum Mutterhaus Trier
city: Trier
country: Germany
facility: Krankenhaus der Barmherzigen Brüder Trier
city: Ulm
country: Germany
facility: Uniklinik Ulm
city: Wiesbaden
country: Germany
facility: St. Josefs Hospital Wiesbaden
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg
city: Bologna
country: Italy
facility: Policlinico S. Orsola Bologna
city: Meldola
country: Italy
facility: Instituto Tumori della Romagna IRST IRCCS
city: Milano
country: Italy
facility: Policlinico di Milano
city: Milano
country: Italy
facility: Instituto di Tumori
city: Pisa
country: Italy
facility: Università di Pisa (UNIPI)
city: Verona
country: Italy
facility: AOUI Verona
city: Hokkaido
country: Japan
facility: Hokkaido University Hospital
city: Kobe
country: Japan
facility: Kobe University Hospital
city: Kumamoto
country: Japan
facility: Kumamoto University Hospital
city: Kyoto
country: Japan
facility: University Hospital Kyoto Prefectural University of Medicine
city: Nagasaki
country: Japan
facility: Nagasaki University Hospital
city: Osaka
country: Japan
facility: Kindai University Hospital
city: Saitama
country: Japan
facility: Saitama Medical University Hospital
city: Toyoake
country: Japan
facility: Fujita Health University Hospital
city: Ube
country: Japan
facility: Yamaguchi University Hospital
city: Alicante
country: Spain
facility: Hospital Universitario de Alicante
city: Badajoz
country: Spain
facility: Hospital Infanta Cristina
city: Badalona
country: Spain
facility: Hospital Germans Trias I Pujol
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebrón
city: Barcelona
country: Spain
facility: Barcelona Clinic Liver Cancer, Universitat de Bracelona
city: Cadiz
country: Spain
facility: Hospital Puerta del Mar
city: Jaén
country: Spain
facility: Hospital de Jaen
city: Madrid
country: Spain
facility: Hospital Universitario Gregorio Marañon
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Madrid
country: Spain
facility: Hospital Fundación Jimenez Diaz
city: Madrid
country: Spain
facility: Hospital Universitario Puerta de Hierro Majadahonda
city: Madrid
country: Spain
facility: Hospital de Alcorcón
city: Malaga
country: Spain
facility: Hospital de Málaga
city: Santander
country: Spain
facility: Hospital Marqués de Valdecilla
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocío
Study officials:
affiliation: Institut für Klinische Krebsforschung IKF GmbH, Frankfurt, Germany
name: Salah Eddin Al-Batran, Prof. Dr.
role: STUDY_DIRECTOR
affiliation: Universitätsmedizin Mainz, Germany
name: Peter Galle, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Barcelona Clinic Liver Cancer, Universitat de Barcelona, Spain
name: Jordi Bruix, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References: