Neoadjuvant Atezolizumab and Adjuvant Atezolizumab + Bevacizumab in Combination with Percutaneous Radiofrequency Ablation of Small HCC: a Multicenter Randomized Phase Ii Trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire De Montpellier

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

20 Nov 2024 → ongoing

Decision date (initial)

2024-11-20

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Roche

External identifiers

EU CT number

2024-519113-59-00

EudraCT number

2020-000569-18

ClinicalTrials.gov

NCT04727307

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

Compare RFS (recurrence-free survival) at 2-years (by the investigator) after randomization.

Secondary objectives 1

1. • To compare RFS at 2 years according to independent central review • To evaluate the compliance to neoadjuvant and adjuvant treatments • To evaluate the tolerance of atezolizumab in the setting of neo-adjuvant therapy to ablation, and atezolizumab + bevacizumab in the setting of adjuvant therapy to ablation • To compare health-related quality of life (HRQoL) in experimental arm vs. control arm • To compare incidences of local-, intrahepatic- and extrahepatic recurrence in experimental arm vs. control arm • To compare time-to-recurrence in experimental arm vs. control arm • To compare overall survival in experimental arm vs. control arm • To compare OS rate at 3 and 5 years after randomization • Translational research (please find details here after)

Conditions and MedDRA coding

Hepatocellular carcinoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. • Male or female patients ≥ 18 years of age • Diagnosis of HCC based on imaging (EASL guidelines) • Patients with HCC eligible for ablation as assessed by multidisciplinary board: o All HCC nodules ≤ 3cm o 1-3 nodules of HCC • At least one uni-dimensional measurable lesion by magnetic resonance imaging (MRI) according to modified RECIST criteria • Liver function status Child-Pugh Class A • Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1 • Adequate bone marrow, liver and renal function as assessed by the following laboratory tests: o Hemoglobin > 8.5 g/dL o Absolute neutrophil count ≥ 1500/mm3 o Platelet count ≥ 50,000/mm3 o Total bilirubin ≤ 2 mg/dL (or ≤ 34 mol/L). o Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 x upper limit of normal (ULN) o Serum creatinine ≤ 1.5 x ULN o Lipase ≤ 2 x ULN o Prothrombin time > 50% o Glomerular Filtration Rate (GFR) ≥ 35 mL/min/1.73 m2 • Life expectancy ≥ 3 months • Women of childbearing potential and men must agree to use adequate contraception • Patients affiliated to a Social Security System

Exclusion criteria 2

1. • Patients with contraindications to ablation or atezolizumab or bevacizumab • Patients with contraindication to contrast medium intravenous injection either gadolinium or iodinate • Patients with contraindication to MRI • Prior liver transplantation • Child-Pugh B or C • Patients with mixed histology (HCC and cholangiocarcinoma, namely hepatocholangiocarcinoma), if a biopsy is available. • Current or recent (≤ 10 days prior to initiation of study treatment) use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to prophylactic) purpose. Prophylactic anticoagulation for the patency of venous access devices is allowed provided the activity of the agent results in an INR < 1.5 x ULN and aPTT is within normal limits within 14 days prior to initiation of study treatment.NB: all anticoagulation treatments, provided they are used as prophylaxis, are allowed. • Current or recent (≤ 10 days prior to initiation of study treatment) use of aspirin (> 325 mg/day) or treatment with clopidogrel, dipyramidole, ticlopidine, or cilostazol. • Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions: a. Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study. b. Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study. c. 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.
2. • 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 after Medical Monitor confirmation has been obtained. – 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 eligiblefor the study. • Portal vein invasion, whatever its extent, shown on baseline imaging • Prior liver arterial embolization, chemoembolization or radioembolization. • Patients with extra-hepatic metastases, either previously-treated or not. One lung nodule (< 5 mm) is allowed. Calcified lung micronodules as well as typical intra-pulmonary lymph nodes are allowed. Hepatic hilum lymph node < 10 mm (short axis) is allowed. • Prior surgery of HCC with micro- or macro-vascular invasion demonstrated at pathology. • Prior systemic treatment for HCC, in particular agents targeting T-cell costimulation or checkpoint pathways (including those targeting PD-1, PD-L1 or PD-L2, CD137, or cytotoxic T-lymphocyte antigen [CTLA-4]). • Patients with uncontrolled HBV infection and viral load above 500 IU/mL. • Untreated or incompletely treated oesophageal and/or gastric varices with bleeding or high risk for bleeding. Unless both pathological analyses showed the absence of cirrhosis and MR scan showed the absence of varices (absence of portal hypertension on imaging), patients must undergo an esophagogastroduodenoscopy (EGD), and all size of varices (small to large) must be assessed and treated per local standard of care prior to enrolment. Patients who have undergone an EGD within 6 months prior to initiation of study treatment do not need to repeat the procedure • Past or concurrent history of neoplasm other than HCC, except for in situ carcinoma of the cervix uteri and/or non-melanoma skin cancer and superficial bladder tumors. Any cancer curatively treated > 3 years prior to study entry is permitted • Known history or symptomatic meningeal tumors • Grade 3 (severe) hypertension ≥160 and/or ≥100 mmHG (systolic and diastolic, according to NCI-CTCAE v5.0) • Patients with phaeochromocytoma • Ongoing infection: Hepatitis B is allowed if no active replication is present (HBV replication below 500 IU/mL) or Hepatitis C is allowed if no antiviral treatment is required • Clinically significant bleeding NCI-CTCAE version 5.0 ≥ Grade 3 within 30 days before enrolment (transfusion indicated) • Arterial or venous thrombotic or embolic events such as cerebrovascular accident, deep vein thrombosis or pulmonary embolism within 6 months before enrolment • Any psychological, familial, sociological, geographical or illness or medical condition that could jeopardize the safety of the patient and/or his compliance with the study protocol and follow-up procedure • Known history of human immunodeficiency virus (HIV) infection • Seizure disorder requiring medication • Non-healing wound, ulcer or bone fracture • Breast feeding • Pregnancy • Legal incapacity (persons in custody or under guardianship) • Deprived of liberty Subject (by judicial or administrative decision) • patient under curatorship

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Recurrence-free survival: Recurrence is defined as recurrence or death, whichever comes first. Recurrence is defined as emergence of ≥ 1cm nodules enhanced at arterial phase followed by washout at portal or late phase observed on MRI, or any atypical nodule on imaging with histological features of HCC (EASL guidelines). Emergence of extrahepatic metastasis is also considered as a recurrence. Patients will be followed by MRI, 3, 6, 9, 12, 15, 18, 21and 24 months after randomization

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire De Montpellier

Sponsor organisation

Centre Hospitalier Universitaire De Montpellier

Address

39 Avenue Charles Flahault

City

Montpellier Cedex 5

Postcode

34295

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire De Montpellier

Contact name

GUIU

Public contact point

Organisation

Centre Hospitalier Universitaire De Montpellier

Contact name

Cadene

Locations

1 EU/EEA country · 21 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 7 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications