DURVALUMAB for Hepatocellular carcinoma

Inclusion criteria

• {"criterion_text":"- Male or female patients ≥ 18 years of age\n- Absolute neutrophil count (ANC ≥1.0 × 109 /L)\n- Platelet count ≥75 × 109/L\n- Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). (This will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician\n- AST (SGOT) and ALT (SGPT) ≤5x ULN\n- Measured creatinine clearance (CL) must not exceed 40 mL/min. For the estimation of glomerular filtration rate (eGFR), the Cockcroft-Gault equation was applied in patients aged ≤65 years, while the MDRD equation was used for those older than 65 years\n- Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.\n- At least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 target lesion (TL) at preinclusion/inclusion. Tumor assessment by computed tomography (CT) scan or magnetic resonance imaging (MRI) must be performed within 28 days prior to inclusion\n- Patients with HCV infection (as characterized by the presence of detectable HCV ribonucleic acid (RNA) or anti-HCV antibody) must be managed per local institutional practice\n- Antiviral therapy in case of HBV active infection or inactive carriage\n- Written informed consent signed (patients must be free from tutelle, curatelle or sauvegarde de justice)\n- Histological or radiological diagnosis of HCC\n- Patients with newly diagnosed or recurrent HCC (following a previous curative procedure performed at least 6 months before inclusion) eligible for PA prcoedure as assessed by multidisciplinary board corresponding to BCLC A stage:  Uninodular HCC ≥ 2 cm and ≤ 5 cm, no macroscopic vascular invasion  Multinodular maximum 3 nodules ≤ 3 cm, \tBody weight >30 kg  Liver function status Child-Pugh Class A <><\n- Adequate bone marrow, liver and renal function as assessed by the following laboratory tests:  Total bilirubin ≤ 2 mg/dL \tSerum creatinine ≤ 1.5 x ULN \tLipase ≤ 2 x ULN  Prothrombine time-international normalized ratio (PT-INR) < 2.3 and PTT < 1.5  Glomerular Filtration Rate (GFR) ≥ 30 mL/min/1.73 m2\n- Life expectancy ≥ 3 months\n- Female of childbearing potential (WOCBP) or male or female patients of reproductive potential must to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy or 180 days after the last dose of durvalumab and tremelimumab combination therapy\n- Patients affiliated to a Social Security System\n- Haemoglobin ≥9.0 g/dL"}

Exclusion criteria

• {"criterion_text":"- Patients with contraindications to PA procedure (Pacemakers or patients who have a history of cardiac arrhythmias or irregular heartbeats considered as contraindication to IRE, ascites, Coagulopathy, Ongoing infection)\n- 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\n- Known history of human immunodeficiency virus (HIV) infection\n- Patients with contraindication to contrast medium intravenous injection either gadolinium or iodinate\n- Non-healing wound, ulcer or bone fracture\n- Known hypersensitivity to the study drug or excipients in the formulation\n- Any malabsorption condition\n- Breast feeding\n- Pregnancy\n- Participation in another clinical study with an investigational product during the last 6 months\n- Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study\n- Congestive heart failure New York Heart Association (NYHA) ≥ class 2\n- Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria. -\tPatients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician. -\tPatients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the Study Physician.\n- Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non–cancer-related conditions (e.g., hormone replacement therapy) is acceptable. <>\n- Prior liver transplantation\n- Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable.\n- History of allogenic organ transplantation\n- Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion: -\tPatients with vitiligo or alopecia -\tPatients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement -\tAny chronic skin condition that does not require systemic therapy -\tPatients without active disease in the last 5 years may be included but only after consultation with the study physician -\tPatients with celiac disease controlled by diet alone\n- Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent\n- History of another primary malignancy except for - Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence - Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease - Adequately treated carcinoma in situ without evidence of disease\n- History of leptomeningeal carcinomatosis\n- Study excludes patients with brain metastases or spinal cord compression: Patients with suspected brain metastases at screening should have an MRI (preferred) or CT each preferably with IV contrast of the brain prior to study entry. Brain metastases will not be recorded as RECIST Target Lesions at baseline if study allows patients with brain metastases.\n- Unstable angina or myocardial infarction within the past 6 months before enrolment\n- Has untreated central nervous system (CNS) metastases and/or carcinomatous meningitis identified either on the baseline brain imaging (RECIST)) for details on the imaging modality) obtained during the screening period or identified prior to signing the ICF. Patients whose brain metastases have been treated may participate provided they show radiographic stability (defined as 2 brain images, both of which are obtained after treatment to the brain metastases. These imaging scans should both be obtained at least four weeks apart and show no evidence of intracranial progression). In addition, any neurologic symptoms that developed either as a result of the brain metastases or their treatment must have resolved or be stable either, without the use of steroids, or are stable on a steroid dose of ≤10mg/day of prednisone or its equivalent <> for at least 14 days prior to the start of treatment. Brain metastases will not be recorded as RECIST Target Lesions at baseline.\n- QT interval measurement one one ECG\n- History of active primary immunodeficiency\n- Known to have tested positive for human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies) or active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice).\n- Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab. The following are exceptions to this criterion: -\tIntranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection) -\tSystemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent - Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)\n- Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.\n- Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients\n- Prior randomisation or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment\n- Patients who have received prior anti–PD-1, anti–PD-L1 or anti–CTLA-4: - Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy. - All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study. - Must not have experienced a ≥Grade 3 immune related AE or an immune related neurologic or ocular AE of any grade while receiving prior immunotherapy NOTE: Patients with endocrine AE of ≤Grade 2 are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic. - Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of > 10 mg prednisone or equivalent per day.\n- 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]).\n- Grade 3 (severe) hypertension ≥180 and/or ≥110 mmHG (systolic and diastolic, according to National Heart Foundation 2016)\n- Patients with large esophageal varices at risk of bleeding that are not being treated with conventional medical intervention\n- 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\n- Major surgical procedure or significant traumatic injury within 28 days before enrolment (note: local surgery for isolated lesions for palliative purposes is acceptable)\n- Patients with phaeochromocytoma\n- Refractory ascites according to EASL guidelines definition (ascites that cannot be mobilized or the early recurrence of which cannot be prevented because of a lack of response to sodium restriction and diuretic treatment)\n- Persistent proteinuria of NCI-CTCAE version 5.0 ≥ Grade 3\n- Ongoing infection > Grade 2 according to NCI-CTCAE version 5.0\n- Clinically significant bleeding NCI-CTCAE version 5.0 ≥ Grade 3 within 30 days before enrolment"}

Primary endpoints

• {"endpoint_text":"- One-year local recurrence-free survival","definition_or_measurement_approach":"To assess local recurrence-free survival at 1-year following neoadjuvant Durvalumab/Tremelimumab and adjuvant Durvalumab therapy associated with percutaneous ablation procedure in patients with Barcelona Clinic Liver Cancer A hepatocellular carcinoma"}

Secondary endpoints

• {"endpoint_text":"- In neoadjuvant phase: changes of tumorous and non-tumorous perfusion parameters observed with CT scan/MRI after one months of neoadjuvant treatment (rates of nodule(s) comprising necrosis and/or hypoperfusion radiological aspect compared before and after neoadjuvant course): analyzed as qualitative variables","definition_or_measurement_approach":"Changes observed with CT scan/MRI after one month of neoadjuvant treatment; analyzed as qualitative variables (rates of nodules comprising necrosis and/or hypoperfusion radiological aspect)"}
• {"endpoint_text":"- In neoadjuvant phase: changes of size of nodules following neoadjuvant course","definition_or_measurement_approach":""}
• {"endpoint_text":"- Nodule rates of early response after a single procedure of PA (defined as absence of active tumor evaluated at one month following PA)","definition_or_measurement_approach":"Defined as absence of active tumor evaluated at one month following PA"}
• {"endpoint_text":"- Incidences of intra segmental/ extra segmental distant recurrence","definition_or_measurement_approach":""}
• {"endpoint_text":"- One-year Overall survival defined as patients who are alive with or without HCC recurrence 1 year after PA procedure. Causes and date of death will be specified when applicable during this timeframe.","definition_or_measurement_approach":"Overall survival at 1 year after PA; causes and date of death specified when applicable"}
• {"endpoint_text":"- Treatment-related adverse events will be monitored according to manufacturer guidelines and recommendation","definition_or_measurement_approach":"Monitored according to manufacturer guidelines and recommendation"}
• {"endpoint_text":"- Timeframe of PA performance defined as number of days of delay in case of safety issues encountered during neo-adjuvant phase","definition_or_measurement_approach":"Measured as number of days of delay in case of safety issues encountered during neoadjuvant phase"}
• {"endpoint_text":"- Compliance to neoadjuvant and adjuvant treatments: respect of scheduled Durvalumab/Tremelimumab infusions","definition_or_measurement_approach":"Assessed as respect of scheduled Durvalumab/Tremelimumab infusions"}
• {"endpoint_text":"- Frequency of SAEs and discontinuations due to AEs","definition_or_measurement_approach":""}
• {"endpoint_text":"- For biomarkers studies, assessment of tumour architecture and cytology from inclusion to Percutaneous Ablation procedure; assessed up to 30 days: absence of tumour cells (binary scale :0/1)","definition_or_measurement_approach":"Assessed up to 30 days: absence of tumour cells (binary scale :0/1)"}
• {"endpoint_text":"- For biomarkers studies, assessment of tumour architecture and cytology from inclusion to Percutaneous Ablation procedure; assessed up to 30 days: assessment of intra and extra tumoral inflammatory infiltrate (semi quantitative scale: 0=non, 1=mild, 2=intense)","definition_or_measurement_approach":"Assessed up to 30 days: intra and extra tumoral inflammatory infiltrate (semi-quantitative scale 0/1/2)"}
• {"endpoint_text":"- For biomarkers studies, assessment Gene expression from inclusion to Percutaneous Ablation procedure; assessed up to 30 days: change in gene expression following sequential whole exome sequencing (binary scale 0/1 with clustering analyses)","definition_or_measurement_approach":"Change in gene expression following sequential whole exome sequencing (binary scale 0/1 with clustering analyses), assessed up to 30 days"}

France

Earliest CTIS Part Ii Submission Date

30-08-2024

Latest Decision Or Authorization Date

04-12-2025

Processing Time Days

461

Number Of Sites

22

Number Of Participants

30

Primary sponsor

Full Name

Assistance Publique Hopitaux De Paris

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

France

Third parties

• {"country":"","full_name":"AstraZeneca","duties_or_roles":"Monetary support","organisation_type":""}