Durvalumab for Hepatocellular carcinoma (non-resectable)

Inclusion criteria

• {"criterion_text":"-1.\tCapable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization (European Union [EU] Data Privacy Directive) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations."}
• {"criterion_text":"-10.\tPatients with HBV infection, characterized by positive hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibodies (anti-HBcAb) with detectable HBV DNA (≥10 IU/ml or above the limit of detection per local or central lab standard), must be treated with antiviral therapy, as per institutional practice, to ensure adequate viral suppression (HBV DNA ≤2000 IU/mL) prior to enrollment. Patients must remain on antiviral therapy for the study duration and for 6 months after the last dose of study medication. Patients who test positive for anti-hepatitis B core (HBc) with undetectable HBV DNA (<10 IU/ml or under the limit of detection per local or central lab standard) do not require anti-viral therapy prior to enrollment. These subjects will be tested at every cycle to monitor HBV DNA levels and initiate antiviral therapy if HBV DNA is detected (≥10 IU/ml or above the limit of detection per local or central lab standard). HBV DNA detectable subjects must initiate and remain on antiviral therapy for the study duration and for 6 months after the last dose of study medication."}
• {"criterion_text":"-11.\tPatients with HCV infection must have confirmed diagnosis of HCV characterized by the presence of detectable HCV RNA or anti-HCV antibody upon enrollment (management of this disease is per local institutional practice)."}
• {"criterion_text":"-12.\tAt least 1 measurable lesion, not previously irradiated, that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes, which must have a short axis ≥15 mm) with computerized tomography (CT) or magnetic resonance imaging (MRI), and that is suitable for accurate repeated measurements as per RECIST 1.1 guidelines. A lesion which progressed after previous ablation or TACE could be measurable if it meets these criteria."}
• {"criterion_text":"-13.\tAdequate organ and marrow function, as defined below. Criteria “a,” “b,” “c,” and “f” cannot be met with transfusions, infusions, or growth factor support administered within 14 days of starting the first dose. a.\tHemoglobin ≥9 g/dL b.\tAbsolute neutrophil count ≥1500/µL c.\tPlatelet count ≥75000/µL d.\tTotal bilirubin (TBL) ≤2.0× upper limit of normal (ULN) e.\tAST and ALT ≤5×ULN f.\tAlbumin ≥2.8 g/dL g.\tInternational normalized ratio (INR) ≤1.6. Note: INR prolongation due to anticoagulants for prophylaxis (e.g., atrial fibrillation) in patients without liver cirrhosis could be exception. h.\tCalculated creatinine clearance ≥50 mL/minute as determined by Cockcroft-Gault (using actual body weight) or 24-hour urine creatinine clearance i.\tUrine dipstick for proteinuria < 2+ (within 7 days prior to initiation of study treatment), unless a subsequent 24-hour urine collection demonstrates < 1 g of protein in 24 hours."}
• {"criterion_text":"-14.\tEvidence of post-menopausal status or negative serum pregnancy test for female pre-menopausal patients."}
• {"criterion_text":"-15.\tPatient 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."}
• {"criterion_text":"-16.\tMust have a life expectancy of at least 12 weeks."}
• {"criterion_text":"-2.\tAge ≥18 years at the time of study entry."}
• {"criterion_text":"-3.\tBody weight >30 kg."}
• {"criterion_text":"-4.\tConfirmed HCC based on histopathological findings from tumor tissues. If no archival sample is available and the specific risk of performing the biopsy according to the investigator’s opinion is considered to outweigh the benefits of diagnostic confirmation, HCC can be diagnosed based on typical diagnostic imaging on dynamic CT or MRI according to AASLD criteria, after consultation with the sponsor."}
• {"criterion_text":"-5.\tMust not have received prior systemic therapy for HCC."}
• {"criterion_text":"-6.\tNot eligible for locoregional therapy for unresectable HCC. For patients who progressed after locoregional therapy for HCC, locoregional therapy must have been completed ≥28 days prior to the baseline scan for the current study."}
• {"criterion_text":"-7.\tBarcelona Clinic Liver Cancer (BCLC) stage B (that is not eligible for locoregional therapy) or stage C or stage A (not eligible for curative therapy, not eligible for locoregional therapy)."}
• {"criterion_text":"-8.\tChild-Pugh Score class A."}
• {"criterion_text":"-9.\tECOG performance status of 0 or 1 at enrollment."}

Exclusion criteria

• {"criterion_text":"-Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)."}
• {"criterion_text":"-19.\tPrior or concomitant malignancy other than HCC unless it has been adequately treated or is considered not to affect the staging and prognosis of the patient."}
• {"criterion_text":"-History of allogeneic organ transplantation (eg, liver transplant)."}
• {"criterion_text":"-History of hepatic encephalopathy within past 12 months or requirement for medications to prevent or control encephalopathy (eg, no lactulose, rifaximin, etc if used for purposes of hepatic encephalopathy)."}
• {"criterion_text":"-Clinically meaningful ascites, defined as any ascites requiring non-pharmacologic intervention (eg, paracentesis) to maintain symptomatic control, within 6 months prior to the first scheduled dose. Subjects on stable doses of diuretics for ascites for ≥2 months are eligible."}
• {"criterion_text":"-Patients with main portal vein thrombosis (i.e., thrombosis in the main trunk of the portal vein, with or without blood flow) on baseline imaging."}
• {"criterion_text":"-Patient currently exhibits symptomatic or uncontrolled hypertension defined as diastolic blood pressure >90 mmHg or systolic blood pressure >140 mmHg."}
• {"criterion_text":"-Any condition interfering with swallowing pills, uncontrolled diarrhea, or other contraindication to oral therapy."}
• {"criterion_text":"-Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, 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]). Patients without active disease in the last 5 years are excluded unless discussed with the Study Physician and considered appropriate for study participation. The following are exceptions to this criterion: a) Patients with vitiligo or alopecia b) Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement c) Any chronic skin condition that does not require systemic therapy d) Patients with celiac disease controlled by diet alone."}
• {"criterion_text":"-Patients co-infected with HBV and HCV, or co-infected with HBV and hepatitis D virus (HDV). HBV positive (presence of HBsAg and/or anti-HBcAb with detectable HBV DNA); HCV positive (presence of anti-HCV antibodies); HDV positive (presence of anti- HDV antibodies)."}
• {"criterion_text":"-Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, ILD, serious chronic GI conditions associated with diarrhea, inferior vena cava thrombosis, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase the risk of incurring AEs, or compromise the ability of the patient to give written informed consent."}
• {"criterion_text":"-Previous study drug(s) assignment in the present study."}
• {"criterion_text":"-History of leptomeningeal carcinomatosis."}
• {"criterion_text":"-History of, or current, 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."}
• {"criterion_text":"-Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart)."}
• {"criterion_text":"-Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC."}
• {"criterion_text":"-History of active primary immunodeficiency."}
• {"criterion_text":"-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)."}
• {"criterion_text":"-Current or prior use of immunosuppressive medication within 14 days before the first dose of study drug(s). The following are exceptions to this criterion: a) Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection) b) Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent c) Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication)."}
• {"criterion_text":"-Receipt of live attenuated vaccine within 30 days prior to the first dose of study drug(s). Note: Patients, if enrolled, should not receive live vaccine while receiving study drug(s) and up to 30 days after the last dose of study drug(s)."}
• {"criterion_text":"-Major gastrointestinal bleeding within 4 weeks prior to randomization."}
• {"criterion_text":"-Patients with untreated or incompletely treated varices with bleeding or high-risk for bleeding. 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 enrollment. Patients who have undergone an EGD within 6 months prior to randomization do not need to repeat the procedure. Those who have received banding and/or sclerotherapy and with no bleeding event within the prior 6 months are eligible provided that a re-endoscopy is performed and that varices remained obliterated, minimal or Grade I."}
• {"criterion_text":"-Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study."}
• {"criterion_text":"-Significant vascular disease including aortic aneurysm requiring surgical repair or peripheral arterial thrombosis with 6 months prior to randomization."}
• {"criterion_text":"-History of abdominal or tracheoesophageal fistula or gastrointestinal perforation, or intraabdominal abscess within 6 months prior to randomization."}
• {"criterion_text":"-History or clinical signs of gastrointestinal obstruction or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding. Evidence of abdominal free air that is not explained by paracentesis or recent surgical procedure."}
• {"criterion_text":"-Evidence of bleeding diathesis or significant coagulopathy."}
• {"criterion_text":"-Severe, non-healing or dehisced wound, active ulcer, or untreated bone fracture."}
• {"criterion_text":"-Current or recent (within 10 days of randomization) use of acetylsalicyclic acid (> 325 mg/day) or treatment with dipyramidole, ticlopidine, clopidogrel, and cilostazol."}
• {"criterion_text":"-Current or recent (within 10 days prior to randomization) use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic purpose Prophylactic anticoagulation is allowed."}
• {"criterion_text":"-Chronic daily treatment with a nonsteroidal anti-inflammatory drug (NSAID). Occasional use of NSAIDs for the symptomatic relief of medical conditions such as headache or fever is allowed."}
• {"criterion_text":"-Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 3 days prior to the first dose of bevacizumab."}
• {"criterion_text":"-Female patients who are pregnant or breastfeeding, or male or female patients of reproductive potential who are not willing 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 plus tremelimumab combination therapy or bevacizumab therapy."}
• {"criterion_text":"-Participation in another clinical study with an investigational product during the last 4 weeks or 5 half-lives of the respective drug/IMP, whichever is longer."}
• {"criterion_text":"-Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment."}
• {"criterion_text":"-Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria: a) Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician. b) Patients 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."}
• {"criterion_text":"-Any concurrent chemotherapy, study drug, or biologic or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is acceptable."}
• {"criterion_text":"-Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients."}
• {"criterion_text":"-Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 28 days of the first dose of study drug(s)."}
• {"criterion_text":"-Major surgical procedure or significant traumatic injury (as defined by the Investigator) within 28 days prior to the first dose of study drug(s), or anticipation of need for major surgical procedure during the course of the study or nonrecovery from side effects of any such procedure. Note: Local surgery of isolated lesions for palliative intent is acceptable."}

Primary endpoints

• {"endpoint_text":"-Objective response rate (ORR)","definition_or_measurement_approach":""}

Secondary endpoints

• {"endpoint_text":"-Overall survival (OS)","definition_or_measurement_approach":""}
• {"endpoint_text":"-Progression-free survival (PFS)","definition_or_measurement_approach":""}
• {"endpoint_text":"-Time to progression (TTP)","definition_or_measurement_approach":""}
• {"endpoint_text":"-Objective response rate acc. to BICR (ORR-BICR)","definition_or_measurement_approach":""}
• {"endpoint_text":"-Duration of response (DOR)","definition_or_measurement_approach":""}
• {"endpoint_text":"-Disease control rate (DCR)","definition_or_measurement_approach":""}
• {"endpoint_text":"-Proportion of patients alive at 18 months (OS-18m)","definition_or_measurement_approach":""}
• {"endpoint_text":"-Proportion of patients alive at 24 months ((OS-24m)","definition_or_measurement_approach":""}
• {"endpoint_text":"-Progression-free survival from escalation treatment (PFS-E)","definition_or_measurement_approach":""}
• {"endpoint_text":"-PFS on next treatment","definition_or_measurement_approach":""}
• {"endpoint_text":"-time to failure of strategy (TTFS)","definition_or_measurement_approach":""}
• {"endpoint_text":"-quality of life (a) European Organisation for Research and Treatment of Cancer (EORTC) 30-item core quality of life questionnaire (QLQC30): Change compared to baseline, Time to deterioration in global health status/QoL, functioning scales. b) EORTC 18-item hepatocellular cancer health-related quality of life questionnaire (QLQ-HCC18): Change compared to baseline).","definition_or_measurement_approach":"Measured with EORTC QLQ-C30 and EORTC QLQ-HCC18 questionnaires; endpoints include change from baseline and time to deterioration in global health status/QoL and functioning scales."}
• {"endpoint_text":"-Time to deterioration of liver function, defined as time from randomization to worsening of CTCAE grade compared with baseline and persisting for ≥ 30 days for any of these parameters: aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, albumin, and international normalized ratio (INR)","definition_or_measurement_approach":"Defined as time from randomization to worsening of CTCAE grade compared with baseline and persisting for ≥30 days for any of AST, ALT, total bilirubin, albumin, or INR."}
• {"endpoint_text":"-Adverse events and laboratory findings","definition_or_measurement_approach":""}

Germany

Earliest CTIS Part Ii Submission Date

20-03-2024

Latest Decision Or Authorization Date

06-03-2026

Processing Time Days

716

Number Of Sites

8

Number Of Participants

35

Italy

Earliest CTIS Part Ii Submission Date

24-02-2025

Latest Decision Or Authorization Date

03-03-2026

Processing Time Days

372

Number Of Sites

5

Number Of Participants

35

Primary sponsor

Full Name

Klinikum der Universitaet Muenchen AöR

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Germany

Third parties

• {"country":"Germany","full_name":"Frankfurter Institut Fuer Klinische Krebsforschung IKF GmbH","duties_or_roles":"Codes: 1,10,12,2,5,6,7","organisation_type":"Pharmaceutical company"}
• {"country":"Italy","full_name":"Mediolanum Cardio Research S.r.l.","duties_or_roles":"Codes: 1,11,12,2,5","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"LMU Klinikum Muenchen AöR","duties_or_roles":"Codes: 8","organisation_type":"Hospital/Clinic/Other health care facility"}