STRIDE (Durvalumab + Tremelimumab) With Lenvatinib vs STRIDE Alone in Unresectable Hepatocellular Carcinoma

Inclusion Criteria:

• Age ≥ 18 years.

• Body weight > 30 kg.

• Life expectancy of at least 12 weeks.

• Confirmed HCC based on histopathological findings from tumour tissues or clinicallyby AASLD criteria in cirrhotic participants.

• Must not have received prior systemic therapy for HCC.

• Must not be eligible for locoregional therapy for unresectable HCC. For patients whoprogressed after locoregional therapy for HCC, locoregional therapy must have beencompleted ≥28 days prior to the baseline scan of the abdomen and pelvis for thecurrent study.

• Barcelona Clinic Liver Cancer (BCLC) stage B (that is not eligible for locoregionaltherapy) or stage C.

• Child-Pugh Score class A or B7 based on low albumin (albumin 25-27 g/L) only.

• Must have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

• At least 1 measurable lesion, not previously irradiated, that can be accuratelymeasured at baseline as ≥10 mm in the longest diameter (except lymph nodes, whichmust have a short axis ≥15 mm) with computerized tomography (CT) or magneticresonance imaging (MRI), and that is suitable for accurate repeated measurements asper RECIST 1.1 guidelines. A lesion which progressed after previous ablation or TACEcould be measurable if it meets these criteria.

• Participants with active HBV infection [characterized by positive hepatitis B virussurface antigen (HBsAg) and/or positive hepatitis B core antibodies (anti-HBcAb)with detectable HBV deoxyribonucleic acid (DNA) (≥10 IU/mL or above the limit ofdetection per local lab standard)] are eligible if:

• The participant is being treated with antiviral therapy, as per institutionalpractice. The HBV antiviral therapy must be initiated prior to randomization, andthe participant must remain on antiviral therapy for the study duration and for 6months after the last dose of study medication.

• The participant must show evidence of HBV stabilization or signs of viral response (eg, reduction of HBV DNA levels) prior to enrollment

• Participants who test positive for HBsAg or anti-hepatitis B core (HBc) withundetectable HBV DNA (< 10 IU/mL or under the limit of detection per local labstandard) are eligible and do not require antiviral therapy prior to randomization.

• These participants will be tested at every cycle to monitor HBV DNA levels andinitiate antiviral therapy if HBV DNA is detected (≥ 10 IU/mL or above the limit ofdetection per local lab standard).

• If HBV DNA becomes detectable during study treatment, antiviral therapy must beinitiated, and the participant must remain on antiviral therapy during the studytreatment period and for 6 months after the last dose of study medication.

• Participants with active HCV infection (as characterized by the presence ofdetectable HCV ribonucleic acid [RNA] or anti-HCV antibody [anti-HCV]) must bemanaged per local institutional practice for the study and for 6 months after thelast dose of study treatment.

• Adequate organ and marrow function, within 14 days prior to enrollment.

• Participants of childbearing potential must have agreed to use a highly effectivecontraceptive method from enrollment to 90 days after the last dose of durvalumab or 180 days after the last dose of tremelimumab (whichever date is later).

• Participants must agree not to donate blood for at least 90 days following the lastinfusion of durvalumab or tremelimumab, or until 7 days after the last dose oflenvatinib, whichever is longest.

Exclusion Criteria:

• Participants with a history of other malignancies, except: adequately treatednon-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or othertumours curatively treated with no evidence of disease for ≥ 5 years.

• Any concurrent chemotherapy, study drug, or biologic or hormonal therapy for cancertreatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.

• Known fibrolamellar HCC, sarcomatoid HCC, infiltrative-type HCC or mixedcholangiocarcinoma and HCC.

• Clinically meaningful ascites, defined as ascites requiring non-pharmacologicintervention

• Uncontrolled arterial hypertension defined by a systolic pressure ≥ 150 mm Hg ordiastolic pressure ≥ 90 mm Hg or other hypertensive cardiovascular complicationsdespite standard medical management.

• Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab, or ananti-CTLA4, including tremelimumab.

• History of primary immunodeficiency, history of organ transplant or prior history ofsevere (grade 3 or 4) immune mediated toxicity from other immune therapy.

• Known to have tested positive for human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies) or active tuberculosis infection (clinical evaluation that mayinclude clinical history, physical examination and radiographic findings, ortuberculosis testing in line with local practice).

• Known allergy or hypersensitivity to any of the study drugs or any of the study drugexcipients.

• Current or prior use of immunosuppressive medication within 28 days before the firstdose of durvalumab or tremelimumab

• Active or prior documented autoimmune or inflammatory disorders includinginflammatory bowel disease (e.g. Crohn's disease, ulcerative colitis),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 with active or uncontrolled intercurrent illness

• History of leptomeningeal carcinomatosis.

• Symptomatic or uncontrolled brain metastases requiring concurrent treatment,inclusive of but not limited to surgery, radiation and/or corticosteroids.

• Major surgical procedure (as defined by the Investigator) within 28 days prior toenrollment.

• Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 mscalculated from 3 ECGs (within 15 minutes at 5 minutes apart).

• Receipt of live attenuated vaccination (examples include, but are not limited to,vaccines for measles, mumps, and rubella, live attenuated influenza vaccine (nasal),chicken pox vaccine, oral polio vaccine, rotavirus vaccine, yellow fever vaccine,BCG vaccine, typhoid vaccine and typhus vaccine) within 30 days prior to enrollment.

• Lactating participants.

• Any active disease condition which would render the protocol treatment dangerous orimpair the ability of the patient to receive protocol therapy.

• Receipt of radiotherapy within four weeks of first planned dose of durvalumab ortremelimumab, except for a single dose of radiation up to 8 Gray (equal to 800 RAD)delivered with palliative intent for pain control up to 14 days before enrollment.

• Active or prior documented GI bleeding (e.g. esophageal varices or ulcer bleeding)within 6 months. (Note: For patients with a history of GI bleeding more than 6months prior or assessed as high risk for esophageal varices by the Investigator ormain trunk portal vein thrombosis (Vp4), adequate endoscopic assessment andtreatment of varices as per institutional standards is required prior toenrollment.)