Durvalumab and Tremelimumab With or Without Hepatic Arterial Infusion of Chemotherapy in Hepatocellular Carcinoma

Inclusion Criteria:

• Age ≥18 years old,

• Patient presenting with hepatocellular carcinoma (HCC), diagnosed either byhistological or radiological criteria as described by EASL criteria, if no biopsycould be performed safely.

• High-tumor burden, defined as at least one of the three criteria: (i) Vp4 PVTT, (ii)Vp3 PVTT with bilobar tumoral involvement and/or (iii) liver involvement >50% (asassessed by the investigator). Extra-hepatic spread is allowed.

• Child-Pugh A liver function

• Performance status Eastern Cooperative Oncology Group (ECOG) 0 to 1

• Must have a life expectancy of at least 12 weeks

• Body weight >30 kg

• At least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 targetlesion (TL) at baseline. Tumor assessment by computed tomography (CT) scan ormagnetic resonance imaging (MRI) must be performed within 28 days prior torandomization

• Adequate organ and marrow function as indicated by the following laboratory values

1. Haemoglobin ≥ 7.5 g/dL. Participants with 7.5 g/dL < haemoglobin < 9.0 g/dLhaving active or chronic bleeding to be excluded,

2. Platelet count ≥75 × 109/L,

3. Absolute neutrophil count (ANC ≥1.0 × 109 /L)

4. creatinine clearance > 40 mL/min (according to Cockcroft or MDRD formula)

5. AST (SGOT)/ALT (SGPT) ≤5x ULN

6. Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN).

7. International normalised ratio (INR) < 2.3

• Women of childbearing potential must be willing to use a highly effective method ofbirth control for the duration of the study, and ≥90 days after the last dose ofstudy drug, and have a negative urine or serum pregnancy test ≤7 days of first doseof study drug. In case of a urine pregnancy test, it must be a highly sensitiveurine pregnancy test.

• Non-sterile males must be willing to use a highly effective method of birth controlfor the duration of the study and for ≥90 days after the last dose of study drug. Asterile male is defined as one for whom azoospermia has been previously demonstratedin a semen sample examination as definitive evidence of infertility. Males withknown "low sperm counts" (consistent with "sub-fertility") are not to be consideredsterile for purposes of this study.

• Men and women patients must consent to not donate or bank sperm or ova duringtreatment and for 180 days after treatment stop

• Patients must have provided consent for the study by signing and dating a writteninformed consent form prior to any study specific procedures, sampling, or analyses.When the patient is physically unable to give their written consent, a trustedperson of their choice, independent from the investigator or the sponsor, canconfirm in writing the patient's consent

• Patient is willing and able to comply with the protocol for the duration of thestudy including undergoing treatment and scheduled visits and examinations includingfollow up

• Patient affiliated to a social security regimen

Exclusion Criteria:

• Previous systemic treatment (either immunotherapy, anti-angiogenics, chemotherapy,or any combination thereof)

• Previous treatment with hepatic arterial infusion of chemotherapy

• Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.

• History of hepatic encephalopathy within the past 6 months or requirement formedications to prevent or control encephalopathy (eg, no lactulose, rifaximin, etcif used for purposes of hepatic encephalopathy).

• Active or prior documented gastrointestinal bleeding (GI; eg, esophageal varices orulcer bleeding) within the past 6 months. Note: For participants with a history ofGI bleeding greater than 6 months or assessed as high risk for esophageal varices bythe investigator, including main trunk portal vein thrombosis, a recent endoscopywithin 3 months of enrolment and adequate endoscopic therapy according toinstitutional standards is required.

• Any unresolved toxicity NCI CTCAE grade ≥2 from previous anticancer therapy with theexception of alopecia, vitiligo, and the laboratory values defined in the inclusioncriteria

1. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basisafter consultation with the Study Physician.

2. Patients with irreversible toxicity not reasonably expected to be exacerbatedby treatment with durvalumab or tremelimumab may be included only afterconsultation with the Study Physician.

• Any concurrent chemotherapy, biologic, or hormonal therapy for cancer treatment.Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormonereplacement therapy) is acceptable.

• Active or prior documented autoimmune or inflammatory disorders (includinginflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [withthe exception of diverticulosis], systemic lupus erythematosus, Sarcoidosissyndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease,rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions tothis criterion:

1. Patients with vitiligo or alopecia

2. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable onhormone replacement

3. Any chronic skin condition that does not require systemic therapy

4. Patients without active disease in the last 5 years may be included but onlyafter consultation with the study physician

5. Patients with celiac disease controlled by diet alone

• History of interstitial lung disease, non-infectious pneumonitis or uncontrolleddiseases including pulmonary fibrosis, acute lung diseases

• History of leptomeningeal carcinomatosis

• Known active hepatitis infection, positive hepatitis C virus (HCV) antibody,hepatitis B virus (HBV) surface antigen (HBsAg) or HBV core antibody (anti-HBc), atscreening. Participants with a past or resolved HBV infection (defined as thepresence of anti HBc and absence of HBsAg) are eligible. Participants positive forHCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.

• Known to have been tested positive for human immunodeficiency virus (HIV) (positiveHIV 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).

• Uncontrolled intercurrent illness, including but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, uncontrolled hypertension, unstableangina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronicgastrointestinal conditions associated with diarrhea

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

• Current or prior use of immunosuppressive medication within 14 days before the firstdose of durvalumab or tremelimumab. The following are exceptions to this criterion:

• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intraarticular injection)

• Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> ofprednisone or its equivalent

• Steroids as premedication for hypersensitivity reactions (e.g., CT scanpremedication)

• Receipt of live attenuated vaccine within 30 days prior to the first dose of studydrug

• History of allogenic organ transplantation, or patient with intent fortransplantation

• Major surgical procedure (as defined by the Investigator) within 28 days prior tothe first dose of study drug. Note: Local surgery of isolated lesions for palliativeintent is acceptable

• Prior malignancy active within the previous 5 years of inclusion except for locallycurable cancers considered cured or successfully resected, such as basal or squamouscell skin cancers, superficial bladder cancer, or gastric cancers, or carcinoma insitu of the prostate, cervix, or breast carcinomas. Any oncological concomitanttreatment is not allowed during the treatment period.

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

• Female patients who are pregnant or breastfeeding or male or female patients ofreproductive potential who are not willing to employ effective birth control fromscreening to 90 days after the last dose of durvalumab monotherapy or180 days afterthe last dose of durvalumab and tremelimumab combination therapy.

• Participation in another therapeutic trial within the 30 days prior to studyinclusion

• Prior randomisation or treatment in a previous durvalumab and/or tremelimumabclinical study regardless of treatment arm assignment.

• Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of aninterventional study

• Patients deprived of their liberty or under protective custody or guardianship

• Patients unable to adhere to the protocol for geographical, social, or psychologicalreasons or psychiatric illness/social situations that would limit compliance withstudy requirement, substantially increase risk of incurring AEs or compromise theability of the patient to give written informed consent