TACE-3: A two-arm multi-stage (TAMS) seamless phase II/III randomised trial of nivolumab in combination with TACE/TAE for patients with intermediate stage HCC

Prior treatment

• Prior embolisation, systemic or radiation therapy for HCC
• vidence of uncontrolled, active infection, requiring parenteral antibacterial, anti-viral or antifungal therapy within 7 days prior to administration of study medication
• Patients who have received a live vaccine within 30 days prior to the first dose of trial treatment
• Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of the first dose of study drug administration (not applicable for France)
• Contra-indications to T-cell checkpoint inhibitor therapy: - Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days of the first dose of study drug administration; unless used as replacement therapy - Organ transplantation - Active, known or suspected autoimmune disease Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, lichen planus or other conditions not expected to recur in the absence of an external trigger are permitted to enrol.
• Investigational therapy or major surgery within 4 weeks of trial entry
• Ascites refractory to diuretic therapy

Other illness

• Hypersensitivity to intravenous contrast agents
• Active clinically serious infection > Grade 2 NCI-CTC
• Known history of HIV infection
• HBV chronic infection with HBV DNA > 500 IU/mL or without antiviral therapy; HBV patients with cirrhosis should be treated.
• History of second malignancy except those treated with curative intent more than three years previously without relapse and non-melanotic skin cancer or cervical carcinoma in situ
• Psychiatric or other disorder likely to impact on informed consent
• Interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected treatment-related pulmonary toxicity
• Hypersensitivity to any of the active substances or excipients
• Any uncontrolled inflammatory GI disease including Crohn’s Disease and ulcerative colitis
• Participants with an active, known or suspected autoimmune disease. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enrol (not applicable for France)
• History of bleeding within the past 4 weeks

Lab values

• Evidence of severe or uncontrolled systemic diseases, or laboratory finding that in the view of the Investigator makes it undesirable for the patient to participate in the trial

Other

• Extrahepatic metastasis
• Documented occlusion of the hepatic artery or main portal vein
• Pregnant or lactating women
• Patient is unable and/or unwilling to comply with treatment and study instructions
• Positive test for latent TB or evidence of active TB
• Any contraindications for hepatic embolisation procedures including portosystemic shunt, hepatofugal blood flow, known severe atheromatosis
• Child-Pugh cirrhosis B or C (score ≥7)
• HAP score D
• Hepatic encephalopathy

• Histological diagnosis of HCC and at least one uni-dimensional lesion measurable according to RECIST 1.1 criteria by CT-scan or MRI.
• HAP score A, B or C
• No contra-indications to T-cell checkpoint inhibitor therapy (use of immunosuppressive drugs including steroids at dose equivalent to prednisolone >10mg/day unless used as replacement therapy; organ transplantation; subjects with an active, known or suspected autoimmune disease. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, lichen planus or other conditions not expected to recur in the absence of an external trigger are permitted to enrol) (not applicable for France)
• Women of child-bearing potential should have a negative pregnancy test prior to study entry. Both men and women must be using an adequate contraception method, which must be continued for 5 months after completion of treatment for women and 7 months for men
• Written informed consent (not applicable for France)
• Aged ≥ 18 years and estimated life expectancy ≥3 months (only for France)
• Patient must have signed a written informed consent prior to any trial specific procedures. When the patient is physically unable to give her written consent, a trusted person of their choice, independent from the investigator or the sponsor, can confirm in writing the patient’s consent. (only for France)
• Patients must be affiliated to a Social Security System (or equivalent). (only for France)
• Intermediate stage HCC (BCLC B) not candidate for surgical resection, ablation therapy or liver transplatation (only for France)
• Not a candidate for surgical resection or liver transplantation (not applicable for France)
• Aged ≥16 years and estimated life expectancy ≥3 months (not applicable for France)
• ECOG performance status 0-1
• Adequate haematological function: - Hb ≥9g/L - absolute neutrophil count ≥1.0x109 /L - platelet count ≥60x109 /L
• Bilirubin ≤50 μmol/L; AST, ALT, and ALP ≤5 x ULN
• Adequate renal function; Creatinine μmol/L ≤1.5 x ULN
• INR ≤1.6
• Child-Pugh A (score ≤6)