Nivolumab in Combination With TACE/TAE for Patients With Intermediate Stage HCC

Study Overview
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Brief Summary
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This study evaluates the addition of nivolumab to TACE/TAE in the treatment of patients with intermediate stage hepatocellular carcinoma. All patients will receive TACE/TAE and half will receive nivolumab.

Detailed Description
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A significant proportion of HCC patients present with, or progress to, intermediate stage disease and these patients are typically treated with transarterial chemo-embolisation (TACE) or transarterial embolisation (TAE). However, since TACE/TAE is generally a palliative therapy, it provides a potential backbone for the addition of effective systemic therapies with the aim of improving survival outcomes. Since TACE may liberate an abundance of tumour antigens and 'danger' signals, it may lend itself to combination with immunotherapeutic strategies. Nivolumab is a human monoclonal antibody. Nivolumab targets the programmed death-1 PD-1) cluster of differentiation 279 (CD279) cell surface membrane receptor. PD-1 is a negative regulatory molecule expressed by activated T and B lymphocytes.

Official Title
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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

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Drug: Nivolumab and TACE/TAE
* Procedure: TACE/TAE


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological diagnosis of HCC and at least one uni-dimensional lesion measurable according to RECIST 1.1 criteria by CT-scan or MRI. Not a candidate for surgical resection or liver transplantation Aged ≥16 years and estimated life expectancy >3 months 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 ≤ 1.5ULN (Using Cockcroft-Gault Formula) INR ≤1.6 Child-Pugh A (score ≤6) (Appendix D) HAP score A, B or C (Appendix E) 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). 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 Exclusion Criteria: Extrahepatic metastasis Prior embolisation, systemic or radiation therapy for HCC Any contraindications for hepatic embolisation procedures including portosystemic shunt, hepatofugal blood flow, known severe atheromatosis Investigational therapy or major surgery within 4 weeks of trial entry History of variceal bleeding within the past 4 weeks Child-Pugh cirrhosis B or C (score ≥7) HAP score D Hepatic encephalopathy Ascites refractory to diuretic therapy Documented occlusion of the hepatic artery or main portal vein5 Hypersensitivity to intravenous contrast agents Active clinically serious infection > Grade 2 NCI-CTC Pregnant or lactating women Known history of HIV infection HBV chronic infection with HBV DNA > 500IU/mL or without antiviral therapy; HBV patients with cirrhosis should be treated. 17. 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 18. Evidence of severe or uncontrolled systemic disease, or laboratory finding that in the view of the Investigator makes it undesirable for the patient to participate in the trial 19. Psychiatric or other disorder likely to impact on informed consent 20. Patient is unable and/or unwilling to comply with treatment and study instructions 20. Interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected treatment-related pulmonary toxicity 21. Evidence of uncontrolled, active infection, requiring parenteral anti-bacterial, anti-viral or antifungal therapy within 7 days prior to administration of study medication 22. Positive test for latent TB or evidence of active TB 23. Hypersensitivity to any of the active substances or excipients 24. Patients who have received a live vaccine within 30 days prior to the first dose of trial treatment 25. 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 26. Any uncontrolled inflammatory GI disease including Crohn's Disease and ulcerative colitis 27. 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

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients shall be randomised on a 1:1 basis throughout the study and allocated using pre-generated lists produced by the study statistician. List shall be produced using permuted blocks algorithm with random block sizes of 2 and 4. Stratification factors used in the study are randomising centre, baseline HAP score (A vs. B vs. C) and vascular invasion (No vs. Yes).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: TACE/TAE Alone<br>Transarterial Chemoembolisation (TACE) and/or Transarterial Embolisation (TAE) Alone. | Procedure: TACE/TAE<br>* TACE/TAE (as per local practice)<br>|
| Experimental: TACE/TAE and Nivolumab<br>As above for TACE/TAE. Nivolumab adminstered as a flat dose of 480mg IV. | Drug: Nivolumab and TACE/TAE<br>* Immunotherapy and TACE/TAE<br>Procedure: TACE/TAE<br>* TACE/TAE (as per local practice)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival - phase III primary outcome | Measured in days | The time until death. Patients discontinuing the study, lost to follow-up or still alive at the end of the study will be censored at the last know date alive, this can be assessed up until 2 years after the last patient. | 
| Time to TACE Progression (TTTP) - phase II primary outcome | Measured in days | The time to confirmatory scan 4 weeks after progression this can be assessed up until 2 years after the last patient is randomised | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression | Measured in days | Time to date of progression confirmed by RECIST1.1 assessed up until 2 years after the last patient is randomised | 
| Radiological response rate | RECIST 1.1 | Through study completion | 
| Safety and Toxicity: the number and percentage of patients reporting a Serious Adverse Event (SAE) and Grade 3 or higher Adverse Event (AE) | the number and percentage of patients reporting a Serious Adverse Event (SAE) and Grade 3 or higher Adverse Event (AE), measured and categorised based on CTCAE (version 4). | Through study completion | 
| Progression Free Survival | Measured in days | Time to progression or death. Assessed up until 2 years. | 
| QOL: EORTC QLQ-C30 | QoL will be scored according to the EORTC QLQ-C30 manual and guidelines. | baseline, pre - TACE (first treatment) and 12 weekly thereafter until end of treatment. Assessed up until 2 years after the last patient is randomised | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Intermediate Stage