Intermediate stage Hepatocellular Carcinoma MedDRA version: 21.0 Level: LLT Classification code 10019828 Term: Hepatocellular carcinoma non-resectable System Organ Class: 100000004864
Conditions
Interventions
Trade Name: Opdivo
Product Name: Opdivo
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Nivolumab
CAS Nu
Sponsors
The Clatterbridge Cancer Centre NHS Foundation Trust
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Histological diagnosis* of HCC and at least one uni-dimensional lesion measurable according to RECIST 1.1 criteria by CT-scan or MRI. 2. Not a candidate for surgical resection or liver transplantation** 3. Aged =16 years and estimated life expectancy >3 months 4. ECOG performance status 0-1 5. Adequate haematological function: • Hb =9g/L • Absolute neutrophil count =1.0x109/L • Platelet count =60x109/L 6. Bilirubin =50 µmol/L, AST,ALT and ALP =5 x ULN 7. Adequate renal function; Creatinine = 1.5ULN (Using Cockcroft-Gault Formula) 8. INR =1.6 9. Child-Pugh A (score =6) (Appendix D) 10. HAP score A, B or C (Appendix E) 11. 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). 12. 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 13. Written informed consent *All patients are required to under a MANDATORY biopsy prior to entry onto the study. **Criteria which establish ‘intermediate’ HCC Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 174 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 348
Exclusion criteria
Exclusion criteria: 1. Extrahepatic metastasis 2. Prior embolisation, systemic or radiation therapy for HCC 3. Any contraindications for hepatic embolisation procedures including portosystemic shunt, hepatofugal blood flow, known severe atheromatosis 4. Investigational therapy or major surgery within 4 weeks of trial entry 5. History of bleeding within the past 4 weeks 6. Child-Pugh cirrhosis B or C (score =7) 7. HAP score D 8. Hepatic encephalopathy 9. Ascites refractory to diuretic therapy 10. Documented occlusion of the hepatic artery or main portal vein 11. Hypersensitivity to intravenous contrast agents 12. Active clinically serious infection > Grade 2 NCI-CTC 13. Pregnant or lactating women 14. Known history of HIV infection 15. HBV chronic infection with HBV DNA = 500 IU/mL or without antiviral therapy; HBV patients with cirrhosis should be treated. 16. 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 17. 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 18. Psychiatric or other disorder likely to impact on informed consent 19. 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase II Component: Phase II Primary Objective The main purpose of Phase II component of the study is to test the effectiveness of nivolumab in combination with TACE/TAE in patients with intermediate stage HCC. This may lead to a recommendation to continue the study into a Phase III component if the treatment shows effectiveness using criteria to help measure this known as TACE/TAE progression (TTTP) as primary outcome measure. Phase III Component: Phase III Primary Objective The main purpose of the Phase III component of the study is to test the difference in overall survival between nivolumab in combination with TACE/TAE in patients with intermediate stage HCC. ; Secondary Objective: Phase II Component: Phase II Secondary Objectives To compare between the 2 treatment groups: • The length of time during and after the treatment that a patient lives with the disease but it does not get worse (aka progression free survival [PFS]) • Safety and Toxicity • Time to Progression of disease (TTP) • Radiological response (by RECIST 1.1) Phase III Component: Phase III Secondary Objectives To compare between the 2 treatment groups: • Progression Free Survival (as above) • Time to Progression • Radiological response (by RECIST 1.1) • Time to TACE/TAE progression - this is determined by comparing pre and post treatment scans, the development of disease outside the liver, or increase in tumour size above a particular threshold when compared with the pre-treatment size. • Safety and Toxicity • Quality Of Life ; Primary end point(s): Phase II Component: To evaluate efficacy | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Phase II: - To evaluate the safety and toxicity profile of Nivolumab in combination with TACE in patients with intermediate stage HCC. - To compare Progression Free Survival between the two treatment arms. - To compare Time to Progression between the two treatment arms. - To compare radiological response rates between the two treatment arms. - Can we determine if there is a strong enough signal to continue onto the Phase III component? Phase III: - To evaluate the difference in Time to TACE progression between the two treatment arms. - To compare toxicity profiles between the two treatment arms. - To compare Progression Free Survival (PFS) between the two treatment arms. - To compare Time to Progression between the two treatment arms. - To compare Objective Response Rate between the two treatment arms. - To evaluate the difference in quality of life between the two treatment arms. Exploratory: - To compare Radiological and Objective Response Rate between the two treatment arms. ; Timepoint(s) of evaluation of this end point: - Safety and toxicity profile of Nivolumab in combination with TACE - AE data collected during treatment and follow-up. - Compare PFS and TTP between 2 arms - progression check throughout. - Compare radiological response rates between 2 arms - scans are pre and post treatment then 12 weekly in follow-up. - Signal to continue onto the Phase III component - end of phase II. - Compare Objective Response Rate between 2 arms - end of phase III. - Difference in quality of life between 2 arms - end of phase III. | — |
Countries
United Kingdom
Contacts
Public ContactLiverpool Cancer Trials Unit -
University of Liverpool
Outcome results
None listed