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

Phase 2

Suspended

• Conditions: Hepatocellular Carcinoma
• Interventions: Procedure: TACE/TAE; Drug: Nivolumab and TACE/TAE

• Registration Number: NCT04268888
• Lead Sponsor: The Clatterbridge Cancer Centre NHS Foundation Trust

Brief Summary

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

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.

Study Timeline

• Study Start: 2019-05-08
• Study First Submitted: 2019-06-05
• Study First Submitted QC: 2020-02-11
• Study First Posted: 2020-02-13
• Status Verified: 2025-02
• Last Update Submitted: 2025-02-24
• Last Update Posted: 2025-02-26
• Primary Completion: 2025-08-01
• Study Completion: 2026-06-30

Recruitment & Eligibility

• Status: SUSPENDED
• Sex: All
• Target Recruitment: 522

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

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 variceal 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 vein5

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 > 500IU/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 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

17. Evidence of uncontrolled, active infection, requiring parenteral anti-bacterial, anti-viral or antifungal therapy within 7 days prior to administration of study medication

18. Positive test for latent TB or evidence of active TB

19. Hypersensitivity to any of the active substances or excipients

20. Patients who have received a live vaccine within 30 days prior to the first dose of trial treatment

21. 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

22. Any uncontrolled inflammatory GI disease including Crohn's Disease and ulcerative colitis

23. 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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
TACE/TAE Alone	TACE/TAE	Transarterial Chemoembolisation (TACE) and/or Transarterial Embolisation (TAE) Alone.
TACE/TAE and Nivolumab	TACE/TAE	As above for TACE/TAE. Nivolumab adminstered as a flat dose of 480mg IV.
TACE/TAE and Nivolumab	Nivolumab and TACE/TAE	As above for TACE/TAE. Nivolumab adminstered as a flat dose of 480mg IV.

Primary Outcome Measures

Name	Time	Method
Overall Survival - phase III primary outcome	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.	Measured in days
Time to TACE Progression (TTTP) - phase II primary outcome	The time to confirmatory scan 4 weeks after progression this can be assessed up until 2 years after the last patient is randomised	Measured in days

Secondary Outcome Measures

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

Trial Locations

Locations (2)

Unicancer; 🇫🇷 Paris, France

University of Liverpool; 🇬🇧 Liverpool, United Kingdom