Nivolumab in Combination With TACE/TAE for Patients With Intermediate Stage HCC (TACE-3)

• ClinicalTrials.gov Identifier: NCT04268888
• Recruitment Status: Recruiting
• First Posted: February 13, 2020
• Last Update Posted: July 16, 2020
• Sponsor: The Clatterbridge Cancer Centre NHS Foundation Trust
• Information provided by (Responsible Party): The Clatterbridge Cancer Centre NHS Foundation Trust

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Hepatocellular Carcinoma	Drug: Nivolumab and TACE/TAE; Procedure: TACE/TAE	Phase 2; Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 522 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention 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)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: May 8, 2019
• Estimated Primary Completion Date: June 2025
• Estimated Study Completion Date: June 2026

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: TACE/TAE Alone; Transarterial Chemoembolisation (TACE) and/or Transarterial Embolisation (TAE) Alone.	Procedure: TACE/TAE; TACE/TAE (as per local practice)
Experimental: TACE/TAE and Nivolumab; As above for TACE/TAE. Nivolumab adminstered as a flat dose of 480mg IV.	Drug: Nivolumab and TACE/TAE; Immunotherapy and TACE/TAE; Procedure: TACE/TAE; TACE/TAE (as per local practice)

Outcome Measures

Primary Outcome Measures :

1. Overall Survival - phase III primary outcome [ Time Frame: 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
2. Time to TACE Progression (TTTP) - phase II primary outcome [ Time Frame: 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 :

1. Time to Progression [ Time Frame: Time to date of progression confirmed by RECIST1.1 assessed up until 2 years after the last patient is randomised ]
   Measured in days
2. Radiological response rate [ Time Frame: Through study completion ]
   RECIST 1.1
3. Safety and Toxicity: the number and percentage of patients reporting a Serious Adverse Event (SAE) and Grade 3 or higher Adverse Event (AE) [ Time Frame: 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).
4. Progression Free Survival [ Time Frame: Time to progression or death. Assessed up until 2 years. ]
   Measured in days
5. QOL: EORTC QLQ-C30 [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: 16 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

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.

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

Contacts and Locations

Contacts

Contact: Maria Maguire, PhD; 0151 556; maria.maguire2@nhs.net

Contact: David Price; 0151 556; david.price9@nhs.net

Locations

United Kingdom

University of Liverpool; Recruiting

Liverpool, United Kingdom, L69 7ZB

Contact: Louise Handley 0151 794 8935 louise.handley@liverpool.ac.uk

Principal Investigator: Daniel Palmer, PhD, MD

Sponsors and Collaborators

The Clatterbridge Cancer Centre NHS Foundation Trust

Investigators

• Study Director: Daniel Palmer, PhD, MD; Clatterbridge Cancer Centre

More Information

• Responsible Party: The Clatterbridge Cancer Centre NHS Foundation Trust
• ClinicalTrials.gov Identifier: NCT04268888
• Other Study ID Numbers: CA209-9Y9
• First Posted: February 13, 2020
• Last Update Posted: July 16, 2020
• Last Verified: July 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by The Clatterbridge Cancer Centre NHS Foundation Trust:

Intermediate Stage

Additional relevant MeSH terms:

Carcinoma, Hepatocellular; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases; Nivolumab; Chlorotrianisene; Antineoplastic Agents, Immunological; Antineoplastic Agents; Estrogens, Non-Steroidal; Estrogens; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal