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

July 14, 2020 updated by: The Clatterbridge Cancer Centre NHS Foundation Trust

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

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Anticipated)

522

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United Kingdom
      • Liverpool, United Kingdom, L69 7ZB
        • Recruiting
        • University of Liverpool
        • Contact:
        • Principal Investigator:
          • Daniel Palmer, PhD, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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.
Procedure: TACE/TAE
TACE/TAE (as per local practice)
Drug: Nivolumab and TACE/TAE
Immunotherapy and TACE/TAE

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
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
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
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
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
Time to date of progression confirmed by RECIST1.1 assessed up until 2 years after the last patient is randomised
Radiological response rate
Time Frame: Through study completion
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)
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).
Through study completion
Progression Free Survival
Time Frame: Time to progression or death. Assessed up until 2 years.
Measured in days
Time to progression or death. Assessed up until 2 years.
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.
baseline, pre - TACE (first treatment) and 12 weekly thereafter until end of treatment. Assessed up until 2 years after the last patient is randomised

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The Clatterbridge Cancer Centre NHS Foundation Trust

Investigators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 8, 2019

Primary Completion (Anticipated)

June 1, 2025

Study Completion (Anticipated)

June 1, 2026

Study Registration Dates

First Submitted

June 5, 2019

First Submitted That Met QC Criteria

February 11, 2020

First Posted (Actual)

February 13, 2020

Study Record Updates

Last Update Posted (Actual)

July 16, 2020

Last Update Submitted That Met QC Criteria

July 14, 2020

Last Verified

July 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CA209-9Y9

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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