Condition category
Cancer
Date applied
10/01/2019
Date assigned
16/01/2019
Last edited
05/03/2019
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Lay summary under review with external organisation

Trial website

Contact information

Type

Scientific

Primary contact

Mr Matthew Bickerstaff

ORCID ID

Contact details

Cancer Research UK Liverpool Cancer Trials Unit
1st Floor
Block C
Waterhouse Building
1-3 Brownlow Street
Liverpool
L69 3GL
United Kingdom

Additional identifiers

EudraCT number

2018-000004-42

ClinicalTrials.gov number

Protocol/serial number

C0993

Study information

Scientific title

A two-arm multi-stage (TAMS) seamless phase II/III randomised trial of nivolumab in combination with TACE for patients with intermediate stage HCC

Acronym

TACE-3

Study hypothesis

The primary purpose of Phase II component of the study is to evaluate efficacy of nivolumab in combination with TACE in patients with intermediate stage HCC and to recommend continuation into Phase III component if a positive efficacy signal1 is observed using TACE progression (TTTP) at 3 months as primary outcome measure.

The primary purpose of the Phase III component of the study is to evaluate the difference in overall survival between nivolumab in combination with TACE in patients with intermediate stage HCC.

The null hypothesis is that the addition of Nivolumab to TACE has no effect on overall survival.

Ethics approval

RES Committee North West – GM South, Health Research Authority, 3rd Floor, Barlow House, 4 Minshull St., Manchester, M1 3DZ, Tel: +44 (0)207 104 8235, Email: nrescommittee.northwest-gmsouth@nhs.net, approval pending, ref: 18/NW/0699

Study design

Interventional multi-centre two-arm open-label seamless phase II/III study

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use contact details to request a participant information sheet.

Condition

Intermediate stage hepatoceullular carcinoma

Intervention

Patients are randomised 1:1 between two treatment arms:
1. TACE treatment (standard treatment - DC Beads loaded with doxorubicin)
2. Nivolumab (480mg IV - 4 weekly) and TACE treatment (experimental arm)

Patients will undergo screening assessments to determine whether they are eligible for inclusion in the study, which may include a liver biopsy. They will also complete some questionnaires.

The length of treatment is partly determined by how well patients respond to treatment. Based on assessment data, the doctor may recommend repeat TACE treatment, with each treatment taking around 1-2 hours to complete with an overnight stay in hospital.

Patients who also receive nivolumab treatment will attend for regular 4 weekly treatment visits until the doctor decides no further nivolumab treatment is necessary or when the maximum treatment period is reached (24 months).

After treatment has ended, patients are followed-up every 4 weeks for a minimum of 24 months if possible (maximum is end of study).

Patients will have CT/MRI scans throughout the study (prior to treatment, 8 weeks after they have entered the study and then 12 weekly). If disease progression occurs, a confirmatory CT/MRI scan will be performed.

In addition to routine blood samples, patients will be asked to provide blood samples throughout the study for future liver cancer research.

Most patients will be identified by the Investigator/Co-Investigator responsible for their care. Some may be identified by colleagues who know about the trial but are not directly involved in the study. In such instances the patients' doctors will refer them to the study doctor.

Patients may also be identified at multi-disciplinary team meetings at their hospital. These meetings are held to discuss the patients' care, and are attended by the clinical care team (consultants, radiologists, research nurses, etc.). Identification is based upon the inclusion/exclusion criteria.

If the patient appears eligible the study doctor will inform the patient of the study and the trial will be discussed during the patient consultation. All patients will be given adequate time to ask questions about the trial before being asked to participate. If the patient agrees to take part the informed consent process will begin.

Patients shall be randomised evenly across the two treatment arms of the study. In phase II of the study, 100 patients will be recruited.

A stop/go decision in the phase II component of the study is based on observing some evidence of effectiveness between the treatment arms with respect to 3-month TACE progression. This will occur after 100 patients have had a 20 week scan for TACE progression, which will occur approximately 18 months following the start of recruitment.

Aside from the stop/go decision, there are no formal stopping rules for efficacy/futility built into the study.

Should the study continue to phase III, 422 patients will be randomised evenly across the two treatment arms. This makes a total of 522 patients being recruited over a 48 month period for phase II and III combined, with a minimum 24 months of follow-up for each patient if possible.

Patient recruitment is planned to take place from 16 contributing centres who (based on estimations from the TACE 2 study) will conservatively be able to recruit at an average rate of 0.75 patients/site/month. Sites will be opened to recruitment at a rate of 2 sites per month. These projections include a 5% shortfall margin (attrition rate).

A Trial Management Group (comprising the Chief Investigator, other lead investigators [clinical and non-clinical] and members of the LCTU Trials Unit) will manage the day to day running of the study and will meet throughout the study.

The Independent Safety and Data Monitoring Committee (ISDMC) (consisting of an independent chairperson, independent statistician and an independent oncologist who are experts in the field of oncology and liver cancer) are responsible for reviewing and assessing recruitment, interim monitoring of safety and effectiveness, trial conduct and external data and will provide a recommendation to the Trial Steering Committee concerning the continuation of the study.

The Trial Steering Committee (consisting of an independent chairperson, independent statistician and independent experts in the field of liver cancer in addition to other non-independent members of the TMG) provides overall supervision and advice for the study. The ultimate decision for the continuation of the trial lies with the TSC.

The patient information sheet and consent forms have been reviewed by members of the University of Liverpool, CR-UK Liverpool Cancer Trials Unit Patient and Public Involvement group, which consists of lay members of the public. The forms have subsequently been re-designed to include suggestions made by the PPI group, with the overall goal being to improve the effectiveness of the forms in communicating the requirements and expectations of the study to patients.

The Trial Steering Committee also includes lay member representation.

Intervention type

Drug

Phase

Phase II

Drug names

Nivolumab, doxorubicin

Primary outcome measure

Phase II:
3 month TACE Progression (TTTP) (binary), assessed using CT/MRI scan at 3 months

Phase III:
Overall survival, assessed using hospital records from randomisation to death

Secondary outcome measures

Phase II:
1. Number of Grade 3+ AEs and SAEs, assessed by asking patient at baseline, each treatment visit, and 4 weekly during follow-up
2. Progression Free Survival (PFS), assessed using CT/MRI scan from randomisation to progression or death
3. Time to progression (TTP), assessed using CT/MRI scan from randomisation to progression
4. Response rate by RECIST 1.1, assessed using CT/MRI scan at 8 weeks post randomisation and then 12 weekly

Phase III:
1. Time to TACE Progression (TTTP), assessed using CT/MRI scan at 8 weeks post randomisation and confirmatory scan 4 weeks after progression
2. Number of Grade 3+ AEs and SAEs, assessed by asking patient at baseline, each treatment visit, 4 weekly during follow-up
3. Progression Free Survival (PFS), assessed using CT/MRI scan, hospital records, from randomisation to progression or death
4. Time to progression (TTP), assessed using CT/MRI scan from randomisation to progression
5. Objective response rate (ORR) by RECIST 1.1, assessed using CT/MRI scan at 8 weeks post randomisation and then 12 weekly
6. Quality of life, assessed using EORTC QLQ_C30, EORTC QLQ-HCC18 and EQ5D questionnaires at baseline, pre-first TACE treatment and then 12 weekly until end of treatment

Overall trial start date

31/08/2017

Overall trial end date

30/09/2025

Reason abandoned (if study stopped)

Eligibility

Participant 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:
5.1. Hb ≥9g/L
5.2. Absolute neutrophil count ≥1.0x109/L
5.3. 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 ≤1.7
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

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 522; UK Sample Size: 422

Participant 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 serious autoimmune disease.
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

*Criteria which establish ‘intermediate’ HCC

Recruitment start date

01/02/2019

Recruitment end date

01/02/2023

Locations

Countries of recruitment

France, Ireland, United Kingdom

Trial participating centre

THE CLATTERBRIDGE CANCER CENTRE NHS FOUNDATION TRUST
CLATTERBRIDGE ROAD
BEBINGTON WIRRAL
CH63 4JY
United Kingdom

Trial participating centre

ROYAL LIVERPOOL AND BROADGREEN UNIVERSITY HOSPITALS NHS FOUNDATION TRUST
PRESCOT STREET
LIVERPOOL
L7 8XP
United Kingdom

Trial participating centre

AINTREE UNIVERSITY HOSPITAL NHS FOUNDATION TRUST
LOWER LANE
LIVERPOOL
L9 7AL
United Kingdom

Trial participating centre

GUY'S AND ST THOMAS' NHS FOUNDATION TRUST
GREAT MAZE POND LONDON
LONDON
SE1 9RT
United Kingdom

Trial participating centre

UNIVERSITY HOSPITALS BIRMINGHAM NHS FOUNDATION TRUST
TRUST HQ, PO BOX 9551 QUEEN ELIZABETH MEDICAL CENTRE EDGBASTON
BIRMINGHAM
B15 2TH
United States Minor Outlying Islands

Trial participating centre

NOTTINGHAM UNIVERSITY HOSPITALS NHS TRUST
TRUST HEADQUARTERS QUEENS MEDICAL CENTRE DERBY ROAD
NOTTINGHAM
NG7 2UH
United Kingdom

Trial participating centre

UNIVERSITY HOSPITAL SOUTHAMPTON NHS FOUNDATION TRUST
MAILPOINT 18 SOUTHAMPTON GENERAL HOSPITAL TREMONA ROAD
SOUTHAMPTON
SO16 6YD
United Kingdom

Trial participating centre

UNIVERSITY HOSPITALS BRISTOL NHS FOUNDATION TRUST
MARLBOROUGH STREET
BRISTOL
BS1 3NU
United Kingdom

Trial participating centre

THE CHRISTIE NHS FOUNDATION TRUST
550 WILMSLOW ROAD WITHINGTON
MANCHESTER
M20 4BX
United Kingdom

Trial participating centre

THE ROYAL MARSDEN NHS FOUNDATION TRUST
FULHAM ROAD
LONDON
SW3 6JJ
United Kingdom

Trial participating centre

LEEDS TEACHING HOSPITALS NHS TRUST
ST. JAMES'S UNIVERSITY HOSPITAL BECKETT STREET
LEEDS
LS9 7TF
United Kingdom

Trial participating centre

CAMBRIDGE UNIVERSITY HOSPITALS NHS FOUNDATION TRUST
ADDENBROOKES HOSPITAL HILLS ROAD
CAMBRIDGE
CB2 0QQ
United Kingdom

Trial participating centre

ROYAL SURREY COUNTY HOSPITAL NHS FOUNDATION TRUST
EGERTON ROAD GUILDFORD
SURREY
GU2 7XX
United Kingdom

Trial participating centre

SHEFFIELD TEACHING HOSPITALS NHS FOUNDATION TRUST
NORTHERN GENERAL HOSPITAL HERRIES ROAD
SHEFFIELD
S5 7AU
United Kingdom

Trial participating centre

NHS Lothian
Waverley Gate 2-4 Waterloo Place
Edinburgh
EH1 3EG
United Kingdom

Trial participating centre

NHS Greater Glasgow and Clyde
J B Russell House Gartnavel Royal Hospital 1055 Great Western Road
Glasgow
G12 0XH
United Kingdom

Trial participating centre

HEART OF ENGLAND NHS FOUNDATION TRUST
BORDESLEY GREEN EAST
BIRMINGHAM
B9 5ST
United Kingdom

Trial participating centre

IMPERIAL COLLEGE HEALTHCARE NHS TRUST
ST. MARYS HOSPITAL PRAED STREET
LONDON
W2 1NY
United Kingdom

Trial participating centre

THE ROYAL BOURNEMOUTH AND CHRISTCHURCH HOSPITALS NHS FOUNDATION TRUST
CASTLE LANE EAST
BOURNEMOUTH
BH7 7DW
United Kingdom

Trial participating centre

OXFORD UNIVERSITY HOSPITALS NHS FOUNDATION TRUST
JOHN RADCLIFFE HOSPITAL HEADLEY WAY HEADINGTON
OXFORD
OX3 9DU
United Kingdom

Trial participating centre

CHRU, Lille
2 Avenue Oscar Lambret
Lille
59000 Lille
France

Trial participating centre

Hôpital Beaujon
100 Boulevard du Général Leclerc
Clichy
92110 Clichy
France

Trial participating centre

Hôpital Jean Verdier
Avenue du 14 Juillet
Bondy
93140 Bondy
France

Trial participating centre

Gustave Roussy
114 Rue Edouard Vaillant
Villejuif
94800 Villejuif
France

Trial participating centre

CHU, Centre Hospitalier Universitaire de Montpellier
191 avenue du Doyen Gaston Giraud
Montpellier
34295 Montpellier cedex 5
France

Trial participating centre

CHU, 2 Rue de la Milétrie
CHU, 2 Rue de la Milétrie
Poitiers
86021 Poitiers
France

Trial participating centre

CHU, Avenue Maquis du Grésivaudan
CHU, Avenue Maquis du Grésivaudan
La Tronche
38700 La Tronche
France

Trial participating centre

CHU Haut leveque
Av. Magellan
Pessac
33600 Pessac
France

Trial participating centre

Hôpital de la Croix Rousse
103 Grande Rue de la Croix-Rousse
Lyon
69004 Lyon
France

Trial participating centre

CHU, 30 Voie Romaine
CHU, 30 Voie Romaine
06000 Nice- CHU, Toulouse
06000 Nice- CHU, Toulouse
France

Trial participating centre

St Vincents University Hospital
Elm Park Dublin 4
Dublin
D04 T6F4
Ireland

Sponsor information

Organisation

The Clatterbridge Cancer Centre NHS Foundation Trust

Sponsor details

Clatterbridge Road
Bebington
CH63 4JY
United Kingdom

Sponsor type

Hospital/treatment centre

Website

https://www.clatterbridgecc.nhs.uk/

Funders

Funder type

Industry

Funder name

Bristol-Myers Squibb

Alternative name(s)

Bristol-Myers Squibb Company, BMS

Funding Body Type

private sector organisation

Funding Body Subtype

corporate

Location

United States of America

Funder name

Biocompatibles UK Ltd, a BTG International group company

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

All study documents will be available by contacting the Trial Coordinator only.

The study will accessible on the following registers:
1. ISRCTN registry
2. eudract.ema.europa.eu

The results will be reported and disseminated via:
1. Peer-reviewed scientific journals
2. Internal reports
3. Conference presentations
4. Submission to regulatory authorities

Results of the research will be made available to all of the participating investigators, who will then communicate the results to the research participants and their families. The results will also be presented at international meetings/conference proceedings which will be accessible to patients.

IPD sharing statement
The datasets generated during and/or analysed during the current study will be stored in a non-publically available repository. The database name is MACRO. The study will collect patient data from participating study centres about patients who have consented to the study. The trialists will collect anonymised patient CRF study data and unblinded consent forms to demonstrate the patient has consented to the study (consent details will never be released). This data will be held at the University of Liverpool for 15 years where it will be analysed by members of the Trial Management Group for the purposes of informing the study oversight committees during the study in addition to producing study publications.

Intention to publish date

30/09/2026

Participant level data

Stored in repository

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

05/03/2019: Internal review. 25/01/2019: Biocompatibles UK Ltd has been added as a funder.