Clinical Trials Register

Summary
EudraCT Number:	2018-000004-42
Sponsor's Protocol Code Number:	C0993
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2018-09-18
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2018-000004-42

A.3

Full title of the trial

TACE-3: 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

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Phase II/III randomised study combining nivolumab with TACE treatment for patients with liver cancer.

A.3.2

Name or abbreviated title of the trial where available

TACE-3

A.4.1

Sponsor's protocol code number

C0993

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

ISRCTN12053408

A.5.4

Other Identifiers

Name:

EudraCT

Number:

2018-000004-42

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	The Clatterbridge Cancer Centre NHS Foundation Trust
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Bristol Myers Squibb
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University of Liverpool
B.5.2	Functional name of contact point	Liverpool Cancer Trials Unit -
B.5.3	Address:
B.5.3.1	Street Address	3 Brownlow Street
B.5.3.2	Town/ city	Liverpool
B.5.3.3	Post code	L69 3GL
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	01517948167
B.5.5	Fax number	01517948930
B.5.6	E-mail	C.Rawcliffe@liverpool.ac.uk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Opdivo
D.2.1.1.2	Name of the Marketing Authorisation holder	Bristol-Myers Squibb Pharma EEIG
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Opdivo
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous drip use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Nivolumab
D.3.9.1	CAS number	946414-94-4
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Intermediate stage Hepatocellular Carcinoma

E.1.1.1

Medical condition in easily understood language

Liver Cancer

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10019828
E.1.2	Term	Hepatocellular carcinoma non-resectable
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

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.

E.2.2

Secondary objectives of the trial

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

E.2.3

Trial contains a sub-study

E.3

Principal 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

E.4

Principal 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

E.5 End points

E.5.1

Primary end point(s)

Phase II Component:
To evaluate efficacy of Nivolumab in combination with TACE/TAE in patients with intermediate stage HCC.

Phase III Component:
To evaluate the difference in survival between the two treatment arms.

E.5.1.1

Timepoint(s) of evaluation of this end point

Phase II component:
Three month TACE Progression is a binary co-variate measuring TACE defined progression between the first scan following completion of first TACE treatment and a scan at week 20 post randomisation (i.e. 12 weeks after the 8 week TTTP baseline scan).

Phase III Component:
Overall Survival defined as time between date of randomisation and death from any cause. 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.

E.5.2

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.

E.5.2.1

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.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Standard of Care - Transcatheter arterial chemoembolization

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

Unless early termination is required, the end of trial is defined as once all patient have completed a minimum follow-up of 24 months or have died /come off study for other reason, together with sufficient time to collect outstanding data and resolve queries.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1