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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

The Clatterbridge Cancer Centre NHS Foundation Trust

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

12 Oct 2022 → ongoing

Decision date (initial)

2024-11-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Bristol Myers Squibb Pharmaceuticals Ltd

External identifiers

EU CT number

2024-513882-38-00

EudraCT number

2018-000004-42

ClinicalTrials.gov

NCT04268888

ISRCTN

ISRCTN12053408

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Therapy

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

Secondary objectives 11

1. Phase II component : To evaluate the safety and toxicity profile of nivolumab in combination with TACE/TAE in patients with intermediate stage HCC
2. Phase II component : To compare Progression Free Survival between the two treatment arms
3. Phase II component : To compare Time to Progression between the two treatment arms
4. Phase II component : To compare radiological response rates between the two treatment arms
5. Phase II component : Can we determine if there is a strong enough signal to continue onto the Phase III component?
6. Phase III component : To evaluate the difference in Time to TACE/TAE progression between the two treatment arms.
7. Phase III component : To compare toxicity profiles between the two treatment arms
8. Phase III component : To compare Progression Free Survival (PFS) between the two treatment arms
9. Phase III component : To compare Time to Progression between the two treatment arms
10. Phase III component : To compare Objective Response Rate between the two treatment arms
11. Phase III component : To evaluate the difference in quality of life between the two treatment arms

Conditions and MedDRA coding

Intermediate stage Hepatocellular carcinoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

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 (not applicable for France)
3. Aged ≥16 years and estimated life expectancy ≥3 months (not applicable for France)
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 μmol/L ≤1.5 x ULN
8. INR ≤1.6
9. Child-Pugh A (score ≤6)
10. HAP score A, B or C
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) (not applicable for France)
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 (not applicable for France)
14. Aged ≥ 18 years and estimated life expectancy ≥3 months (only for France)
15. Patient must have signed a written informed consent prior to any trial specific procedures. When the patient is physically unable to give her written consent, a trusted person of their choice, independent from the investigator or the sponsor, can confirm in writing the patient’s consent. (only for France)
16. Patients must be affiliated to a Social Security System (or equivalent). (only for France)
17. Intermediate stage HCC (BCLC B) not candidate for surgical resection, ablation therapy or liver transplatation (only for France)

Exclusion criteria 28

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. vidence of uncontrolled, active infection, requiring parenteral antibacterial, 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 (not applicable for France)
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 (not applicable for France)
28. Contra-indications to T-cell checkpoint inhibitor therapy: - Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days of the first dose of study drug administration; unless used as replacement therapy - Organ transplantation - 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Phase II component : Time to TACE/TAE Progression (TTTP)
2. Phase III component : Overall Survival

Secondary endpoints 10

1. Phase II component : Number of Grade 3+ AEs and SAEs
2. Phase II component : Progression Free Survival (PFS)
3. Phase II component : Time to progression (TTP)
4. Phase II component : Response rate by RECIST 1.1
5. Phase III component : Time to TACE/TAE Progression (TTTP)
6. Phase III component : Number of Grade 3+ AEs and SAEs
7. Phase III component : Progression Free Survival (PFS)
8. Phase III component : Time to progression (TTP)
9. Phase III component : Objective response rate (ORR) by RECIST 1.1
10. Phase III component : EORTC QLQ_C30 EORTC QLQ-HCC18 EQ5D

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

The Clatterbridge Cancer Centre NHS Foundation Trust

Sponsor organisation

The Clatterbridge Cancer Centre NHS Foundation Trust

Address

65 Pembroke Place

City

Liverpool

Postcode

L7 8YA

Country

United Kingdom

Scientific contact point

Organisation

The Clatterbridge Cancer Centre NHS Foundation Trust

Contact name

Maria MAguire

Public contact point

Organisation

The Clatterbridge Cancer Centre NHS Foundation Trust

Contact name

Maria MAguire

Locations

1 EU/EEA country · 4 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 14 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications