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Trial registered on ANZCTR


Registration number
ACTRN12624001345572p
Ethics application status
Submitted, not yet approved
Date submitted
9/10/2024
Date registered
7/11/2024
Date last updated
7/11/2024
Date data sharing statement initially provided
7/11/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Multicentre, randomized trial of immunotherapy prior to surgical resection for early-stage hepatocellular carcinoma
Scientific title
DEFINERx050: A Multicentre, Randomized, Open-Label Study of Atezolizumab (Anti-PD-L1 Antibody) Plus Bevacizumab (Anti-VEGF Antibody) as Neo-Adjuvant ImmunoTherapy Versus Active Surveillance in Hepatocellular Carcinoma Patients with high Onco-Fetal Characteristics Before Surgical Resection
Secondary ID [1] 313115 0
NHMRC 2032407
Universal Trial Number (UTN)
Trial acronym
DEFINERx050
Linked study record

Health condition
Health condition(s) or problem(s) studied:
hepatocellular carcinoma 335374 0
liver cancer 335598 0
Condition category
Condition code
Cancer 331950 331950 0 0
Liver

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Interventional arm: Treatment of early-stage hepatocellular carcinoma with neoadjuvant immunotherapeutic agents atezolizumab (Tecentriq) and bevacizumab (Avastin) followed by surgical resection with active surveillance in patients with high onco-fetal characteristics.

Patients will be tested for onco-fetal characteristics (high onco-fetal score, determined as >10% onco-fetal cells and/or high Glypican-3, determined as positive staining in >10% cells and/or alpha fetoprotein (AFP) >400 ng/mL). Patients with high onco-fetal characteristics will be randomised 1:1 into intervention and control arms. Patients with low onco-fetal score will receive control treatment only.

Intervention Regime:
Participants will receive 2 cycles of immunotherapy in total, 3 weeks apart, as follows:
Cycle 1: Day 0 - Atezolizumab will be administered by intravenous infusion at a fixed dose of 1200 mg and Bevacizumab will be administered intravenous infusion at a dose of 15 mg/kg.
Cyle 2: Day 21 - Atezolizumab will be administered by intravenous infusion at a fixed dose of 1200 mg as monotherapy.
Day 22-23 - Surgical resection

Patients will be followed up every 3 months for 3 years following surgery.

Details of all treatments and follow up assessments will be recorded in patient medical records.
Intervention code [1] 329693 0
Treatment: Drugs
Intervention code [2] 329852 0
Treatment: Surgery
Comparator / control treatment
Control arm: Surgical resection only (current standard of care) with active surveillance every 3 months for 3 years.
Control group
Active

Outcomes
Primary outcome [1] 339557 0
Efficacy of neoadjuvant atezolizumab plus Bevacizumab compared with active surveillance
Timepoint [1] 339557 0
24 months post-treatment randomisation
Secondary outcome [1] 440428 0
Overall survival
Timepoint [1] 440428 0
36 months from treatment randomisation

Eligibility
Key inclusion criteria
- Signed Informed Consent Form
- Age greater than or equal to 18 years
- Ability to comply with the study protocol
- First diagnosis of HCC and MDT recommendation of curative resection
- Absence of major macrovascular invasion
- Absence of extrahepatic spread
- AST and ALT less that or equal to 5 × upper limit of normal (ULN) and total bilirubin less than or equal to 51 µmol/L
- Baseline FFPE tumour tissue biopsy
- Documented virology status of hepatitis B and C
- ECOG Performance Status of 0 or 1
- Child-Pugh Class A status or up to B7
- Adequate hematologic and end-organ function
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
- Evidence of residual, recurrent, or metastatic disease
- Clinically significant ascites
- History of hepatic encephalopathy
- Prior bleeding event due to untreated or incompletely treated oesophageal and/or gastric varices
- Active or history of autoimmune disease or immune deficiency
- History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
- Significant cardiovascular disease
- History of malignancy other than HCC within 5 years prior to screening
- Active tuberculosis
- Severe infection within 4 weeks prior to treatment
- Prior allogeneic stem cell or solid organ transplantation
- On the waiting list for liver transplantation
- Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
- Pregnant or breastfeeding, or intending to become pregnant during the study or within 5 months after the final dose of atezolizumab or within 6 months after the final dose of bevacizumab
- Women of childbearing potential without a negative serum pregnancy test result within 14 days prior to Day 1 of Cycle 1
- Co-infection with HBV and hepatitis D viral infection
- Clinically significant hypercalcemia
- History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
- Hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab or bevacizumab formulations
- Any prior treatment for HCC
- History of hypertensive crisis or hypertensive encephalopathy
- Significant vascular disease
- History of hemoptysis
- Evidence of bleeding diathesis or significant coagulopathy
- History of GI fistula, GI perforation, or intra-abdominal abscess within 6 months prior to treatment
- Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture
- Major surgical procedure within 4 weeks prior to treatment

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Randomisation will be carried out using a computer-generated list of random numbers. An independent staff member will assign the treatments according to consecutive numbers that are kept in sealed envelopes. Consented participants with high OFC will be randomly assigned to receive:
- Control treatment: Surgical resection and active surveillance, as per standard of care; or
- Immunotherapy: Immunotherapy followed by surgery and active surveillance
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
2/12/2024
Actual
Date of last participant enrolment
Anticipated
4/12/2026
Actual
Date of last data collection
Anticipated
7/12/2029
Actual
Sample size
Target
208
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC

Funding & Sponsors
Funding source category [1] 317560 0
Government body
Name [1] 317560 0
National Health and Medical research Council
Country [1] 317560 0
Australia
Primary sponsor type
Government body
Name
Western Sydney Local Health District
Address
Country
Australia
Secondary sponsor category [1] 319864 0
None
Name [1] 319864 0
Address [1] 319864 0
Country [1] 319864 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 316271 0
Western Sydney Local Health District Human Research Ethics Committee
Ethics committee address [1] 316271 0
Ethics committee country [1] 316271 0
Australia
Date submitted for ethics approval [1] 316271 0
17/10/2024
Approval date [1] 316271 0
Ethics approval number [1] 316271 0
2024/ETH02271

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 137346 0
Prof Jacob George
Address 137346 0
Storr Liver Centre, Westmead Hospital, PO Box 533, WENTWORTHVILLE NSW 2145
Country 137346 0
Australia
Phone 137346 0
+61288907705
Fax 137346 0
Email 137346 0
jacob.george@sydney.edu.au
Contact person for public queries
Name 137347 0
Prof Jacob George
Address 137347 0
Storr Liver Centre, Westmead Hospital, PO Box 533, WENTWORTHVILLE NSW 2145
Country 137347 0
Australia
Phone 137347 0
+61288907705
Fax 137347 0
Email 137347 0
jacob.george@sydney.edu.au
Contact person for scientific queries
Name 137348 0
Prof Jacob George
Address 137348 0
Storr Liver Centre, Westmead Hospital, PO Box 533, WENTWORTHVILLE NSW 2145
Country 137348 0
Australia
Phone 137348 0
+61288907705
Fax 137348 0
Email 137348 0
jacob.george@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.