Hepatocellular CarcinomaPhase 2ADVANCE HCCNCT05137899
Neoadjuvant Combination of Atezolizumab/Bevacizumab Versus Neoadjuvant Radiation Therapy
A Phase 2 study testing Neoadjuvant in people with Hepatocellular Carcinoma and Portal Vein Tumour Thrombosis, run by Ontario Clinical Oncology Group (OCOG) at 7 sites in Canada.
Trial summary
A multicentre, parallel group, randomized controlled Phase II clinical trial evaluating neoadjuvant Atezolizumab/Bevacizumab versus neoadjuvant SBRT in patients with biopsy proven solitary HCC with PVTT involving the portal vein branches. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Hepatocellular Carcinoma, Portal Vein Tumour Thrombosis
- What is being tested?
- Neoadjuvant
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 1 participants
- Where
- 7 sitesCanada
- Study dates
- 18 Oct 2022to 26 Feb 2025
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Biopsy proven solitary HCC without biliary invasion, or metastases,
- PVTT involving the portal vein branches: Vp1-Vp3 (Japanese Classification for HCC with PVTT, see Appendix II),
- <10 cm maximal diameter on CT or MRI,
- Child-Pugh Class A (see Appendix III), within 14 days prior to randomization. (All parameters without transfusion within 3 months).
- Age > 18 years.
Who cannot join
- Abnormal laboratory parameters (within 14 days of randomization):
- Hemoglobin < 90 g/L
- Platelet count < 75 x 109/L without transfusion
- INR >1.25
- Serum creatinine > 1.5 x ULN
- Urine dipstick for proteinuria > 2 (unless a 24-hour urine collection demonstrates < 1.5 g of protein in 24 hours.
Show all 38Show fewer
- Previous therapy for HCC:
- Systemic therapy, surgery or radiation therapy,
- Local therapy to the liver (e.g., ablation or embolization) within 28 days prior to randomization.
- ECOG performance status > 2 (see Appendix IV).
- Non-healing wound, skin ulcers, or incompletely healed bone fracture.
- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to planned start of study therapy.
- History of bleeding from esophageal and/or gastric varices or high risk of bleeding from varices seen on endoscopy (normal EGD required within 6 months of randomization).
- History of GI perforation, abdominal fistulae, or intra-abdominal abscess.
- Significant cardiovascular disease:
- New York Heart Association cardiac disease (Class II or greater),
- Myocardial infarction, unstable angina or cerebrovascular accident within past 3 months,
- Unstable arrhythmia,
- Poorly controlled arterial hypertension (defined as systolic blood pressure (BP) > 150 mmHg and/or diastolic blood pressure > 100 mmHg) based on an average of > 3 BP readings on > 2 sessions), or prior history of hypertensive crisis or hypertensive encephalopathy,
- Aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis within 6 months prior to randomization
- Known contraindication to Bevacizumab or Immune Checkpoint Inhibitor (ICI): Active or history of autoimmune disease or immune deficiency, including, but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, autoimmune hypophysitis, or autoimmune pancreatitis. Includes known hypersensitivity to any component of Bevacizumab; Chinese hamster ovary cell products or other recombinant human or humanized antibodies. Known hypersensitivity to Atezolizumab or any of the excipients. (Note: Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone and those with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study).
- Known history of (Human immunodeficiency virus (HIV), HBV and HCV co-infection). For patients with active HBV: HBV DNA <500IU/mL obtained within 28 days prior to randomization and anti-HBV treatment (per local standard of care, e.g., entecavir) for a minimum of 14 days prior to study entry and willingness to continue treatment for the length of the study.
- Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia.
- History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis.
- Active tuberculosis.
- Prior allogeneic stem cell or solid organ transplantation.
- Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment.
- Recent administration of live vaccine.
- History of malignancy other than HCC within 5 years prior to screening, with the exception of adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ of breast, or Stage I uterine cancer.
- Treatment with strong CYP3A4 inducers within 14 days prior to randomization.
- Treatment with an immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-α agents) within 14 days prior to randomization, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions: a) patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy), or b) patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency.
- Current or recent (within 7 days of randomization) use of aspirin (325mg/day), dipyramidole, ticlopidine, clopidogrel, or cilostazol, Vitamin K antagonists, direct oral anticoagulants (DOACs), LMWH.
- Recent history (within 4 weeks) of hemoptysis.
- History of TIA, CVA, or any arterial thrombotic event within 12 months before randomization.
- Sensory/motor neuropathy greater than or equal to grade 2, as defined by the NCI CTCAE and history of hypomagnesemia.
- Known severe allergic reaction to contrast (e.g., anaphylaxis).
- Pregnancy or lactating women.
- Inability to provide informed consent.
Trial locations and contacts
7 sites in 1 country.
7 sites in 1 country
Canada7 sites
Tom Baker Cancer Centre
Calgary, Alberta
Cross Cancer Institute
Edmonton, Alberta
Juravinski Cancer Centre
Hamilton, Ontario, L8V5C2
8. Centre the recherche du Centre hospitalier de l'Université de Montréal - CHUM
Montreal, Quebec
McGill Cedars Cancer Centre
Montreal, Quebec
Ottawa Regional Cancer Centre
Ottawa, Ontario, K1H8L6
Princess Margaret Cancer Centre
Toronto, Ontario
About this study
Official title: Neoadjuvant Combination of Atezolizumab/Bevacizumab Versus Neoadjuvant Radiation Therapy Prior to Hepatectomy in Hepatocellular Carcinoma with Portal Vein Tumour Thrombus (ADVANCE HCC) Hoffmann La Roche Protocol Number: ML42525
A multicentre, parallel group, randomized controlled Phase II clinical trial evaluating neoadjuvant Atezolizumab/Bevacizumab versus neoadjuvant SBRT in patients with biopsy proven solitary HCC with PVTT involving the portal vein branches. Both arms are considered experimental, and as such, a Simon two-stage design will be initially used within both arms. Only if both arms are deemed of interest for further study will a comparison between arms, using a pick-the-winner design, be conducted. Following the completion of neoadjuvant therapy, study participants will undergo a CT scan or MRI to assess tumour response to neoadjuvant therapy. Hepatic resection will be performed for those participants who meet the surgical resection criteria.
Read the detailed description
Surgical resection without adjuvant therapy is the standard of care for most patients with solitary hepatocellular carcinoma (HCC). The presence of portal vein tumour thrombus (PVTT) is associated with a poor prognosis, and as a result patients usually do not undergo surgery.1 One potential strategy to improve the outcome of patients with HCC and PVTT is to administer treatment to the tumour prior to surgery, i.e. "neoadjuvant" therapy. This strategy has been proven to be effective in other types of cancer, and results in tumour downstaging and potentially eliminates micro-metastatic disease In a recent randomized controlled trial (RCT) in patients with HCC and PVTT, the addition of radiation therapy (RT) to the tumour prior to hepatic surgery was compared with surgery alone.4 There was a statistically significant improvement in survival with RT. Systemic therapy with the tyrosine kinase inhibitor Sorafenib improved survival compared to placebo in patients with advanced HCC and PVTT.5 Another recent trial in patients with advanced HCC demonstrated improved survival with the combination of Atezolizumab, an immune checkpoint inhibitor (ICI), and Bevacizumab, an antibody to vascular endothelial growth factor compared to Sorafenib alone.6
Currently, there is no standard of care for the neoadjuvant treatment of solitary HCC. Radiotherapy has not been widely adopted despite recent evidence suggesting some benefit. It is conceivable that RT will downsize the tumour increasing the surgical resection rate and reducing the shedding of tumour cells. Stereotactic Body Radiation Therapy (SBRT) is a type of RT that provides high dose, focal radiation to tumours using highly precise imaging and treatment fields, with rapid dose fall-off thereby sparing normal tissue. Based on experience in other cancers, it would seem judicious that effective systemic therapy be considered for the neoadjuvant treatment of HCC to downsize the primary tumour and eradicate occult micro-metastases.2,3
We hypothesize that treating patients with HCC and PVTT with either 1) neoadjuvant systemic therapy, or 2) neoadjuvant SBRT may lead to improved hepatic resection rates. Complete hepatic resection is being considered as a surrogate for good long-term outcomes. The aim of our randomized Phase II trial is to select the treatment arm with the most favourable outcomes based on a trade-off between resection rate and toxicity for study in a future trial.
- Being tested
- Neoadjuvant
- Keywords
- Neoadjuvant Atezolizumab/Bevacizumab, Neoadjuvant Stereotactic Body Radiation Therapy
- Medical subject headings
- Carcinoma, Hepatocellular
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NeoadjuvantCombination product
Neoadjuvant atezolizumab/bevacizumab or neoadjuvant SBRT prior to hepatectomy
| Study group | Role | What they receive |
|---|---|---|
| Neoadjuvant Atezolizumab/Bevacizumab | Experimental | • Arm 1: neoadjuvant atezolizumab 1200 mg IV q3weeks x 4 cycles, and bevacizumab 15 mg/kg IV q3weeks x 4 cycles Receives: Combination Product: Neoadjuvant |
| Neoadjuvant SBRT | Experimental | • Arm 2: neoadjuvant stereotactic body radiation therapy (SBRT), target volume 30 40 Gy, in 6-8 Gy per day over five days, delivered every other day Receives: Combination Product: Neoadjuvant |
What is being measured
The primary outcome is the main question the study is designed to answer.
Hepatectomy
Proportion of patients who undergo hepatectomy in each arm (number of patients who undergo hepatectomy divided by the number of patients randomized to each arm).
Measured: 17 Weeks
Secondary outcomes (6)
Response rate
Radiological and pathological response rate to neoadjuvant therapy.
Measured: 2 years
Toxicity to SBRT
Toxicity rate related to neoadjuvant SBRT.
Measured: 2 years
Postoperative complications
Postoperative complication rate and mortality
Measured: 90 days post operatively
Survival Progression Free
Progression free survival (PFS).
Measured: 2 years
Survival
Overall survival (OS).
Measured: 2 years
Toxicity to Atezolizumab/Bevacizumab
Toxicity to Atezolizumab/Bevacizumab in the neoadjuvant setting
Measured: 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Nov 2021
- Study start18 Oct 2022
- Primary completion26 Feb 2025
- Study completion26 Feb 2025
Why it stopped: Recruitment challenges, Hoffman La Roche strategic priority shift
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Hepatocellular CarcinomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Neoadjuvant Atezolizumab/Bevacizumab versus neoadjuvant SBRT in patients with biopsy proven solitary HCC with PVTT involving the portal vein branches.
- Masking
- None (open label)
- Enrolment
- 1 participants (actual)
Sponsor and investigators
- Lead sponsor
- Ontario Clinical Oncology Group (OCOG)
- Sponsor type
- University, hospital or other
- Collaborators
- Hoffmann-La Roche
- Responsible party
- Sponsor
- Investigators
- Brandon Meyers, MD, Principal investigator, principle investigatorJim Wright, MD, Study director, OCOG Director
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05137899
- Sponsor's protocol ID
- OCOG-2021-ADVANCE HCC ML42545
- Acronym
- ADVANCE HCC
- Status last verified
- Mar 2025
- First submitted
- 10 Nov 2021
- Last updated
- 11 Mar 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 11 Mar 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Neoadjuvant Combination of Atezolizumab/Bevacizumab Versus Neoadjuvant Radiation Therapy Prior to Hepatectomy in Hepatocellular Carcinoma with Portal Vein Tumour Thrombus (ADVANCE HCC) Hoffmann La Roche Protocol Number: ML42525
- ClinicalTrials.gov ID
- NCT05137899
- Acronym / sponsor ID
- ADVANCE HCC / OCOG-2021-ADVANCE HCC ML42545
- Keywords
- Neoadjuvant Atezolizumab/Bevacizumab, Neoadjuvant Stereotactic Body Radiation Therapy
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Recruitment challenges, Hoffman La Roche strategic priority shift
- Enrolment
- 1 participants (actual)
- Lead sponsor
- Ontario Clinical Oncology Group (OCOG)University, hospital or other
- Collaborators
- Hoffmann-La Roche
- Study start
- 18 Oct 2022 (actual)
- Primary completion
- 26 Feb 2025 (actual)
- Study completion
- 26 Feb 2025 (actual)
- First posted
- 30 Nov 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
A multicentre, parallel group, randomized controlled Phase II clinical trial evaluating neoadjuvant Atezolizumab/Bevacizumab versus neoadjuvant SBRT in patients with biopsy proven solitary HCC with PVTT involving the portal vein branches. Both arms are considered experimental, and as such, a Simon two-stage design will be initially used within both arms. Only if both arms are deemed of interest for further study will a comparison between arms, using a pick-the-winner design, be conducted. Following the completion of neoadjuvant therapy, study participants will undergo a CT scan or MRI to assess tumour response to neoadjuvant therapy. Hepatic resection will be performed for those participants who meet the surgical resection criteria.
Detailed description
Surgical resection without adjuvant therapy is the standard of care for most patients with solitary hepatocellular carcinoma (HCC). The presence of portal vein tumour thrombus (PVTT) is associated with a poor prognosis, and as a result patients usually do not undergo surgery.1 One potential strategy to improve the outcome of patients with HCC and PVTT is to administer treatment to the tumour prior to surgery, i.e. "neoadjuvant" therapy. This strategy has been proven to be effective in other types of cancer, and results in tumour downstaging and potentially eliminates micro-metastatic disease In a recent randomized controlled trial (RCT) in patients with HCC and PVTT, the addition of radiation therapy (RT) to the tumour prior to hepatic surgery was compared with surgery alone.4 There was a statistically significant improvement in survival with RT. Systemic therapy with the tyrosine kinase inhibitor Sorafenib improved survival compared to placebo in patients with advanced HCC and PVTT.5 Another recent trial in patients with advanced HCC demonstrated improved survival with the combination of Atezolizumab, an immune checkpoint inhibitor (ICI), and Bevacizumab, an antibody to vascular endothelial growth factor compared to Sorafenib alone.6
Currently, there is no standard of care for the neoadjuvant treatment of solitary HCC. Radiotherapy has not been widely adopted despite recent evidence suggesting some benefit. It is conceivable that RT will downsize the tumour increasing the surgical resection rate and reducing the shedding of tumour cells. Stereotactic Body Radiation Therapy (SBRT) is a type of RT that provides high dose, focal radiation to tumours using highly precise imaging and treatment fields, with rapid dose fall-off thereby sparing normal tissue. Based on experience in other cancers, it would seem judicious that effective systemic therapy be considered for the neoadjuvant treatment of HCC to downsize the primary tumour and eradicate occult micro-metastases.2,3
We hypothesize that treating patients with HCC and PVTT with either 1) neoadjuvant systemic therapy, or 2) neoadjuvant SBRT may lead to improved hepatic resection rates. Complete hepatic resection is being considered as a surrogate for good long-term outcomes. The aim of our randomized Phase II trial is to select the treatment arm with the most favourable outcomes based on a trade-off between resection rate and toxicity for study in a future trial.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Neoadjuvant Atezolizumab/Bevacizumab versus neoadjuvant SBRT in patients with biopsy proven solitary HCC with PVTT involving the portal vein branches.
| Arm | Type | Receives |
|---|---|---|
| Neoadjuvant Atezolizumab/Bevacizumab | Experimental | Combination Product: Neoadjuvant• Arm 1: neoadjuvant atezolizumab 1200 mg IV q3weeks x 4 cycles, and bevacizumab 15 mg/kg IV q3weeks x 4 cycles |
| Neoadjuvant SBRT | Experimental | Combination Product: Neoadjuvant• Arm 2: neoadjuvant stereotactic body radiation therapy (SBRT), target volume 30 40 Gy, in 6-8 Gy per day over five days, delivered every other day |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Biopsy proven solitary HCC without biliary invasion, or metastases,
- PVTT involving the portal vein branches: Vp1-Vp3 (Japanese Classification for HCC with PVTT, see Appendix II),
- <10 cm maximal diameter on CT or MRI,
- Child-Pugh Class A (see Appendix III), within 14 days prior to randomization. (All parameters without transfusion within 3 months).
- Age > 18 years.
Key exclusion criteria (38 listed)
- Abnormal laboratory parameters (within 14 days of randomization):
- Previous therapy for HCC:
- ECOG performance status > 2 (see Appendix IV).
- Non-healing wound, skin ulcers, or incompletely healed bone fracture.
- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to planned start of study therapy.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| NeoadjuvantNeoadjuvant atezolizumab/bevacizumab or neoadjuvant SBRT prior to hepatectomy | Combination product | Neoadjuvant Atezolizumab/Bevacizumab, Neoadjuvant SBRT |
Primary outcome
Hepatectomy
Time frame: 17 Weeks
Proportion of patients who undergo hepatectomy in each arm (number of patients who undergo hepatectomy divided by the number of patients randomized to each arm).
6 secondary outcomes
Response rate
Time frame: 2 years
Toxicity to SBRT
Time frame: 2 years
Postoperative complications
Time frame: 90 days post operatively
Survival Progression Free
Time frame: 2 years
Survival
Time frame: 2 years
Toxicity to Atezolizumab/Bevacizumab
Time frame: 2 years
Results and safety
The study was stopped early (reason given: Recruitment challenges, Hoffman La Roche strategic priority shift). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Mar 2025.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Brandon Meyers, MD principal investigator
principle investigator
Jim Wright, MD study director
OCOG Director
7 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Neoadjuvant in people with Hepatocellular Carcinoma and Portal Vein Tumour Thrombosis, run by Ontario Clinical Oncology Group (OCOG) at 7 sites in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 38 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 11 Mar 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 7 sites in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Recruitment challenges, Hoffman La Roche strategic priority shift). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Hepatectomy (time frame: 17 Weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Mar 2025.