Clinical trial NCT05137899: Neoadjuvant Combination of Atezolizumab/Bevacizumab Versus Neoadjuvant Radiation Therapy
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Hepatocellular Carcinoma
Portal Vein Tumour Thrombosis
Keywords: Neoadjuvant Atezolizumab/Bevacizumab
Neoadjuvant Stereotactic Body Radiation Therapy
Lead sponsor: Ontario Clinical Oncology Group (OCOG)
Sponsor class: OTHER
Collaborators: name: Hoffmann-La Roche
First posted: 2021-11-30
Enrollment: 1
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Neoadjuvant Atezolizumab/Bevacizumab versus neoadjuvant SBRT in patients with biopsy proven solitary HCC with PVTT involving the portal vein branches.
Primary purpose: TREATMENT

Brief 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. 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.

Eligibility criteria: Inclusion Criteria:

1. Biopsy proven solitary HCC without biliary invasion, or metastases,
2. PVTT involving the portal vein branches: Vp1-Vp3 (Japanese Classification for HCC with PVTT, see Appendix II),
3. \<10 cm maximal diameter on CT or MRI,
4. Child-Pugh Class A (see Appendix III), within 14 days prior to randomization. (All parameters without transfusion within 3 months).
5. Age \> 18 years.

Exclusion Criteria:

1. Abnormal laboratory parameters (within 14 days of randomization):

   1. Hemoglobin \< 90 g/L
   2. Platelet count \< 75 x 109/L without transfusion
   3. INR \>1.25
   4. Serum creatinine \> 1.5 x ULN
   5. Urine dipstick for proteinuria \> 2 (unless a 24-hour urine collection demonstrates \< 1.5 g of protein in 24 hours.
2. Previous therapy for HCC:

   1. Systemic therapy, surgery or radiation therapy,
   2. Local therapy to the liver (e.g., ablation or embolization) within 28 days prior to randomization.
3. ECOG performance status \> 2 (see Appendix IV).
4. Non-healing wound, skin ulcers, or incompletely healed bone fracture.
5. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to planned start of study therapy.
6. 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).
7. History of GI perforation, abdominal fistulae, or intra-abdominal abscess.
8. Significant cardiovascular disease:

   1. New York Heart Association cardiac disease (Class II or greater),
   2. Myocardial infarction, unstable angina or cerebrovascular accident within past 3 months,
   3. Unstable arrhythmia,
   4. 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,
   5. Aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis within 6 months prior to randomization
9. 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).
10. 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.
11. 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.
12. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis.
13. Active tuberculosis.
14. Prior allogeneic stem cell or solid organ transplantation.
15. 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.
16. Recent administration of live vaccine.
17. 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.
18. Treatment with strong CYP3A4 inducers within 14 days prior to randomization.
19. 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.
20. 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.
21. Recent history (within 4 weeks) of hemoptysis.
22. History of TIA, CVA, or any arterial thrombotic event within 12 months before randomization.
23. Sensory/motor neuropathy greater than or equal to grade 2, as defined by the NCI CTCAE and history of hypomagnesemia.
24. Known severe allergic reaction to contrast (e.g., anaphylaxis).
25. Pregnancy or lactating women.
26. Inability to provide informed consent.

Primary outcomes:
measure: Hepatectomy
timeFrame: 17 Weeks
Secondary outcomes:
measure: Response rate
timeFrame: 2 years
measure: Toxicity to SBRT
timeFrame: 2 years
measure: Postoperative complications
timeFrame: 90 days post operatively
measure: Survival Progression Free
timeFrame: 2 years
measure: Survival
timeFrame: 2 years
measure: Toxicity to Atezolizumab/Bevacizumab
timeFrame: 2 years
Other outcomes:
Locations:
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre
state: Alberta
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Hamilton
country: Canada
facility: Juravinski Cancer Centre
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Regional Cancer Centre
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
state: Ontario
city: Montreal
country: Canada
facility: 8. Centre the recherche du Centre hospitalier de l'Université de Montréal - CHUM
state: Quebec
city: Montréal
country: Canada
facility: McGill Cedars Cancer Centre
state: Quebec
Study officials:
affiliation: principle investigator
name: Brandon Meyers, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: OCOG Director
name: Jim Wright, MD
role: STUDY_DIRECTOR
References: