A PHASE III, MULTICENTER, RANDOMIZED, OPEN-LABEL STUDY OF ATEZOLIZUMAB (ANTI-PD-L1 ANTIBODY) PLUS BEVACIZUMAB VERSUS ACTIVE SURVEILLANCE AS ADJUVANT THERAPY IN PATIENTS WITH HEPATOCELLULAR CARCINOMA AT HIGH RISK OF RECURRENCE AFTER SURGICAL RESECTION OR ABLATIO
- Conditions
- carcinomahepatocellular carcinomaliver cancer
- Registration Number
- NL-OMON54966
- Lead Sponsor
- Roche Nederland
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Recruiting
- Sex
- Not specified
- Target Recruitment
- 6
- For the 1st, 2nd, 5th, and 10th patients at each site: Medical Monitor
approval prior to randomization in order to monitor adherence to key
eligibility criteria
- Age >= 18 years
- Participants with a first diagnosis of HCC who have undergone either a
curative resection or ablation within 4-12 weeks of randomization (not
applicable for crossover)
- Documented diagnosis of HCC that has been completely resected or
ablated (not applicable for crossover).
- Absence of major macrovascular (gross vascular) invasion and of the
portal vein (Vp3 or Vp4) or any grade of macrovascular invasion in the
hepatic vein or inferior vena cava (not applicable for crossover)
Note: Patients undergoing resection with minor vascular invasion of the
portal vein (Vp1 or Vp2) as detected by either imaging or pathological
examination are allowed
- Absence of extrahepatic spread as confirmed by CT or MRI scan of the
chest abdomen, pelvis, and head prior to and following curative
procedure
- Full recovery from surgical resection or ablation within 4 weeks prior to
randomization
- High risk for HCC recurrence after resection or ablation
- For patients who received post-operative transarterial
chemoembolization: full recovery from the procedure within 4 weeks
prior to randomization
- For patients with resected HCC, availability of a representative
baseline tumor tissue sample
- Negative HIV test at screening
- Documented virology status of hepatitis, as confirmed by screening
hepatitis B virus (HBV) and hepatitis C virus (HCV) tests
- For patients with active HBV: HBV DNA < 500 IU/mL during
screening, initiation of anti-HBV treatment at least 14 days prior to
randomization and willingness to continue anti-HBV treatment during
the study
- For patients enrolled in the extended China enrollment phase: current
resident of mainland China and of Chinese ancestry
- Performance of an esophagogastroduodenoscopy either before
resection or ablation as part of pre-procedure work-up or during
screening, and assessment and treatment of varices of all sizes per local
standard of care prior to randomization
- Eastern Cooperative Oncology Group Performance Status of 0 or 1
- Child-Pugh Class A status
- Adequate hematologic and end-organ function
- For women of childbearing potential: agreement to remain abstinent
or use contraceptive methods and agreement to refrain from donating
eggs for 5 months after the final dose of atezolizumab and for 6 months after
the final dose of bevacizumab
- For men: agreement to remain abstinent or use a condom, and
agreement to refrain from donating sperm for during the treatment
period and for 6 months after the final dose of bevacizumab to avoid
exposing the embryo
Additional Inclusion Criteria for Crossover for Patients in Arm B
- Documentation of unequivocal recurrence as defined by European
Association for the Study of the Liver Clinical Practice Guidelines or
RECIST v1.1 criteria that is confirmed by the IRF
- For Arm B patients who undergo surgical resection or ablation for
first recurrence: full recovery from surgical resection or ablation within 4
weeks prior to Day 1 of Cycle 1
- Availability of a representative tumor specimen obtained at the time
of recurrence for exploratory biomarker research
- After recurrence assessments are performed by the investigator an
- Known fibrolamellar HCC, sarcomatoid HCC, or mixed
cholangiocarcinoma and HCC
- Recurrent HCC prior to randomization
- Evidence of residual, recurrent, or metastatic disease at
randomization (not applicable for crossover)
- Clinically significant ascites
- History of hepatic encephalopathy
- Prior bleeding event due to untreated or incompletely treated
esophageal and/or gastric varices within 6 months prior to
randomization
- Active or history of autoimmune disease or immune deficiency
- History of idiopathic pulmonary fibrosis, organizing pneumonia, druginduced
pneumonitis, or idiopathic pneumonitis, or evidence of active
pneumonitis on screening chest CT scan
- Significant cardiovascular disease (such as New York Heart
Association Class II or greater cardiac disease, myocardial infarction, or
cerebrovascular accident) within 3 months prior to Day 1 of Cycle 1,
unstable arrhythmia, or unstable angina
- History of malignancy other than HCC within 5 years prior to
screening, with the exception of malignancies with a negligible risk of
metastasis or death, such as adequately treated carcinoma in situ of the
cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal
carcinoma in situ, or Stage I uterine cancer
- Active tuberculosis
- Severe infection within 4 weeks prior to Day 1 of Cycle 1, including,
but not limited to, hospitalization for complications of infection,
bacteremia, or severe pneumonia, or any active infection that in the
opinion of the investigator, could impact patient safety
- Treatment with therapeutic oral or IV antibiotics within 2 weeks prior
to Day 1 of Cycle 1
- 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
- Co-infection with HBV and HCV
- Co-infection with HBV and hepatitis D viral infection
- Clinically significant uncontrolled or symptomatic hypercalcemia
- History of severe allergic anaphylactic reactions to chimeric or
humanized antibodies or fusion proteins
- Known hypersensitivity to Chinese hamster ovary cell products or to
any component of the atezolizumab or bevacizumab formulations
- Any treatment for HCC prior to resection or ablation, including
systemic therapy and locoregional therapy such as TACE
- Treatment with a live, attenuated vaccine within 4 weeks prior to Day
1 of Cycle 1, or anticipation of need for such a vaccine during
atezolizumab treatment or within 5 months after the final dose of
atezolizumab
- Treatment with investigational therapy within 4 weeks prior to Day 1
of Cycle 1
- Prior treatment with CD137 agonists or immune checkpoint blockade
therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic
antibodies
- Treatment with systemic immune stimulatory agents within 4 weeks
or 5 drug elimination half-lives prior to Day 1 of Cycle 1
- Treatment with systemic immunosupp
Study & Design
- Study Type
- Observational invasive
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Primary endpoint:<br /><br>1. RFS</p><br>
- Secondary Outcome Measures
Name Time Method <p>Secundary endpoint<br /><br>1. OS rate at 24 months and 36 months<br /><br>2. OS<br /><br>3. RFS as determined by the investigator<br /><br>4. TTR<br /><br>5. Time to EHS or macrovascular invasion<br /><br>6. RFS after randomization as determined by the investigator and by an IRF,<br /><br>among patients in the PD-L1-high subgroup<br /><br>7. Incidence and severity of adverse events, with severity determined according<br /><br>to NCI CTCAE v5.0<br /><br>8. Change from baseline in targeted vital signs<br /><br>9. Change from baseline in targeted clinical laboratory test results<br /><br>10. Serum concentration of atezolizumab at specified timepoints<br /><br>11. Prevalence of anti-drug antibody (ADAs) to atezolizumab at baseline and<br /><br>incidence of ADAs to atezolizumab during the study</p><br>