Study of Atezolizumab and Bevacizumab With Y-90 TARE in Patients With Unresectable Hepatocellular Carcinoma (HCC)
This is an open-label, multi-center, randomized phase II study comparing the Y90 TARE followed by bevacizumab and atezolizumab treatment to the Y90 TARE treatment alone in unresectable intermediate stage HCC.
- Hepatocellular Carcinoma
- Eligible Ages
- Over 18 Years
- Eligible Genders
- Accepts Healthy Volunteers
- Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately. Patients must be willing and able to provide written informed consent for this trial. 2. Age ≥ 18 years at the time of consent. 3. ECOG Performance Status of 0-1 at screening 4. Histological or cytological evidence/confirmation per AJCC, 8th edition, of hepatocellular carcinoma (HCC). 5. Measurable disease by RECIST 1.1. 6. Patients must have a Child-Pugh score of A. 7. Patients must have at least Barcelona Clinic Liver Cancer (BCLC) stage B HCC and must be outside of downstaging criteria (downstaging criteria are defined as: one lesion > 5 cm and </= 8 cm; two to three lesions each </= 5 cm; four to five lesions </= 3 cm with a total tumor diameter of </= 8 cm); six lesions or more regardless of size; and/or HCC peripheral vascular involvement of any size or number of tumor (segment peripheral, vp1 and vp2 are allowed, but vp3 and vp4 are excluded). NOTE: absence of extrahepatic spread, must be confirmed by computed tomography (CT) or magnetic resonance imaging (MRI) scan of the chest, abdomen, and pelvis 8. Archival tissue obtained within 6 months of registration is required. If archival tissue is not available, subjects are not eligible. 9. Patients must not be suitable for or amenable to transplant or resection. 10. Patients may be treatment naive or have received any number of prior therapies except systemic therapy. No prior systemic therapy is permitted. NOTE: Patients who received prior local therapy (e.g., radiofrequency ablation, percutaneous ethanol or acetic acid injection, cryoablation, high-intensity focused ultrasound) are eligible provided the target lesion(s) have not been previously treated with local therapy or the target lesion(s) within the field of local therapy have subsequently progressed in accordance with RECIST 1.1. Prior TACE IS allowed if FLR is ≥ 40%. 11. Patients must demonstrate adequate hepatic, bone marrow, and renal function as defined in Table below. All screening labs should be performed within 14 days of treatment initiation. - Absolute Neutrophil Count (ANC) ≥ 1,500 /μL - Hemoglobin (Hgb) ≥ 9 g/dL without transfusion or EPO dependency (within 7 days of assessment) - Platelet count (Plt) ≥ 50,000 / μL - Serum creatinine OR Measured or calculated CrCl ≤ 1.5 X upper limit of normal (ULN) OR ≥ 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN - Bilirubin ≤ 3.0 X ULN upper limit of normal (ULN) - Aspartate aminotransferase (AST) ≤ 5 X ULN for subjects with cancer in liver - Alanine aminotransferase (ALT) ≤ 5 X ULN for subjects with cancer in liver - Albumin > 2.5 mg/dL - Urine Protein ≤ 2 g - International Normalized Ratio (INR) or Prothrombin Time (PT) or Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 X ULN unless subject is receiving anticoagulant therapy, in which case PT/aPTT must be within therapeutic range for intended use of anticoagulants 12. Negative HIV test at screening; NOTE: patients with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy, have a CD4 count >/= 200/µL, and have an undetectable viral load. 13. Urine dipstick for proteinuria < 2+ (within 14 days prior to initiation of study treatment) Patients discovered to have >/= 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate <1 g of protein in 24 hours. 14. Documented virology status of hepatitis, as confirmed by screening HBV and HCV serology test : For patients with active hepatitis B virus (HBV): HBV DNA < 500 IU/mL obtained within 28 days prior to initiation of study treatment, 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. 15. Co-infection of HBV and HCV is an exclusion. Patients with a history of HCV infection but who are negative for HCV RNA by PCR will be considered non-infected with HCV. 16. Prior cancer treatment must be completed at least six months prior to registration and the subject must have recovered from all reversible acute toxic effects of the regimen (other than alopecia) to Grade ≤ 1 or baseline. 17. Females of childbearing potential must have a negative serum pregnancy test within 14 days prior to registration. NOTE: Females are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months. 18. Females of childbearing potential must be willing to abstain from heterosexual activity or to use 2 forms of effective methods of contraception from the time of informed consent until 150 days after treatment discontinuation (Arm B). Males of childbearing potential must be willing to abstain from heterosexual activity or to use 2 forms of effective methods of contraception from the time of informed consent until 210 days after treatment discontinuation (Arm B). The timeframe for female and male subjects that randomize to Arm A is from the time of informed consent until 60 days after treatment discontinuation. 19. As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study.
- Have signs of liver failure, e.g. clinically significant ascites, encephalopathy, or variceal bleeding within six months from enrollment. 2. Prior bleeding event due to esophageal and/or gastric varices within 6 months prior to initiation of study treatment. NOTE: Patients must undergo an esophagogastroduodenoscopy (EGD), and all size of varices (small to large) must be assessed and treated per local standard of care prior to enrollment. Patients who have undergone an EGD within 6 months of prior to initiation of study treatment do not need to repeat the procedure. 3. Untreated or incompletely treated esophageal and/or gastric varices with bleeding or high-risk for bleeding. 4. Have evidence of excessive hepatopulmonary shunting (> 20% in 99mTc macro-aggregated albumin scan) or angiographically demonstrable and non-occludable gastrointestinal shunting, precluding from Y-90 treatment). 5. Prior history of TACE or transarterial treatment via hepatic artery. 6. Subject not a TARE candidate, as defined by a lung dose threshold for Y-90 of 30Gy and an estimated (future liver remnants) FLR of < 40% at the time of forming the comprehensive treatment plan. 7. Inadequately 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. NOTE: Anti-hypertensive therapy to achieve these parameters is allowable. 8. Prior history of hypertensive crisis or hypertensive encephalopathy. 9. 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 initiation of study treatment, unstable arrhythmia, or unstable angina. 10. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC. 11. Major surgery within 4 weeks prior to registration or anticipation of a major surgical procedure during study. 12. Have had prior transplant of any kind. 13. Have active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Have history of idiopathic pulmonary fibrosis (including bronchiolitis obliterans with organizing pneumonia) or evidence of active pneumonitis on screening chest CT scan. 14. Have untreated central nervous system (CNS) metastatic disease (including spinal cord and leptomeningeal disease). NOTE: Subjects with previously treated CNS metastases that are radiographically and neurologically stable for at least 6 weeks and do not require corticosteroids (of any dose) for symptomatic management are permitted to enroll. 15. Have unresolved toxicities from prior anticancer therapy, defined as having not resolved to National Cancer Institute (NCI) CTCAE v5 grade 0 or 1 with the exception of alopecia and laboratory values listed per the inclusion criteria. NOTE: Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by any of the investigational products may be included (e.g., hearing loss) after consultation with the sponsor-investigator. 16. Diagnosed or treated for malignancy other than HCC, unless they meet one of the following exceptions: - Malignancy treated with curative intent and with no known active disease present for ≥ 2 years before registration and felt to be at low risk for recurrence by the treating physician. - Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. - Adequately treated cervical carcinoma in situ without evidence of disease. 17. Have a known or suspected allergy to bevacizumab or atezolizumab or known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab or bevacizumab formulation. 18. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to initiation of study treatment. 19. History of hemoptysis (≥ 2.5 mL of bright red blood per episode) within 1 month prior to initiation of study treatment. 20. Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation). 21. Current or recent (within 10 days of first dose of study treatment) use of aspirin (≥ 325 mg/day) or treatment with dipyramidole, ticlopidine, clopidogrel, and cilostazol. 22. Current or recent (within 10 days prior to study treatment start) use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to prophylactic) purpose. NOTE: Prophylactic anticoagulation for the patency of venous access devices is allowed provided the activity of the agent results in an INR < 1.5 x ULN and aPTT is within normal limits within 14 days prior to initiation of study treatment. 23. Have an uncontrolled intercurrent illness including, but not limited to any of the following: - Psychiatric illness/social situations that would limit compliance with study requirements - Have any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications. - Active alcohol use, drug use, or a psychiatric disease that would, in the opinion of the sponsor-investigator or a sub-investigator (sub-I), prevent the subject from complying with the study protocol and/or endanger the subject during their participation in the study. 24. 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. NOTE: Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study. 25. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study). 26. ave received a live vaccine within 30 days of the planned start of study therapy. NOTE: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed. 27. Have received or are receiving any investigational therapy within 28 days prior to the first dose of bevacizumab and atezolizumab. NOTE: Subjects may be enrolled in an observational (non-interventional) clinical study or in the follow-up period of an interventional study.
- Phase 2
- Study Type
- Intervention Model
- Parallel Assignment
- Primary Purpose
- None (Open Label)
|TARE then Bevacizumab and Atezolizumab||
- Aiwu Ruth He, MD
Study ContactAiwu R He, MD, PhD
Subjects will be randomized to Y-90 TARE alone (Arm A) or Y-90 TARE followed by the combination of atezolizumab and bevacizumab (Arm B). The first 10 subjects randomized to Arm B (Y-90 TARE + bevacizumab + atezolizumab) will be assessed for safety after two cycles. If there are no Grade ≥ 3 unexpected toxicities; possibly, probably or definitely related to TARE in combination with bevacizumab and atezolizumab the combination will be deemed safe and accrual will continue. Subjects randomized to receive bevacizumab and atezolizumab (Arm B) will start the combination of bevacizumab and atezolizumab 4 weeks (± 1 week) after TARE treatment. Full recovery from the procedure is required prior to systemic treatment: - AST and ALT ≤ 5 x upper limit of normal (ULN) and total bilirubin ≤ 3 mg/dL - Manifestations of post-embolization syndrome (e.g., fever, nausea, vomiting, and abdominal pain) have resolved to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 Grade 1 - No significant medical events (e.g., gastrointestinal [GI] bleeding, cardiac events, hepatorenal syndrome) during or after the TARE procedure. These subjects will continue the study drugs for a total of 24 months from the TARE treatment, until intolerable toxicity or disease progression occur.