Phase IB Study of Atezolizumab and Bevacizumab With SBRT for Unresectable Hepatocellular Carcinoma
This research study is evaluating the safety and tolerability of the drugs atezolizumab and bevacizumab with stereotactic body radiation therapy (SBRT) for treating unresectable hepatocellular carcinoma. This study involves the following interventions: * Atezolizumab * Bevacizumab * Stereotactic body radiation therapy (SBRT)
• Participants must have diagnosis of hepatocellular carcinoma (HCC) that is deemed unsuitable for surgical resection, transplant, or radiofrequency ablation (RFA). Participants may have up to 5 lesions with a total maximal tumor dimension of \< 20 cm, and no one lesion \> 15 cm. Diagnosis may be confirmed by at least 1 criteria listed below:
‣ Histologically or cytologically proven diagnosis of HCC within 180 days prior to study registration.
⁃ At least 1 solid liver lesion or vascular tumor thrombus (involving portal vein, IVC, and/or hepatic vein) \> 1 cm with arterial enhancement and delayed washout on multiphasic CT or MRI. Radiologic imaging evaluation must occur within 28 days prior to study registration.
⁃ Enhancing vascular thrombosis demonstrating arterial enhancement and delayed washout of multiphasic MRI. Radiologic imaging evaluation must occur within 30 days prior to study registration.
• Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥20 mm (≥2 cm) by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam. See Section 12 (Measurement of Effect) for the evaluation of measurable disease.
• Small volume extrahepatic disease permitted, defined as \<2.0 cm in sum of maximal diameters (e.g. presence of one 1.8 cm metastatic lymph node, or two 0.8 cm lung lesions are allowed). Bony lesions are included in the \<2.0 cm of extrahepatic disease. Note that benign periportal lymphadenopathy is not unusual in the presence of hepatitis and is permitted, even if the sum of enlarged nodes is \> 2.0 cm. Radiologic imaging of chest, abdomen, and pelvis via CT or MRI is required within 28 days prior to study registration. CT with contrast is required unless contrast is contraindicated.
• Participants may have received transarterial chemoembolization (TACE) or drug eluting beads (DEB). A 2 week (14 day) washout period is required prior to initiating study treatment.
• Age ≥18 years at the time of signing informed consent document.
• ECOG performance status 0-1.
• Child-Pugh A liver function within 7 days of study registration.
• Barcelona Clinic Liver Cancer (BCLC) stages Intermediate (B) or Advanced (C) within 7 days of study registration.
• No evidence of significant portal hypertension.
• Participants must have adequate organ and marrow function as defined the following laboratory results, obtained within 7 days prior to study registration:
‣ absolute neutrophil count ≥1,500/mcL
⁃ absolute lymphocyte count ≥500/mcL
⁃ platelets ≥75,000/mcL without transfusion
⁃ hemoglobin ≥9 g/dL, transfusion allowed to meet this criterion
⁃ total bilirubin ≤ 3 × institutional upper limit of normal (ULN)
⁃ AST(SGOT)/ALT(SGPT) ≤5 × institutional ULN
⁃ alkaline phosphatase(ALP) \<2 × institutional ULN
⁃ creatinine ≤ 1.5 × institutional ULN OR
⁃ estimated creatinine clearance ≥50 mL/min/1.73 m2 (according to the Cockcroft-Gault formula)
⁃ serum albumin ≥2.8 g/dL
⁃ INR or aPTT ≤2 × institutional ULN for participants not receiving therapeutic anticoagulation
⁃ Urine dipstick for proteinuria \<2+; participants discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate \<1g of protein in 24 hours.
• Resolution of any acute, clinically significant treatment-related toxicity from prior therapy to Grade ≤ 1 prior to study entry, with the exception of alopecia.
• No known HIV infection.
• Documented virology status of hepatitis B virus (HBV), as confirmed by screening HBV serology test within 28 days prior to study registration.
‣ For participants with evidence of chronic HBV infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
⁃ For participants with active 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.
• Documented virology status of hepatitis C virus (HCV), as confirmed by screening HCV serology test within 28 days prior to study registration.
• Women of childbearing potential (WOCBP) must agree to use appropriate method(s) of contraception to avoid pregnancy during the treatment period and for at least 5 months after the last dose of Atezolizumab or 6 months after the last dose of Bevacizumab. A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy).
• WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 14 days prior to study registration.
• Women must not be breastfeeding.
• Men who are sexually active with WOCBP must agree to use any contraceptive method with a failure rate of less than 1% per year during the treatment period and for 6 months after the last dose of Bevacizumab. Men must refrain from donating sperm during this same period.
• Ability to understand and the willingness to sign a written informed consent document