Atezolizumab Plus Bevacizumab for Patients With Advanced Hepatocellular Carcinoma (HCC) and Chronic Hepatitis B Virus (HBV) Infection
Overview
- Phase
- Not Applicable
- Intervention
- Bevacizumab
- Conditions
- Carcinoma, Hepatocellular
- Sponsor
- National Health Research Institutes, Taiwan
- Enrollment
- 51
- Locations
- 8
- Primary Endpoint
- Best overall response rate
- Status
- Active, not recruiting
- Last Updated
- 23 days ago
Overview
Brief Summary
This is a single-arm clinical trial. The main objective is to determine the efficacy of atezolizumab+bevacizumab therapy in patients with advanced hepatocellular carcinoma and with chronic hepatitis B virus infection. All eligible patients will receive atezolizumab + bevacizumab therapy.
Detailed Description
Combination of atezolizumab, an immune checkpoint inhibitors (ICI), and bevacizumab, an anti-angiogenic antibody, has shown promising anti-tumor activity and good safety profile in patients with advanced hepatocellular carcinoma (HCC) and good liver function reserves (Child-Pugh class A). Currently all trials of ICI-based therapy for HCC enrolled only patients with very low HBV viral loads if they had chronic HBV infection because of the concern of the risk of HBV reactivation on the severity and management of liver-related adverse events, particularly immune-related hepatitis. The investigators hypothesize that in patients with advanced HCC, chronic HBV infection, and adequate liver function reserves, the safety profile of ICI-based therapy should be similar to those in other patient populations as long as prophylactic anti-HBV treatment is given, regardless the baseline HBV viral load. This is because in patients with patients with lymphoma and chronic HBV infection, who have the highest risk of HBV reactivation after cytotoxic or immunosuppressive therapy, no HBV-related complications of clinical significance were noted as long as prophylactic anti-HBV treatment started before the administration of cytotoxic or immunosuppressive therapy. This is a single-arm clinical trial. Key eligibility criteria will include the following: histologically proven, locally advanced or metastatic and/or unresectable HCC that is not amenable to curative surgical and/or locoregional therapies; no prior systemic therapy for HCC; documented chronic HBV infection with HBV DNA \> 2000 IU/mL obtained within 28 days prior to initiation of study treatment; at least one measurable (per RECIST 1.1) lesion; ECOG Performance Status of 0 or 1; and Child-Pugh class A. All eligible patients will receive atezolizumab 1200 mg IV plus bevacizumab 15 mg/kg IV on day 1 every 3 weeks. Study treatment will continue until documented tumor progression or occurrence of unacceptable toxicity. All eligible subjects will receive anti-HBV treatment (per local standard of care; e.g., entecavir) prior to start of study treatment and continue anti-HBV treatment for the length of the study. The primary endpoint is overall response rate defined as a complete or partial response, as determined by the investigator according to RECIST v1.1. The secondary endpoints will include safety measures (e.g., the proportion of subjects with ≥ grade 3 liver-related adverse events (AE) (according to NCI CTCAE v5.0), incidence and severity of all adverse events/ immune-related adverse events, incidence of HBV reactivation/ HBV-related hepatitis flare) and efficacy measures (e.g., objective response rate, progression-free survival, duration of response, and overall survival). This study plan to enroll 48 evaluable subjects, defined as subjects who receive 3 cycles of study treatment and the first image evaluation for tumor response. The estimated time of enrollment will be 2 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Age ≥ 20 years, according to local regulation in Taiwan, at time of signing Informed Consent Form.
- •Locally advanced or metastatic and/or unresectable HCC with diagnosis confirmed by histology.
- •Agreement to receive a mandatory tumor biopsy for enrollment into this study.
- •Disease that is not amenable to curative surgical and/or locoregional therapies, or progressive disease after surgical and /or locoregional therapies.
- •No prior systemic therapy (including systemic investigational agents) for HCC.
- •Documented chronic HBV infection, defined by positive serum surface antigen (HBsAg), and HBV DNA \> 2000 IU/mL obtained within 28 days prior to initiation of study treatment.
- •Agreement to receive anti-HBV treatment (per local standard of care; e.g., entecavir)
- •1 to 2 weeks prior to study entry and willingness to continue treatment for the length of the study.
- •At least one measurable (per RECIST 1.1) lesion. Patients who received prior local therapy (e.g., radiofrequency ablation or transarterial chemoembolization, etc.) 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 version 1.
- •ECOG Performance Status of 0 or 1 within 7 days prior to registration.
Exclusion Criteria
- •Histological diagnosis of fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
- •Imaging finding for HCC corresponding to any of the following:
- •o Clear invasion into the bile duct
- •Co-infection of HBV and HCV. Patients with a history of HCV infection but who are negative for HCV RNA by PCR will be considered non-infected with HCV.
- •Known human immunodeficiency virus (HIV) infection.
- •History of esophageal/gastric varices or active peptic ulcers that are considered to have high risk of bleeding.
- •History of upper gastrointestinal bleeding within 1 year.
- •Major systemic diseases that the investigator considers inappropriate for participation.
- •History of severe allergic anaphylactic reactions to antibodies or fusion proteins
- •Prior allogeneic stem cell or solid organ transplantation.
Arms & Interventions
Atezolizumab plus bevacizumab
Atezolizumab 1200 mg IV plus bevacizumab 15 mg/kg IV on day 1 every 3 weeks. Study treatment will continue until documented tumor progression or occurrence of unacceptable toxicity.
Intervention: Bevacizumab
Atezolizumab plus bevacizumab
Atezolizumab 1200 mg IV plus bevacizumab 15 mg/kg IV on day 1 every 3 weeks. Study treatment will continue until documented tumor progression or occurrence of unacceptable toxicity.
Intervention: Atezolizumab
Outcomes
Primary Outcomes
Best overall response rate
Time Frame: The last patient in has been treated for 6 months. All patients who have a PR or CR before that are responders
Complete or partial response, as determined by the investigator according to RECIST v1.1
Secondary Outcomes
- Overall survival(The time from registration to death from any cause assessed up to 100 months)
- Proportion of subjects with ≥ grade 3 liver-related adverse events (AE)(12 weeks after the first drug administration.)
- AFP response(9 weeks ± 1 week after the first drug administration)
- Incidence and severity of total AE, liver related AE, and liver immune-related AE(30 days after the last dose of study treatment or until initiation of new systemic anti-cancer therapy, whichever occurs first)
- HBV reactivation(Baseline up to approximately 2.5years.)
- HBV-related hepatitis flare(Every 4 weeks for 6 months in permanent discontinuation of study drug treatment)
- Progression-free survival(The time from registration to the first occurrence of disease progression or death from any cause (whichever occurs first assessed up to 100 months))
- Time to tumor progression(The time from registration to the first occurrence of disease progression assessed up to 100 months)
- Duration of response(The time from the first occurrence of a documented objective response to disease progression or death from any cause (whichever occurs first assessed up to 100 months))
- Disease stabilization rate(Complete response + partial response + stable disease lasting for ≧16 weeks approximately1years.)