A Phase II Randomized Study of Atezolizumab Plus Multi-Kinase Inhibitor Versus Multi-Kinase Inhibitor Alone in Subjects With Unresectable, Advanced Hepatocellular Carcinoma Who Previously Received Atezolizumab Plus Bevacizumab
Overview
- Phase
- Phase 2
- Intervention
- Atezolizumab
- Conditions
- Locally Advanced Hepatocellular Carcinoma
- Sponsor
- Academic and Community Cancer Research United
- Enrollment
- 122
- Locations
- 16
- Primary Endpoint
- Overall survival (OS)
- Status
- Recruiting
- Last Updated
- 7 months ago
Overview
Brief Summary
This phase II trial tests whether atezolizumab in combination with a multi-kinase inhibitor (cabozantinib or lenvatinib) compared to multi-kinase inhibitor alone in treating patients with liver cancer that cannot be removed by surgery (unresectable), has spread to has spread to nearby tissue or lymph nodes (locally advanced), or has spread to other places in the body (metastatic), for which the patient has received treatment in the past (previously treated). Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Cabozantinib and lenvatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving atezolizumab with cabozantinib or lenvatinib may kill more tumor cells in patients with liver cancer.
Detailed Description
PRIMARY OBJECTIVE: I. To determine the progression-free and overall survival in subjects with advanced hepatocellular carcinoma who previously progressed on atezolizumab/bevacizumab who are treated using atezolizumab plus a multi-kinase inhibitor compared to multi-kinase inhibitor alone. SECONDARY OBJECTIVES: I. To determine the overall response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 response in subjects who are treated using atezolizumab plus a multi-kinase inhibitor compared to multi-kinase inhibitor alone. II. To determine the duration of response in subjects who are treated using atezolizumab plus a multi-kinase inhibitor compared to multi-kinase inhibitor alone. III. To determine the safety profile of adding atezolizumab to multi-kinase inhibitor in subjects who are treated using atezolizumab plus a multi-kinase inhibitor compared to multi-kinase inhibitor alone. EXPLORATORY OBJECTIVE: I. To explore for potential predictive biomarkers for response and resistance to anti-PD-L1 and/or multi-kinase inhibitor therapy in subject population. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: Patients receive atezolizumab intravenously (IV) over 30-60 minutes on day 1 and cabozantinib orally (PO) once daily (QD) or lenvatinib PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive cabozantinib PO QD or lenvatinib PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed-up every 9 weeks for up to 2 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Provide written informed consent =\< 28 days prior to randomization
- •Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study)
- •NOTE: During the Active Monitoring Phase of a study (i.e., active treatment and clinical follow-up), participants must be willing to return to the consenting institution for follow-up
- •Age \>= 18 years
- •Hepatocellular carcinoma (HCC) confirmed by histological/cytological diagnosis or clinically per the American Association for the Study of Liver Diseases (AASLD) or WASL 2018 criteria
- •Locally advanced, metastatic and/or unresectable disease that is not amendable to curative treatment
- •Previously progressed on atezolizumab in combination with bevacizumab as first line systemic therapy for advanced disease
- •NOTE: 2nd line patients only
- •Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1
- •Child Pugh class A
Exclusion Criteria
- •Known diagnosis of fibrolamellar carcinoma, sarcomatoid carcinoma or mixed hepatocellular cholangiocarcinoma
- •Prior multi-kinase inhibitor treatment for advanced disease (e.g., cabozantinib, lenvatinib, sorafenib, regorafenib)
- •NOTE: Use of multi-kinase inhibitor(s) for adjuvant or as part of loco-regional therapies is allowed as long as the therapy was completed \>= 6 months prior to randomization
- •Any of the following prior therapies:
- •Major surgery =\< 4 weeks prior to randomization; Minor surgery =\< 7 days prior to randomization (e.g., simple excision, tooth extraction, insertion of central lines/Mediport). Subjects with clinically relevant complications from prior surgery are not eligible
- •Any anti-cancer agent =\< 2 weeks prior to randomization
- •Radiation therapy =\< 4 weeks (1 week for palliative radiation for bone metastases and/or for pain control) or radionuclide treatment (e.g., I-131 or Y-90) =\< 6 weeks prior to randomization
- •Treatment with investigational therapy =\< 28 days prior to randomization
- •Known brain or leptomeningeal metastasis
- •Known co-infection of HBV and HCV. Subjects with a history of HCV infection but who are negative for HCV ribonucleic acid (RNA) by polymerase chain reaction (PCR) will be considered non-infected with HCV
Arms & Interventions
Arm A (atezolizumab, cabozantinib or lenvatinib)
Patients receive atezolizumab IV over 30-60 minutes on day 1 and cabozantinib PO QD or lenvatinib PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Atezolizumab
Arm A (atezolizumab, cabozantinib or lenvatinib)
Patients receive atezolizumab IV over 30-60 minutes on day 1 and cabozantinib PO QD or lenvatinib PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Cabozantinib
Arm A (atezolizumab, cabozantinib or lenvatinib)
Patients receive atezolizumab IV over 30-60 minutes on day 1 and cabozantinib PO QD or lenvatinib PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Lenvatinib
Arm B (cabozantinib or lenvatinib)
Patients receive cabozantinib PO QD or lenvatinib PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Cabozantinib
Arm B (cabozantinib or lenvatinib)
Patients receive cabozantinib PO QD or lenvatinib PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Lenvatinib
Outcomes
Primary Outcomes
Overall survival (OS)
Time Frame: From randomization to death from any cause, assessed up to 3 years
The final analysis for OS will be conducted when 84 OS events are observed, approximately 36 months after first subject in and will be evaluated with a one-sided p-value from stratified log-rank test.
Progression-free survival (PFS)
Time Frame: From randomization to first documentation of disease progression (per Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) or death, assessed up to 2 years
PFS analysis will be conducted when 89 PFS events are observed. The one-sided p-value from stratified log-rank test will be used for decision making.
Secondary Outcomes
- Duration of response(Up to 2 years)
- Incidence of adverse events (AEs)(Up to 30 days after last dose)
- Objective response rate (ORR)(Up to 2 years)