Testing Immunotherapy With or Without Stereotactic Body Radiation Therapy in Patients With Advanced Liver Cancer, HELIO-RT Trial

This phase III trial compares the effect immunotherapy (IO) with stereotactic body radiation therapy (SBRT) to IO alone in treating patients with liver cancer (hepatocellular cancer) that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). The usual approach is treatment with IO-based drug combinations, such as atezolizumab and bevacizumab, durvalumab and tremelimumab, or ipilimumab and nivolumab. Durvalumab and tremelimumab are monoclonal antibodies that may interfere with the ability of tumor cells to grow and spread. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). IO with monoclonal antibodies, such as atezolizumab, nivolumab and ipilimumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Bevacizumab is in a class of medications called antiangiogenic agents. It works by stopping the formation of blood vessels that bring oxygen and nutrients to tumor. This may slow the growth and spread of tumor cells. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. SBRT is a type of external radiation therapy that uses special equipment to position a patient and precisely deliver radiation to tumors in the body (except the brain). The total dose of radiation is divided into smaller doses given over several days. This type of radiation therapy helps spare normal tissue. Giving IO with SBRT may be more effective than IO alone in helping patients with advanced hepatocellular cancer live longer.

PRIMARY OBJECTIVE:

1. To determine if liver SBRT in combination with IO-based systemic therapy improves survival compared to IO-based systemic therapy alone, in patients with hepatocellular cancer with macrovascular invasion.

SECONDARY OBJECTIVES:

1. To evaluate and compare progression-free survival between treatment arms. II. To evaluate and compare objective response rate between treatment arms. III. To evaluate and compare vascular recanalization between treatment arms. IV. To evaluate and compare biochemical decline in alpha-fetoprotein (AFP) between treatment arms.
2. To evaluate and compare toxicity within and between treatment arms. VI. To evaluate and compare liver decompensation per Child Pugh score between treatment arms.

VII. To evaluate and compare liver decompensation per modified albumin-bilirubin (ALBI) (mALBI) score between treatment arms.

HEALTH-RELATED QUALITY OF LIFE (HRQOL) OBJECTIVES:

1. To compare Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) total score at 6 months between the treatment arms. (Primary) II. To evaluate and compare quality-adjusted survival using European Quality of Life Five Dimension (EQ-5D) between treatment arms. (Secondary) III. To evaluate FACT-Hep total scores over time between the treatment arms. (Exploratory)

EXPLORATORY OBJECTIVES:

1. Biospecimen collection for future correlative analyses.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM 1: Patients receive 1 of 3 IO-based systemic treatments per physicians decision.

TREATMENT A: Patients receive atezolizumab and bevacizumab intravenously (IV) every 3 weeks in the absence of disease progression or unacceptable toxicity.

TREATMENT B: Patients receive tremelimumab IV once and durvalumab IV every 4 weeks in the absence of disease progression or unacceptable toxicity.

TREATMENT C: Patients receive nivolumab and ipilimumab IV every 3 weeks for up to 4 doses followed by nivolumab IV every 4 weeks in the absence of disease progression or unacceptable toxicity.

ARM 2: Patients receive 1 of 3 IO-based systemic treatments per physicians decision.

TREATMENT A: Patients undergo liver SBRT once daily (QD), once every other day (QOD), or twice weekly for 5 fractions over up to 3 weeks. Patients also receive atezolizumab and bevacizumab IV every 3 weeks in the absence of disease progression or unacceptable toxicity.

TREATMENT B: Patients undergo liver SBRT QD, QOD, or twice weekly for 5 fractions over up to 3 weeks. Patients also receive tremelimumab IV once and durvalumab IV every 4 weeks in the absence of disease progression or unacceptable toxicity.

TREATMENT C: Patients undergo liver SBRT QD, QOD, or twice weekly for 5 fractions over up to 3 weeks. Patients receive nivolumab and ipilimumab IV every 3 weeks for up to 4 doses followed by nivolumab IV every 4 weeks in the absence of disease progression or unacceptable toxicity.

Additionally, patients undergo blood sample collection, chest computed tomography (CT) and CT and/or magnetic resonance imaging (MRI) throughout the study and may also undergo positron emission tomography (PET)/CT prior to registration.

After completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 3 years then yearly.