Testing Immunotherapy With or Without Stereotactic Body Radiation Therapy in Patients With Advanced Liver Cancer, HELIO-RT Trial
Purpose
This phase III trial compares the effect of 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. IO with monoclonal antibodies, such as durvalumab, tremelimumab, 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.
Conditions
- Advanced Hepatocellular Carcinoma
- Stage III Hepatocellular Carcinoma AJCC v8
- Stage IV Hepatocellular Carcinoma AJCC v8
Eligibility
- Eligible Ages
- Over 18 Years
- Eligible Sex
- All
- Accepts Healthy Volunteers
- No
Criteria
Inclusion Criteria:
- PRIOR TO STEP 1 REGISTRATION:
- Diagnosis of hepatocellular carcinoma (HCC) by at least 1 criterion listed below:
- Pathologically (histologically or cytologically) proven diagnosis of HCC
(strongly recommended)
- Radiographically proven (American Association for the Study of Liver Diseases
[AASLD] criteria) diagnosis of HCC by multiphasic MRI and/or CT scan is
allowed.
- For patients with a prior or concurrent malignancy, pathologic confirmation of
hepatocellular cancer is required.
- HCC macrovascular invasion, defined as enhancing vascular thrombosis demonstrating
arterial enhancement and venous or delayed venous washout on multiphasic MRI and/or
CT is required.
- Presence of extrahepatic metastatic disease on CT chest and CT or MRI pelvis, or
PET/CT chest/abdomen/pelvis is permitted.
- 5 or fewer discrete intrahepatic parenchymal foci of HCC.
- Total maximal sum of hepatocellular carcinoma tumors, as a single conglomerate,
multiple lesions, or infiltrative HCC < 20 cm in total summed diameter.
- No direct primary tumor extension into the stomach, duodenum, small bowel, or large
bowel.
- No known fibrolamellar HCC, sarcomatoid HCC, or biphenotypic HCC.
- Child-Pugh class A or B7 liver function.
- Age ≥ 18.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
- Not pregnant and not nursing
- Negative urine or serum pregnancy test (in persons of childbearing potential)
within 30 days prior to registration. Childbearing potential is defined as any
person who has experienced menarche and who has not undergone surgical
sterilization (hysterectomy or bilateral oophorectomy) or who is not
postmenopausal.
- Absolute neutrophil count (ANC) ≥ 1,500 cells/mm^3.
- Platelets ≥ 60,000 cells/mm^3.
- Hemoglobin ≥ 8g/dl (Note: The use of transfusion or other intervention to achieve
hemoglobin [Hgb] ≥ 8g/dl is acceptable).
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 6 x
institutional upper limit of normal (ULN).
- Total bilirubin < 4 x institutional ULN.
- Creatinine clearance (CrCL) ≥ 30 mL/min/1.73 m^2 by the Cockcroft-Gault formula.
- For treatment of HCC:
- Prior surgical resection, transarterial chemoembolization (TACE), and ablation
are permitted.
- No prior systemic therapy or transarterial radioembolization (TARE) for HCC.
- No history of liver transplantation.
- For prior treatment for any malignancy:
- Prior systemic therapy for a different cancer is allowable, except for prior
immunotherapy.
- No prior radiotherapy to the region of the study cancer that would result in
significant overlap of radiation therapy fields that would lead to excessive
cumulative toxicity at the discretion of the investigator.
- No medical contraindication to the standard of care immunotherapy.
- For patients to be treated with atezolizumab/bevacizumab:
- No history of a gastrointestinal (GI) bleed or other clinically significant
bleeding event within 6 months prior to study registration.
- Systemic immunostimulatory agents (including, but not limited to, interferons and
interleukin-2 [IL-2]) are prohibited within 4 weeks or five drug elimination
half-lives (whichever is longer) prior to registration and during the study period.
- No history of allergic reaction to the systemic therapy agent(s), compounds of
similar chemical or biologic composition to the systemic therapy agent(s) (or any of
its excipients).
- PRIOR TO STEP 2 RANDOMIZATION:
- Obtain confirmation of payment coverage (insurance or other) for both possible
treatment arms.
Study Design
- Phase
- Phase 3
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel Assignment
- Primary Purpose
- Treatment
- Masking
- None (Open Label)
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
|
Active Comparator Arm 1 (IO-based systemic therapy alone [Treatment A/B/C]) |
Treatment A: Patients receive atezolizumab and bevacizumab 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. Additionally, patients undergo blood sample collection, chest CT and CT and/or MRI throughout the study and may also undergo PET/CT prior to registration. |
|
|
Experimental Arm 2 (SBRT + IO-based systemic therapy [Treatment A/B/C]) |
Patients undergo liver SBRT QD, QOD, or twice weekly for 5 fractions over up to 3 weeks in addition to one of the treatment regimens described below. Treatment A: Patients receive atezolizumab and bevacizumab 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. Additionally, patients undergo blood sample collection, chest CT and CT and/or MRI throughout the study and may also undergo PET/CT prior to registration. |
|
Recruiting Locations
Berkeley, California 94704
Cameron Park, California 95682
Fremont, California 94538
Irvine, California 92612
Mountain View, California 94040
Orange, California 92868
Palo Alto, California 94301
Roseville, California 95661
Roseville, California 95661
Sacramento, California 95816
Sacramento, California 95817
Site Public Contact
916-734-3089
San Francisco, California 94115
Santa Rosa, California 95403
Sunnyvale, California 94086
Fort Collins, Colorado 80524
Site Public Contact
970-297-6150
Fort Collins, Colorado 80528
Grand Junction, Colorado 81501
Greeley, Colorado 80631
Loveland, Colorado 80538
Site Public Contact
970-203-7083
Derby, Connecticut 06418
Fairfield, Connecticut 06824
Glastonbury, Connecticut 06033
Greenwich, Connecticut 06830
Guilford, Connecticut 06437
Hamden, Connecticut 06518
Hartford, Connecticut 06105
New Haven, Connecticut 06510
New Haven, Connecticut 06520
North Haven, Connecticut 06473
Stamford, Connecticut 06902
Torrington, Connecticut 06790
Trumbull, Connecticut 06611
Waterbury, Connecticut 06708
Waterford, Connecticut 06385
Atlanta, Georgia 30303
Site Public Contact
404-778-1868
Atlanta, Georgia 30308
Atlanta, Georgia 30308
Site Public Contact
888-946-7447
Atlanta, Georgia 30322
Site Public Contact
404-778-1868
Atlanta, Georgia 30342
Site Public Contact
404-851-7115
Chicago, Illinois 60637
New Lenox, Illinois 60451
Orland Park, Illinois 60462
Shiloh, Illinois 62269
Crown Point, Indiana 46307
Ankeny, Iowa 50023
Site Public Contact
515-241-3305
Clive, Iowa 50325
Site Public Contact
515-241-3305
Clive, Iowa 50325
Site Public Contact
515-241-3305
Creston, Iowa 50801
Site Public Contact
515-241-3305
Des Moines, Iowa 50309
Site Public Contact
515-241-6727
Des Moines, Iowa 50309
Site Public Contact
515-241-3305
Des Moines, Iowa 50314
Site Public Contact
515-241-3305
Des Moines, Iowa 50314
Site Public Contact
515-241-3305
Waukee, Iowa 50263
Site Public Contact
515-241-3305
West Des Moines, Iowa 50266
Site Public Contact
515-241-3305
West Des Moines, Iowa 50266
Site Public Contact
515-875-9815
Lexington, Kentucky 40536
Site Public Contact
859-257-3379
Brownstown, Michigan 48183
Dearborn, Michigan 48126
Detroit, Michigan 48202
Jackson, Michigan 49201
Novi, Michigan 48377
West Bloomfield, Michigan 48322
Brainerd, Minnesota 56401
Deer River, Minnesota 56636
Duluth, Minnesota 55805
Duluth, Minnesota 55805
Duluth, Minnesota 55805
Hibbing, Minnesota 55746
Site Public Contact
218-786-3308
Sandstone, Minnesota 55072
Virginia, Minnesota 55792
City of Saint Peters, Missouri 63376
Creve Coeur, Missouri 63141
St Louis, Missouri 63110
St Louis, Missouri 63129
St Louis, Missouri 63136
Albuquerque, New Mexico 87106
New York, New York 10029
The Bronx, New York 10461
The Bronx, New York 10467
Columbus, Ohio 43210
Clackamas, Oregon 97015
Newberg, Oregon 97132
Oregon City, Oregon 97045
Portland, Oregon 97213
Portland, Oregon 97225
Danville, Pennsylvania 17822
Lewisburg, Pennsylvania 17837
Wilkes-Barre, Pennsylvania 18711
Alexandria, Virginia 22304
Fairfax, Virginia 22031
Fairfax, Virginia 22033
Falls Church, Virginia 22042
Leesburg, Virginia 20176
Ashland, Wisconsin 54806
Ashland, Wisconsin 54806
Eau Claire, Wisconsin 54701
Hayward, Wisconsin 54843
Marshfield, Wisconsin 54449
Mukwonago, Wisconsin 53149
Oconomowoc, Wisconsin 53066
Site Public Contact
262-928-7878
Rice Lake, Wisconsin 54868
Spooner, Wisconsin 54801
Stevens Point, Wisconsin 54482
Superior, Wisconsin 54880
Site Public Contact
701-364-6272
Waukesha, Wisconsin 53188
Weston, Wisconsin 54476
More Details
- Status
- Recruiting
- Sponsor
- NRG Oncology
Study Contact
Detailed Description
PRIMARY OBJECTIVE: I. 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: I. 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. V. 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: I. Primary: To compare Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) total score at 6 months between the treatment arms. II. Secondary: To evaluate and compare quality-adjusted survival using European Quality of Life Five Dimension (EQ-5D) between treatment arms. (Will be done if the overall survival primary endpoint is met and/or if EQ-5D significantly differs between treatment arms.) III. Exploratory: To evaluate FACT-Hep total scores over time between the treatment arms. EXPLORATORY OBJECTIVES: I. 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 physician's 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 physician's 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 also 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.