Stereotactic Body Radiation Therapy and Nivolumab with or without Ipilimumab in Treating Patients with Unresectable Liver Cancer
This phase I trial studies the side effects of stereotactic body radiation therapy and nivolumab with or without ipilimumab in treating patients with liver cancer that cannot be removed by surgery (unresectable). Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method can kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. Monoclonal antibodies, such as nivolumab and ipilimumab, may interfere with the ability of tumor cells to grow and spread. Giving stereotactic body radiation therapy, nivolumab and ipilimumab may work better at treating liver cancer.
Inclusion Criteria
- Be willing and able to provide written informed consent for the trial
- Have Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- Pretreatment computed tomography (CT) chest /abdomen /pelvis within 28 days of protocol enrollment
- Pathologic diagnosis of hepatocellular carcinoma (including fibrolamellar variants and biphenotypic tumors with a hepatocellular carcinoma [HCC] component)
- Child Pugh class A (score = 5 or 6) cirrhosis (assessed within 14 days of SBRT)
- Deemed ineligible for curative intent therapy with surgical resection or liver transplantation
- Patients with diffuse/multifocal liver involvement are eligible
- Patients with extrahepatic disease are eligible
- Prior systemic therapies for HCC are allowed but not required
- Must have at least one intrahepatic lesion amenable to SBRT
- Prior transarterial chemoembolization (TACE) or radiofrequency ablation (RFA) allowed, however, patient must have separate intrahepatic lesion amenable to SBRT and biopsy
- Intrahepatic lesion amenable to pre and post SBRT biopsies, unless the investigator determines that the tumor biopsies would be unsafe
- Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
- Platelets >= 40,000/mcL (performed within 14 days of treatment initiation)
- Serum total bilirubin =< 3 mg/dL (performed within 14 days of treatment initiation)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 X upper limit of normal (ULN) (performed within 14 days of treatment initiation)
- Negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication for female subjects of childbearing age
- Subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 150 days after the last dose of study therapy (for women of child-bearing potential) or 210 days after the last dose of study therapy (for men who have partners of child-bearing potential)
- Have a life expectancy of greater than 6 months (in the opinion of the treating physician)
Exclusion Criteria
- Prior external beam radiation therapy to the liver (defined as > 1 gray [Gy])
- Prior yttrium-90 radioembolization treatment
- Patients with hepatitis B virus (HBV) viral load > 100 IU/mL (antiviral therapy per local practice is required)
- Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy at a dose of > 10 mg prednisone daily or equivalent at time of first dose of trial treatment
- Has a known history of active TB (Bacillus tuberculosis)
- Hypersensitivity to nivolumab or ipilimumab or any of its excipients
- Has had prior anticancer therapy within 4 weeks of study day 1 or has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
- Has a known additional malignancy that is progressing or requires active treatment
- Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment; patients with allografts (including liver transplants) are not eligible for this protocol
- Has known history of, or any evidence of active, non-infectious pneumonitis
- Has an active infection requiring systemic therapy
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
- Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment
- Has received a live vaccine within 30 days of planned start of study therapy * Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT03203304.
PRIMARY OBJECTIVE:
I. Determine the safety and tolerability of stereotactic body radiation therapy (SBRT) followed by nivolumab or ipilimumab with nivolumab for hepatocellular carcinoma by establishing the rates of toxicity that occur within 6 months from start of SBRT.
SECONDARY OBJECTIVES:
I. Estimate the investigator determined best overall response rate.
II. Estimate the rates of long-term adverse events (after 6 months) from the end of SBRT.
III. Summarize the distant disease control, progression-free survival, and overall survival.
IV. Summarize the local control of the SBRT treated lesion.
EXPLORATORY OBJECTIVES:
I. Explore changes in inflammatory biomarkers (including, but not limited to CD8/regulatory T cells [Treg] ratio, total CD4 counts, total lymphocyte count) in pretreatment and on-treatment serially collected peripheral blood samples.
II. Explore changes in the tumor microenvironment induced by radiation on pre and post treatment biopsies.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients undergo SBRT over 5 fractions within 21 days with a minimum of 40 hours between treatments. Beginning up to 14 days of last SBRT, patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Courses repeat every 2 weeks for 24 months or 50 doses in the absence of disease progression or unacceptable toxicity, or 12 months beyond disease progression in the absence of unacceptable toxicity, whichever is later.
ARM II: Patients undergo SBRT as Arm I, and beginning up to 14 days of last SBRT, patients receive nivolumab IV over 30 minutes on day 1 and ipilimumab IV over 30 minutes on day 1. Courses repeat every 2 weeks for nivolumab and every 6 weeks for ipilimumab for 24 months or 50 doses in the absence of disease progression or unacceptable toxicity, or 12 months beyond disease progression in the absence of unacceptable toxicity, whichever is later.
After completion of study treatment, patients are followed up at 30 and 100 days, then every 8 weeks for up to 1 year, then every 12 weeks thereafter.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationUniversity of Chicago Comprehensive Cancer Center
Principal InvestigatorChih-Yi Liao
- Primary IDIRB17-0578
- Secondary IDsNCI-2017-01736
- ClinicalTrials.gov IDNCT03203304