Nivolumab and Ipilimumab for the Treatment of Relapsed or Refractory Pediatric Liver Cancer

Inclusion Criteria

• Patients must be < 30 years of age at the time of study enrollment
• Patients must have relapsed/refractory, histologically confirmed HCC, FLC or HCN NOS to be eligible for enrollment
• Participants must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) measured at >= 20 mm with conventional technique or >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
• Karnofsky performance status >= 60% for patients >= 16 years of age or Lansky >= 60% for patients < 16 years of age
• Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy
• Peripheral absolute neutrophil count (ANC) >= 750/uL
• Platelet count >= 75,000/uL (can be transfused)
• Total bilirubin < 1.5 x institutional upper limit of normal (ULN) * If liver function studies are more elevated than the thresholds above, and if this elevation is felt secondary to tumor, patients may still be eligible for enrollment after discussion with the study principle investigator (PI)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) =< 2.5 x ULN * If liver function studies are more elevated than the thresholds above, and if this elevation is felt secondary to tumor, patients may still be eligible for enrollment after discussion with the Sponsor-Investigator
• Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN * If liver function studies are more elevated than the thresholds above, and if this elevation is felt secondary to tumor, patients may still be eligible for enrollment after discussion with the Sponsor-Investigator
• A serum creatinine based on age/gender as follows OR creatinine clearance >= 60 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal: * Age: 1 to < 2 years; Maximum serum creatinine (mg/dL): 0.6 (male); 0.6 (female) * Age: 2 to < 6 years; Maximum serum creatinine (mg/dL): 0.8 (male); 0.8 (female) * Age: 6 to < 10 years; Maximum serum creatinine (mg/dL): 1.0 (male); 1.0 (female) * Age: 10 to < 13 years; Maximum serum creatinine (mg/dL): 1.2 (male); 1.2 (female) * Age: 13 to < 16 years; Maximum serum creatinine (mg/dL): 1.5 (male); 1.4 (female) * Age: >= 16 years; Maximum serum creatinine (mg/dL): 1.7 (male); 1.4 (female)
• Amylase =< 1.5 x ULN
• Lipase =< 1.5 x ULN
• If amylase/lipase studies are stably elevated above the thresholds above, and if this elevation is felt secondary to tumor, patients may still be eligible for enrollment after discussion with the Sponsor-Investigator
• Thyroid-stimulating hormone (TSH) =< 1.5 ULN. Patients can be receiving thyroid supplementation
• Confirmation of insurance pre-authorization approval for nivolumab and ipilimumab OR record of assistance program approvals or a signed waiver
• Patients, their parent, and/or legally authorized representative must be able to understand and be willing to sign a written informed consent document. Assent for participants < 18 years will follow institutional guidelines. The protocol will require approval by each institution’s Institutional Review Board
• The effects of nivolumab and ipilimumab on the developing human fetus are unknown. For this reason, patients of child-bearing and child-fathering potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 4 months after completion of treatment. Should a female become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Males treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of treatment
• Women of child bearing potential (WOCBP) must have a negative serum or urine pregnancy test within 24 hours of each treatment
• Confirmation that tumor tissue is available for submission to the central laboratory (Dana-Farber Cancer Institute). If surgery was performed at the time of recurrence, this sample, in addition to a diagnostic sample should be submitted. If no re-operation was performed, archived tissue from diagnosis or the most recent procedure should be submitted

Exclusion Criteria

• Patients must not have received standard or targeted treatment regimens within 14 days of initiation of treatment
• Patients must not have received prior radiotherapy within 7 days of initiation of treatment. Patients who have experienced radiation-induced adverse events must recover to a grade 1 prior to enrollment
• Participants who are receiving any other investigational agents are not eligible
• Participants who have received prior PD-1 or PD-1 blockade are eligible including patients who enrolled on Cohort 1. Prior receipt of CTLA-4 inhibition in concert with PD-1/PD-L1 blockade renders a patient ineligible
• Participants who have received antibody-based therapies are not eligible if they are within 3 half-lives of receipt of the last antibody dose
• Participants who are receiving chronic steroids are not eligible. Chronic steroids are defined as either >= 2 mg/kg/day of body weight or >= 20 mg/day of prednisone or equivalent for persons who weigh >= 10 kg administered for >= 14 consecutive days
• Participants who are receiving anti-inflammatory or immunosuppressive medications are not eligible
• Participants with known autoimmune disease, with the exceptions of childhood asthma or atopic dermatitis, are not eligible
• Patients with a history of a positive test for human immunodeficiency virus or acquired immunodeficiency syndrome are not eligible
• Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to the agents proposed for use in this study. History of severe allergy to monoclonal antibody therapies (i.e. anaphylaxis) are likewise an exclusion
• Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, or psychiatric illness/social situations that would limit compliance with study requirements are not eligible
• Patients with prior solid organ transplantation are not eligible