Study of (1) Everolimus, (2) Estrogen Deprivation Therapy (EDT) With Leuprolide + Letrozole and (3) Everolimus + EDT in Patients With Unresectable Fibrolamellar Hepatocellular Carcinoma (FLL-HCC)

Inclusion Criteria

• Patients ≥ 12 years old.
• Pathologically confirmed diagnosis of advanced and/or unresectable FLL-HCC. This will be performed by the participating centers on submitted specimens. If the submitted material is insufficient for analysis, a repeat biopsy is recommended.
• ECOG performance status 0-2 ; Lansky performance score of ≥ 60% for patients 12-16 years old
• Adequate hematologic, renal and hepatic function defined as:

Hematologic: ANC ≥ 1.0 x 10^9/L, platelets ≥ 50 x 10^9/L o Renal: creatinine ≤ 2 x upper limit of normal, or creatinine Clearance of ≥60 cc/mL/1.73 m^2 for patients > 16 years old. For patients ≤ 16 years of age, creatinine Clearance of ≥70 cc/mL/1.73 m^2 or serum creatinine based on the following chart: Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m^2 or serum creatinine based on age/gender as follows: Age Maximum Serum Creatinine (mg/dL) Male Female 10 to 1.5 x upper limit of normal, adequate glycemic control (fasting glucose 4 weeks before the start of study therapy. The date of last palliative radiation must be > 2 weeks from the start of study therapy. Palliative radiation is permitted on protocol with MSK PI discretion on treatment modifications.

• Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) .
• Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent. Topical or inhaled corticosteroids are allowed.
• Concurrent oral contraceptive use or hormonal replacement therapy.
• Use of an aromatase inhibitor, GnRH agonist and/or tamoxifen within the past 30 days. Patients previously on fulvestrant or a q3 month GnRH agonist must have discontinued these medications for at least 3 months.
• Concurrent use of potent CYP3A4 and/or P-glycoprotein inhibitors or potent CYP3A4 inducers (please see Appendices 3 and 4). Where possible, otherwise eligible patients should be switched to alternative agents; otherwise, they will be excluded from the study.
• Potent CYP3A4 inducers decrease serum everolimus levels and should not be given concomitantly. Dose modifications of everolimus are not indicated in the presence of moderate CYP3A4 inducers [108]. Please refer to Appendix 3 for a complete list of potent and moderate inducers of CYP3A4.
• Potent CYP3A4 and/or P-glycoprotein inhibitors can increase serum levels of everolimus and should not be co-administered. Moderate inhibitors may mildly-moderately increase serum everolimus levels, though there is no definitive evidence supporting a dose reduction [108]. Please refer to Appendix 4 for a complete list of potent and moderate inhibitors of CYP3A4.
• Any investigational drug received within one month of study enrollment.
• Any severe, uncontrolled medical conditions that, in the opinion of the investigator, may be exacerbated by study therapy including infection, diabetes and cardiopulmonary disease.
• Any psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant or nursing women.
• Patients with a known hypersensitivity to everolimus, letrozole, leuprolide and/or related compounds or their excipients.
• Patients who received any form of transplant and who are on any form of immunosuppressive therapy. However transplanted patients who are off immunosuppressive therapy for at least 4 weeks are allowed on the study, provided that any of their immunosuppressive-related toxicities have recovered to at least a grade 1.
• Known HIV positive with a CD4 count < 500 cells/mm3.
• Immunization with a live vaccine < 1 week of initiating study therapy or during therapy.
• BSA <1 m^2