A Randomized Three Arm Phase II 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)
- 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
- Adequate hematologic, renal and hepatic function defined as:
Hematologic: ANC > 1.0 x 109/L, platelets > 50 x 109/L o Renal: creatinine < 2 x upper
limit of normal, or creatinine Clearance of ≥60 cc/mL/1.73 m2 for patients > 16 years old.
For patients ≤ 16 years of age, creatinine Clearance of ≥70 cc/mL/1.73 m2 or serum
creatinine based on the following chart: Creatinine clearance or radioisotope GFR ≥
70ml/min/1.73 m2 or serum creatinine based on age/gender as follows: Age Maximum Serum
Creatinine (mg/dL) Male Female 10 to < 13 years 1.2 1.2 13 to < 16
years 1.5 1.4
≥ 16 years 1.7 1.4 The threshold creatinine values in this
Table were derived from the Schwartz formula for estimating GFR (Schwartz et al. J. Peds,
106:522, 1985) utilizing child length and stature data published by the CDC.
- Hepatic: total bilirubin < 2 mg/dL, alanine and aminotransferase levels < 5 x upper
limit of normal for age.
- At least 1 target lesion measurable by Response Evaluation Criteria in Solid
Tumors (RECIST 1.1) guidelines.
- Target lesion(s) must not lie within a previously resected, irradiated, ablated, or
chemoembolized area. If a lesion does lie in such an area, there must be evidence of
a ≥ 20% increase in diameter and/or the appearance of a new lesion on subsequent
imaging in order for such a lesion to be considered a target lesion.
- Prior systemic therapy is allowed. Prior surgery, locoregional ablative or
embolic therapies are also permitted provided that the criteria for measurable
disease as outlined above are met.
- Prior liver transplantation is permitted. Patients who subsequently received
immunosuppressive therapy with an mTOR inhibitor are still eligible to
participate provided that such therapy was completed or discontinued ≥ 2 weeks
before study enrollment.
- Women of childbearing potential must be practicing an effective method of birth
control that may include intrauterine devices (both hormonal and non-hormonal
are acceptable), double-barrier method, male partner sterilization or
abstinence, before enrollment, and throughout the study and for 6 months after
receiving the last dose of study drug.
- Men must agree to use a double barrier method of birth control and to not donate
sperm during the study and for 6 months after receiving the last dose of study
drugs. Sperm banking is acceptable for interested male patients enrolled on
study prior to initiating treatment. Prescription oral contraceptives,
contraceptive injections, and contraceptive patch are not approved methods of
contraception in this study.
- Negative pregnancy test (serum hCG) at screening (applicable to women of child
bearing potential) within 7 days prior to starting treatment.
- Concurrent anticancer, or radiation therapy.
- 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 . 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 . 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
- Any psychiatric illness/social situations that would limit compliance with study
- Pregnant or nursing women.
- Known HIV positive with a CD4 count ≤ 500 cells/mm3.
- Immunization with a live vaccine < 1 week of initiating study therapy or during