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)

Status: Recruiting
Phase: Phase 2
Diagnosis: Gastrointestinal Malignancies
NCT ID: NCT01642186 (View complete trial on
DFCI Protocol ID: 12-219


There is no effective standard treatment for fibrolamellar liver cancer that cannot be removed by surgery. The investigators want to find out what effects, good and/or bad, 3 drugs called letrozole, leuprolide and everolimus will have on cancer. All of these drugs are FDA approved for the treatment of different cancers. Letrozole and leuprolide stop the body from producing estrogen, a normal hormone produced by the body. Too much estrogen may help fibrolamellar liver cancer grow. Everolimus is a drug that may block other chemicals in the body that can help cancer grow. The combination of letrozole and leuprolide plus everolimus may work well together.


Conducting Institutions:
Massachusetts General Hospital, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Children's Hospital Boston

Overall PI:
Robert Mayer, MD, Dana-Farber Cancer Institute

Site-responsible Investigators:
Andrew Zhu, MD, PhD, Massachusetts General Hospital
Allison O'Neill, MD, Children's Hospital Boston

Massachusetts General Hospital: Cancer Trials Call Center, 877-789-6100
Dana-Farber Cancer Institute: Gastrointestinal Research Line, 617-632-5960
Dana-Farber Cancer Institute: Childrens Hospital Pediatric Clinical Translation Investigation Program CTIP,

Eligibility Criteria

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 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. Exclusion Criteria: - 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 [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. - Known HIV positive with a CD4 count ≤ 500 cells/mm3. - Immunization with a live vaccine < 1 week of initiating study therapy or during therapy.
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