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)

Brief Title

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)

Official Title

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)

Brief Summary

      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.

Study Phase

Phase 2

Study Type


Primary Outcome

efficacy endpoints for Part 1 of the study is progression-free survival at 6 months (PFS6)

Secondary Outcome

 median PFS


Fibrolamellar Carcinoma



Study Arms / Comparison Groups

 Arm A everolimus
Description:  Everolimus will be administered at the following doses:
Patients with a BSA ≤ 1.5 m2 will receive everolimus 5 mg PO QD.
Patients with a BSA > than or = to 1.5 m2 will receive everolimus 7.5 mg PO QD. If the patient is randomized to everolimus alone (1) or leuprolide and letrozole (2) and the cancer continues to grow, they may have the option to receive all three drugs together.


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

July 12, 2012

Completion Date

July 16, 2021

Primary Completion Date

July 16, 2021

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 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 < 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.

          -  Fasting blood glucose <1.5 x upper limit of normal . If fasting glucose > 1.5 x upper
             limit of normal, adequate glycemic control (fasting glucose < 1.5 x upper limit of
             normal ) for three weeks is recommended before starting protocol therapy.

               -  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.

               -  Concurrent antiviral therapy for hepatitis B is permitted

               -  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) result (applicable to women of child bearing
                  potential) within 7 days before Cycle 1 Day 1 of study treatment.

        Exclusion Criteria:

          -  Concurrent anticancer, or radiation therapy. Patients must have completed all
             anticancer therapy > 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

          -  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

          -  Any psychiatric illness/social situations that would limit compliance with study

          -  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

          -  BSA <1 m^2




12 Years - N/A

Accepts Healthy Volunteers



Ghassan Abou-Alfa, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Responsible Party


Study Sponsor

Memorial Sloan Kettering Cancer Center


 The Fibrolamellar Cancer Foundation

Study Sponsor

Ghassan Abou-Alfa, MD, Principal Investigator, Memorial Sloan Kettering Cancer Center

Verification Date

July 2021