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)

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by Memorial Sloan-Kettering Cancer Center
Sponsor:
Collaborators:
The Fibrolamellar Cancer Foundation
Dana-Farber Cancer Institute/Brigham and Women¹s Cancer Center and Massachusetts General Hospital Cancer Center
Johns Hopkins University
University of California, San Francisco
Abbott
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier:
NCT01642186
First received: July 12, 2012
Last updated: April 24, 2014
Last verified: April 2014
  Purpose

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.


Condition Intervention Phase
Fibrolamellar Carcinoma
Fibrolamellar Liver Cancer
Drug: everolimus
Drug: letrozole plus leuprolide
Drug: combination of everolimus, letrozole and leuprolide
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
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)

Resource links provided by NLM:


Further study details as provided by Memorial Sloan-Kettering Cancer Center:

Primary Outcome Measures:
  • efficacy endpoints for Part 1 of the study is progression-free survival at 6 months (PFS6) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    for Part 1 of the study is progression-free survival at 6 months (PFS6). A progression event refers to the first evidence of radiographic disease progression, clinical progression as determined by study investigators, or death. Imaging performed in 6 months will be used to determine PFS6.


Secondary Outcome Measures:
  • median PFS [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    Kaplan-Meier PFS will be measured from the date that study therapy is initiated until the date of first evidence of radiographic disease progression, global clinical deterioration as determined by study investigators, or death.

  • median overall survival (OS) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    Kaplan-Meier OS will be measured from the date that study therapy was commenced until the date of death.

  • response rate [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    Objective responses will be reported using RECIST guidelines (version 1.1). Objective response will be estimated using binomial proportions and exact 95% CIs will be provided.

  • to evaluate toxicity in patients [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    Adverse events/toxicity will be monitored and recorded using the CTCAE version 4.0 and summarized descriptively.

  • correlative serum [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    Baseline serum measurements will be correlated with PFS6 (binary endpoint) using Fisher's exact test for categorical serum measurements and using Wilcoxon rank sum test for continuous measurements. For each time point at which serum measurements are collected, changes in the different binary serum markers from baseline will be correlated with PFS6 using conditional logistic regression to account for the paired nature of the data while Wilcoxon signed-rank test will be used for continuous measurements.

  • tissue biomarker studies [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    Associations between baseline tissue biomarkers and PFS6 will be assessed using Fisher's exact test for categorical biomarkers, trend tests for ordinal biomarkers and Wilcoxon rank-sum test for continuous biomarkers. For patients undergoing surgery, changes in tissue biomarkers from baseline to surgery will be summarized descriptively in an exploratory fashion.

  • to evaluate safety in patients [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    Adverse events/toxicity will be monitored and recorded using the CTCAE version 4.0 and summarized descriptively.


Estimated Enrollment: 84
Study Start Date: July 2012
Estimated Study Completion Date: July 2016
Estimated Primary Completion Date: July 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm A everolimus

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.
Drug: everolimus
Experimental: Arm B letrozole plus leuprolide

Day 1 of Cycle 1: Leuprolide 7.5 mg IM will be administered by a nurse in clinic.

Letrozole will be dispensed and will be taken at home. Patients will be instructed to take letrozole at the same time each day, consistently with food or without food, and swallowed whole with a glass of water. 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.

Drug: letrozole plus leuprolide
Experimental: Arm C combination everolimus, letrozole and leuprolide
  • 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. Leuprolide 7.5 mg IM will be given every 4 weeks (+/- 7 days). Everolimus and letrozole will be administered continuously using the same dose, schedule and administration. Everolimus, letrozole and leuprolide should be administered concurrently at all times.
Drug: combination of everolimus, letrozole and leuprolide

  Eligibility

Ages Eligible for Study:   12 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01642186

Contacts
Contact: Ghassan Abou-Alfa, MD 646-888-4184

Locations
United States, California
University of California San Francisco Recruiting
San Francisco, California, United States, 94143
Contact: Alan Venook         
Principal Investigator: Alan Venook, MD         
United States, Maryland
John Hopkins Medical Center Recruiting
Baltimore, Maryland, United States, 21287
Contact: David Cosgrove, MD         
Principal Investigator: David Cosgrove, MD         
United States, Massachusetts
Brigham and Women's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Robert Mayer         
Principal Investigator: Robert Mayer, MD         
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02115
Contact: Robert Mayer, MD         
Principal Investigator: Robert Mayer, MD         
Massachusetts General Hospital Cancer Center Recruiting
Boston, Massachusetts, United States, 02114
Contact: Robert Mayer, MD         
Principal Investigator: Robert Mayer, MD         
United States, New York
Memorial Sloan-Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Ghassan Abou-Alfa, MD    646-888-4184      
Principal Investigator: Ghassan Abou-Alfa, MD         
Sponsors and Collaborators
Memorial Sloan-Kettering Cancer Center
The Fibrolamellar Cancer Foundation
Dana-Farber Cancer Institute/Brigham and Women¹s Cancer Center and Massachusetts General Hospital Cancer Center
Johns Hopkins University
University of California, San Francisco
Abbott
Novartis Pharmaceuticals
Investigators
Principal Investigator: Ghassan Abou-Alfa, MD Memorial Sloan-Kettering Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT01642186     History of Changes
Other Study ID Numbers: 11-211
Study First Received: July 12, 2012
Last Updated: April 24, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Memorial Sloan-Kettering Cancer Center:
LETROZOLE
LUPRON DEPOT
RAD001 (EVEROLIMUS)
11-211

Additional relevant MeSH terms:
Carcinoma
Liver Neoplasms
Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Adenocarcinoma
Estrogens
Everolimus
Sirolimus
Letrozole
Leuprolide
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Antifungal Agents
Anti-Infective Agents
Anti-Bacterial Agents
Antineoplastic Agents, Hormonal
Fertility Agents, Female

ClinicalTrials.gov processed this record on July 24, 2014