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

July 12, 2012
April 24, 2014
July 2012
July 2016   (final data collection date for primary outcome measure)
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.
Same as current
Complete list of historical versions of study NCT01642186 on ClinicalTrials.gov Archive Site
  • 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.
Same as current
Not Provided
Not Provided
 
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)
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)

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.

Not Provided
Interventional
Phase 2
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Fibrolamellar Carcinoma
  • Fibrolamellar Liver Cancer
  • Drug: everolimus
  • Drug: letrozole plus leuprolide
  • Drug: combination of everolimus, letrozole and leuprolide
  • 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.
    Intervention: 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.

    Intervention: 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.
    Intervention: Drug: combination of everolimus, letrozole and leuprolide
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
84
July 2016
July 2016   (final data collection date for primary outcome measure)

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.
Both
12 Years and older
No
Contact: Ghassan Abou-Alfa, MD 646-888-4184
United States
 
NCT01642186
11-211
Not Provided
Memorial Sloan-Kettering Cancer Center
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
Principal Investigator: Ghassan Abou-Alfa, MD Memorial Sloan-Kettering Cancer Center
Memorial Sloan-Kettering Cancer Center
April 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP