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)

• ClinicalTrials.gov Identifier: NCT01642186
• Recruitment Status: Completed
• First Posted: July 17, 2012
• Results First Posted: December 29, 2022
• Last Update Posted: December 29, 2022
• Sponsor: Memorial Sloan Kettering Cancer Center
• 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

Tracking Information

• First Submitted Date: July 12, 2012
• First Posted Date: July 17, 2012
• Results First Submitted Date: July 15, 2022
• Results First Posted Date: December 29, 2022
• Last Update Posted Date: December 29, 2022
• Actual Study Start Date: July 12, 2012
• Actual Primary Completion Date: July 16, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 1, 2022)

Efficacy Endpoints for Part 1 of the Study is Progression-free Survival at 6 Months (PFS6) [ Time Frame: 6 months ]

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.

Original Primary Outcome Measures (submitted: July 13, 2012)

efficacy endpoints for Part 1 of the study is progression-free survival at 6 months (PFS6) [ Time Frame: 6 months ]

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.

Current Secondary Outcome Measures (submitted: December 1, 2022)

• Median PFS [ Time Frame: 2 years ]
  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: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months ]
  Kaplan-Meier OS will be measured from the date that study therapy was commenced until the date of death.
• Percentage of Participants With Stable Disease [ Time Frame: 2 years ]
  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. Stable Disease is defined as neither sufficient shrinkage (compared to baseline) to qualify for Partial Reponse nor sufficient increase (taking as reference the smallest sum diameters while on study) to qualify for Progressive Disease.
• Number of Participants With One or More Adverse Events/Toxicity [ Time Frame: 2 years ]
  Adverse events/toxicity will be monitored and recorded using the CTCAE version 4.0 and summarized descriptively.
• Number of Participants With Tissue Biomarkers Collected [ Time Frame: 2 years ]
  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.

Original Secondary Outcome Measures (submitted: July 13, 2012)

• median PFS [ Time Frame: 2 years ]
  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 ]
  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 ]
  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 ]
  Adverse events/toxicity will be monitored and recorded using the CTCAE version 4.0 and summarized descriptively.
• correlative serum [ Time Frame: 2 years ]
  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 ]
  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 ]
  Adverse events/toxicity will be monitored and recorded using the CTCAE version 4.0 and summarized descriptively.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Fibrolamellar Carcinoma
• Fibrolamellar Liver Cancer

Intervention

• Drug: everolimus
• Drug: letrozole plus leuprolide
• Drug: combination of everolimus, letrozole and leuprolide

Study Arms

• 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

• Publications *: Lim II, Farber BA, LaQuaglia MP. Advances in fibrolamellar hepatocellular carcinoma: a review. Eur J Pediatr Surg. 2014 Dec;24(6):461-6. doi: 10.1055/s-0034-1396420. Epub 2014 Dec 8.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 13, 2012): 28
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: July 16, 2021
• Actual Primary Completion Date: July 16, 2021 (Final data collection date for primary outcome measure)

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 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.
• 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 therapy.
• BSA <1 m^2

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01642186
• Other Study ID Numbers: 11-211
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Memorial Sloan Kettering Cancer Center
• Original Responsible Party: Same as current
• Current Study Sponsor: Memorial Sloan Kettering Cancer Center
• Original Study Sponsor: Same as current

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

Investigators

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

• PRS Account: Memorial Sloan Kettering Cancer Center
• Verification Date: July 2021