Safety and Efficacy of Everolimus Treatment in Liver Transplantation for Liver Cancer

Tracking Information
First Submitted Date ICMJE	March 5, 2014
First Posted Date ICMJE	March 7, 2014
Last Update Posted Date	July 13, 2018
Actual Study Start Date ICMJE	March 2014
Estimated Primary Completion Date	August 2019 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: March 5, 2014)	Disease free survival (DFS) defined as the time from randomization to the time of tumor recurrence or death, whichever occurs first. [ Time Frame: Through Month 36 ]
Original Primary Outcome Measures ICMJE	Same as current
Change History	Complete list of historical versions of study NCT02081755 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: February 14, 2017)	Tumor recurrence sites [ Time Frame: Through Month 36 ]; Hepatitis C recurrence rate [ Time Frame: Through Month 36 ]; Renal function [ Time Frame: Through Month 36 ]; Acute cellular rejection [ Time Frame: Through Month 36 ]; Post-transplant diabetes [ Time Frame: Through Month 36 ]; Hypertension [ Time Frame: Through Month 36 ]; Hyperlipidemia [ Time Frame: Through Month 36 ]; Wound healing and associated risk factors [ Time Frame: Through Month 36 ]; Hernia repair [ Time Frame: Through Month 36 ]; Hepatic arterial thrombosis [ Time Frame: Through Month 36 ]
Original Secondary Outcome Measures ICMJE; (submitted: March 5, 2014)	Tumor recurrence sites [ Time Frame: Through Month 36 ]; Hepatitis C recurrence rate [ Time Frame: Through Month 36 ]; Renal function [ Time Frame: Through Month 36 ]; Acute cellular rejection [ Time Frame: Through Month 36 ]; Post-transplant diabetes [ Time Frame: Through Month 36 ]; Hypertension [ Time Frame: Through Month 36 ]; Hyperlipidemia [ Time Frame: Through Month 36 ]
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Safety and Efficacy of Everolimus Treatment in Liver Transplantation for Liver Cancer
Official Title ICMJE	A 36 Month Multi-center, Open Label, Randomized, Comparator Study to Evaluate the Efficacy and Safety of Everolimus Immunosuppression Treatment in Liver Transplantation for Hepatocellular Carcinoma Exceeding Milan Criteria
Brief Summary	This study is a prospective Phase IV study to determine if the use of Everolimus results in lower liver tumor recurrence and improved patient and graft survival after liver transplant for hepatocellular carcinoma (HCC). The immunosuppressive comparators will be Everolimus and Tacrolimus therapy compared to Tacrolimus and Mycophenolic acid/Mycophenolate Mofetil/Azathioprine. Primary outcomes data is disease free survival (the time from randomization to HCC recurrence or death). Secondary outcomes are rate of recurrence of Hepatitis C, problems related to wound healing, hernia repair within the first 12 months, hepatic arterial thrombosis, renal function, acute cellular rejection, post-transplant diabetes, hypertension, and hyperlipidemia.
Detailed Description	The study population will consist of approximately 336 patients (224 Everolimus and Tacrolimus and 112 Tacrolimus and Mycophenolic acid/Mycophenolate Mofetil/Azathioprine). Initial screening criteria will include the presence of hepatocellular carcinoma in patients 18 years or older who are candidates to receive a primary orthotopic liver transplant (from deceased or living donor). Within 7 - 12 days post-transplant, patients will be re-evaluated for eligibility for randomization. The criteria include: pre-transplant imaging that shows HCC disease exceeding Milan criteria; pathology review for tumor burden and/or presence of microvascular invasion; AFP >200IU/mL; pre-transplant ablation or resection with HCC recurrence; progression or new tumors; evaluation to rule out any hepatic vessel complication. Subjects will remain in study treatment until Month 12 at which time the subject and investigator will determine the preferred immunosuppressive regimen. Subjects will be followed for an additional 24 months for outcome data as described above.
Study Type ICMJE	Interventional
Study Phase	Phase 4
Study Design ICMJE	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Carcinoma, Hepatocellular
Intervention ICMJE	Drug: Everolimus Everolimus Dosing: 1.5 mg BID (3.0 mg/day) for 12 months Other Names: Zortress Afinitor; Drug: Tacrolimus Tacrolimus Dosing: 0.05 mg/kg BID for 12 months Other Name: Prograf; Drug: Myfortic Myfortic®: 360 mg to 1080 mg BID for 12 months Other Name: Mycophenolic Acid; Drug: CellCept CellCept: 500 mg to 1500 mg BID for 12 months Other Name: Mycophenolate Mofetil; Drug: Imuran 0.5 mg/kg to 2 mg/kg QD for 12 months Other Name: Azathioprine
Study Arms	Experimental: Everolimus and Tacrolimus Everolimus Dosing: 1.5 mg BID (3.0 mg/day) Tacrolimus Dosing: 0.05 mg/kg BID Interventions: Drug: Everolimus Drug: Tacrolimus; Active Comparator: Tacrolimus and Myfortic or CellCept or Imuran Myfortic: 360 mg to 1080 mg BID OR CellCept: 500 mg to 1500 mg BID OR Imuran: 0.5mk/kg to 2mg/kg QD AND Tacrolimus Dosing: 0.05 mg/kg BID Interventions: Drug: Tacrolimus Drug: Myfortic Drug: CellCept Drug: Imuran
Publications *	Not Provided
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Recruiting
Estimated Enrollment ICMJE; (submitted: March 5, 2014)	336
Original Estimated Enrollment ICMJE	Same as current
Estimated Study Completion Date	August 2019
Estimated Primary Completion Date	August 2019 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	Screening Inclusion Criteria: Have a diagnosis of hepatocellular carcinoma (HCC) and high risk for HCC recurrence; Able to provide written informed consent; Male and female patients of any race, 18 years or older; De novo recipients of a primary orthotopic liver transplant from a deceased or living donor; Patients willing to comply with study requirements; Women of child-bearing potential (WOCBP) must agree to use an effective method(s) of contraception during treatment and during the post treatment follow-up period Screening Exclusion Criteria: Past or present malignancy within the last 5 years.; Severe infection considered by the local site investigator to be unsafe for study participation.; Use of other investigational drugs at the time of screening or within the last 30 days.; Patients scheduled for a combined transplant (such as liver-kidney), or having a previous solid organ, bone marrow, or autologous islet cell transplant.; Recipients of donor/recipient ABO incompatible grafts.; Recipients of organs from human immunodeficiency virus (HIV) or HBsAg positive donors.; Macrovascular tumor invasion.; Proteinuria greater than 2 grams/24 hours.; Conditions which can result in impaired absorption, distribution, metabolism or excretion of the study treatment.; Patients with non-infectious pneumonitis.; Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test.; Women of child-bearing potential (WOCBP) not practicing an effective method(s) of contraception.; Patients who receive sirolimus (Rapamune®) as part of their transplant immunosuppression regimen Randomization Screening Inclusion Criteria : - For patients with a history of any hepatic vessel thrombosis, occlusion, stent placement, or major revision of liver vessels, must have a Doppler ultrasound prior to randomization to rule out any hepatic vessel complication, including hepatic arterial thrombosis (HAT). Randomization Exclusion Criteria: Patients who receive sirolimus (Rapamune) any time prior to randomization will be withdrawn from the study.; Patients who develop clinically significant systemic infections requiring active use of IV antibiotics any time prior to randomization.; Wound healing problem, per Investigator's assessment, that would make the patient ineligible for study randomization; Confirmed presence of a thrombosis in a major hepatic artery(s), major hepatic vein(s), portal vein or inferior vena cava via Doppler ultrasound or other imaging obtained prior to randomization.; Proteinuria greater than 2 grams/24 hours.; Consideration by the investigator, for any reason, that the subject is an unsuitable candidate to receive everolimus or be randomized into the study.
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years and older (Adult, Older Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact: Darlene Bunpian, MPH Darlene.Bunpian@BSWHealth.org
Listed Location Countries ICMJE	United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT02081755
Other Study ID Numbers ICMJE	013-307
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Plan to Share IPD: No
Responsible Party	Baylor Research Institute
Study Sponsor ICMJE	Baylor Research Institute
Collaborators ICMJE	Not Provided
Investigators ICMJE	Principal Investigator: Goran Klintmalm, MD, PhD Baylor Health Care System
PRS Account	Baylor Research Institute
Verification Date	July 2018
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP