Hepatocellular Carcinoma
A validation study of Des-gamma carboxy-prothrombin for the detection of early hepatocellular carcinoma
Aim
To develop better biomarkers for the early detection of hepatocellular carcinoma (HCC).
Inclusion Criteria
A. HCC Cases
- Age >18 years of age
- Diagnosis of HCC will be based on the following:
-Histology
-2 imaging tests (CT/MRI/Angiography) showing a vascular lesion of >2 cm
-AFP >400 ng/mL and a vascular lesion on 1 imaging test (CT/MRI/Angiography)
B. Controls
- Age >18 years of age
- Diagnosis of cirrhosis based on imaging showing a cirrhotic-appearing liver with splenomegaly and a platelet count of <120 x 103 cells/mm3
- Normal ultrasound or other imaging within 6 months of enrollment
- Patients with AFP >20 ng/mL will be included if MRI or CT scan within 3 months prior to enrollment revealed no mass suggestive of HCC
Exclusion Criteria
- Prior treatment of HCC (for cases)
- Clinical evidence of significant hepatic decompensation (for controls)
- Detection of HCC at initial evaluation (for controls)
Cirrhotics will be followed for an additional 6 months to assure no HCC.
Please notify of HCC cases: Sherry Fu at 734-647-3635 or Dr. Jorge A. Marrero at 734-615-5480.
Prospective evaluation of tumor markers for the early detection of hepatocellular carcinoma
This is an extension of the above study. We plan to follow a cohort of patients with cirrhosis over time to identify the rate of development of hepatocellualr carcinoma (HCC), to validate novel biomarkers, and to stratify cirrhotic patients into high- and low-risk for development of HCC based on their exposures to tobacco, alcohol, obesity, and other factors.
Specific Aims
- To determine if serum DCP, GP73, or a combination of these markers is more sensitive than AFP for the detection of early HCC.
- To determine if studies of the proteomics of HCC can lead to the development of novel serum markers of early HCC.
- To determine if tobacco, alcohol, obesity, demographics, and etiology of liver disease are important factors for the development of HCC in patients with cirrhosis.
Inclusion Criteria
• All adult patients with liver cirrhosis
• Diagnosis of cirrhosis will be based on histology or an ultrasound showing a cirrhotic-appearing liver with splenomegaly and a platelet count of <120 x 103 cells/mm3
• Child class A or B
• All patients must have normal ultrasond or other imaging within 6 months of enrollment
• Patients with AFP >20 ng/mL will be included if MRI or CT scan within 3 months prior to enrollment revealed no mass suggestive of HCC
Exclusion Criteria
- Clinical evidence of significant hepatic decompensation (refractory ascites, grades 3 to 4 encephalopathy, or hepatorenal syndrome), Child class C, or MELD score >15.
- Detection of HCC at initial evaluation.
- Inability to comply with long-term follow-up
- Significant comorbid medical conditions with life expectancy less than 1 year.
- Require long-term immunosuppressive therapy.
- Prior solid organ transplant.
- Primary tumor in an extrahepatic site.
Study Design
• Patients will be seen every 6 months over a 5-year period
• Lifetime alcohol and tobacco questionnaires at baseline
• Clinical and laboratory data will be obtained every 6 months
• Serum, plasma, and DNA obtained every 6 months
Please notify of patients with Child A or B cirrhosis who will be followed long-term: Sherry Fu at 734-647-3635 or Jorge A. Marrero, MD at 734-615-5480.
Diagnosis and prognosis of patients with hepatocellular carcinoma
Patients with chronic liver disease are at risk of developing hepatocellular carcinoma (HCC). This research study will evaluate the potential outcome of patients with liver tumors. This study plans to evaluate the Barcelona staging system in patients with HCC and evaluate if new biomarker at the time of HCC diagnosis improves the accuracy of the Barcelona staging system in predicting the outcome of patients with liver cancer.
Specific Aims
- Evaluation of the prognosis of patients with HCC
- To prospectively evaluate the Barcelona staging system in patients with HCC
- To determine if novel biomarker expression at the time of HCC diagnosis improves the accuracy of the Barcelona staging system in predicting the prognosis of patients with HCC.
Please notify of HCC cases: Sherry Fu 734-647-3635 or Jorge A. Marrero, MD.
A Phase III randomized, double-blind, placebo-controlled study of sorafenib as adjuvant treatment for hepatocellular carcinoma after surgical resection or local ablation.
Sorafenib as adjuvant Treatment in the prevention Of Recurrence of hepatocellular carcinoMa (STORM)
Primary Objective
To evaluate efficacy and safety of sorafenib versus placebo in the adjuvant treatment of HCC after potentially curative treatment with surgical resection or local ablation. The Primary efficacy objective is Recurrence Free Survival (RFS). Secondary efficacy objectives are time to recurrence and overall survival.
Study Design
- This is a randomized, double blind, placebo-controlled phase III study to evaluate the clinical benefit of sorafenib versus placebo as adjuvant treatment in subjects with HCC
- Subjects will be randomized 1:1 to receive either Sorafenib or placebo
- Subjects will be stratified according to prior curative treatment (surgical resection, local ablation), geographical region (Europe, Americas and Asia-Pacific) risk of tumor recurrence (intermediate risk, high risk) and Child-Pugh status (Child-Pugh A, Child-Pugh B).
- Subjects will take 2 tablets of sorafenib (200 mg tablets) or placebo twice daily for up to 4 years or until tumor recurrence or other reason for withdrawal.
Main Inclusion Criteria
- Confirmation of diagnosis of HCC:
- for subjects undergoing surgical resection histological confirmation is mandatory.
- for subjects undergoing local ablation either histological confirmation or clinical diagnosis by AASLD criteria
- Confirmation of CR (absence of residual tumor after curative treatment), on the eligibility scan by independent radiological review.
- Intermediate or high risk of recurrence as assessed by tumor characteristics.
- Child-Pugh score 5 -7 points. A Child-Pugh score of 7 points is allowed only in the absence of ascites.
- ECOG Performance Status of 0.
- Adequate bone marrow, liver and renal function as assessed by central lab approximately 14 days prior to randomization
Main Exclusion Criteria
- Recurrent HCC
- Child-Pugh score 7 points with presence of ascites.
- History of cardiovascular disease:
- congestive heart failure >NYHA class 2 (Appendix 3)
- active CAD (MI more than 6 months prior to study entry is allowed); cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted)
- uncontrolled hypertension
- History of HIV infection
- Active clinically serious infections (> grade 2 NCI-CTCAE version 3.0)
- Subjects with seizure disorder requiring medication (such as steroids or anti-epileptics)
- History of organ allograft
- Subjects with evidence or history of bleeding diathesis
- Subjects undergoing renal dialysis
- Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors [Ta, Tis & T1] or any cancer curatively treated > 3 years prior to study entry.
- Uncontrolled ascites (defined as not easily controlled with diuretic treatment)
- Encephalopathy
- History of GI bleeding within 30 days
- Subjects with a history of esophageal varices bleeding which has not been followed by effective therapy and/or treatment to prevent bleeding recurrence
- Prior anticancer therapy for treatment of HCC (including sorafenib or any other molecular therapy) is excluded
Costs for the Patient
All costs for study drug and study-only tests will be covered by the sponsor and provided free of charge to the patient.
Contact persons
Mary Maliarik at 734-615-8627 (e-mail: marymali@med.umich.edu)Ted Welling, MD at 734 936-9623 (e-mail: twelling@med.umich.edu)
Jorge Marrero, MD by e-mail jmarrero@med.umich.edu
Global investigation of therapeutic decision in hepatocellular carcinoma and of its treatment with sorafenib
Primary Objective
The primary objective of this international non-interventional surveillance study is to evaluate the safety of Nexavar® in all patients with unresectable HCC who are candidates for systemic therapy and in whom a decision to treat with Nexavar® has been made under real-life practice conditions and in a variety of patient subsets regionally and globally.
Study Design
- This study is an international prospective, open-label, multi-center, non-interventional study.
- Patients enrolled in this study must have unresectable HCC who are candidates for systemic therapy and in whom a decision to treat with Nexavar® has been made.
- The observation period for each patient is the time from the start of therapy with Nexavar® to withdrawal of consent, death, or the last visit.
- This non-interventional study will use paper and electronic versions of the CRF.
- In this international study data will be collected for approximately 3,000 patients globally over 5 years.
- Outpatients with histologically/cytologically documented or radiographically diagnosed unresectable HCC who are candidates for systemic therapy and for whom a decision to treat with Nexavar® has been made.
- Patients must have signed an informed consent form.
- Patients must have a life expectancy of at least 8 weeks.
- The physician must be willing to submit to a site audit with verification of source documents and validation of data reported
Main Inclusion Criteria
- Outpatients with histologically/cytologically documented or radiographically diagnosed unresectable HCC who are candidates for systemic therapy and for whom a decision to treat with Nexavar® has been made
- Patients must have signed an informed consent form
- Patients must have a life expectancy of at least 8 weeks
- The physician must be willing to submit to a site audit with verification of source documents and validation of data reported.
Main Exclusion Criteria
Exclusion criteria must follow the approved local product information.
Costs for the Patient
There is no study-related cost to the patient.
Contact persons
Sherry Fu at (734) 647-3635 (e-mail: sherryfu@med.umich.edu) or
Whitney Wright at (734) 763-7997 (e-mail: wmwright@med.umich.edu) or
Jorge Marrero, MD by e-mail: jmarrero@med.umich.edu
A randomized, double-blind, multi-center phase III study of brivanib versus sorafenib as first-line treatment in patients with advanced hepatocellular carcinoma (BRISK FL Study)
Primary Objective:
The main purpose of this study is to determine if patients who have liver cancer and have not received prior systemic treatment for their liver cancer live longer when given the investigational drug brivanib alaninate (also known as brivanib) compared to those who receive sorafenib (Nexavar®).
Study Design:
- This is a multicenter, double-blinded, randomized, Phase III study in subjects with advanced HCC.
- After screening for eligibility and signing of informed consent, qualifed subjects will be randomized in a 1:1 ratio to receive brivanib (arm A) or sorafenib (arm B).
- Subjects randomized to treatment arm A will take orally brivanib 800 mg once daily and sorafenib matched placebo twice daily.
- Subjects randomized to treatment arm B will take orally sorafenib 400 mg twice daily and brivanib matched placebo once daily.
- Treatment assignment will remain blinded throughout the study.
Main Inclusion Criteria:
- Signed Written Informed Consent
- Target Population
- Histologic or cytologic confirmed diagnosis of HCC
- Advanced HCC
- disease not eligible for surgical and / or locoregional therapies
- progressive disease after surgical and / or locoregional therapies
- Child-Pugh Class
- ECOG performance status 0-1
- Life expectancy of at least 12 weeks
- Accessible for treatment and follow-up
- Locoregional therapy must be completed at least 3 weeks prior to the baseline scan; previously treated lesions are not to be selected as target lesions
- At lease one measurable untreated lesion.
- Physical and Laboratory Test Finding
- Adequate hematologic function with absolute neutrophil counts ≥ 1,500/mm3, platelet count ≥ 60 x 109/L, and hemoglobin ≥ 8.5 g/dL
- Adequate hepatic function with serum total bilirubin ≤ 3 mg/dL, serum albumin ≥ 2.8 g/dL and ALT and AST ≤ 5 times the institutional upper limits of normal
- Amylase and lipase ≤ 1.5 times the institutional upper limit of normal
- Adequate renal function with serum creatinine ≤ 2.0 mg/dL
- INR ≤ 2.3 or PT ≤ 6 seconds above control
- Left ventricular ejection fraction (LVEF) ≥ 50% as measured by 2-D echocardiogram
- Age and Sex
- Men and women, ages 18 or older
- Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 12 weeks after the last dose of investigational
Main Exclusion Criteria:
- Sex and Reproductive Status
- Women who are pregnant or breastfeeding
- Target Disease Exceptions
- Brain metastasis or evidence of leptomeningeal disease
- Known fibrolamellar HCC or mixed cholangiocarcinoma and HCC
- History of encephalopathy
- Ascites
- Evidence of portal hypertension with bleeding esophageal or gastric varices within the past 2 months
- Main portal vein* or vena cava thrombosis or occlusion.
- Medical History and Concurrent Diseases
- Previous or concurrent cancer that is distinct in primary site or histology from HCC, except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis & T1). (Any cancer curatively treated > 5 years prior to entry is permitted.)
- History of active cardiac disease:
- Thrombotic or embolic events within the past 6 months, such as a cerebrovascular accident (including transient ischemic attacks), pulmonary embolism
- Any other hemorrhage/bleeding event ≥ CTCAE Grade 3 within 4 weeks except for esophageal or gastric varices
- Active, untreated hepatitis B
- History of non-healing wounds or ulcers, or bone fractures within 3 months of fracture
- Major surgical procedure, open biopsy, or significant traumatic injury less than 3 weeks or those who receive minor surgical procedures (eg core biopsy or fine needle aspiration) within 1 week
- Portal-caval shunts
- Pre-existing thyroid abnormality with thyroid function that cannot be maintained in the normal range with medication
- History of human immunodeficiency virus (HIV) infection
- Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results.
- Any medical condition that is unstable or which could jeopardize the safety of the patient and his/her compliance in the study.
- Previous or concurrent cancer that is distinct in primary site or histology from HCC, except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis & T1). (Any cancer curatively treated > 5 years prior to entry is permitted.)
- Physical and Laboratory Test Findings
- Baseline serum sodium < 130 mmol/L
- Baseline serum potassium < 3.5 mmol/L (potassium supplementation may be given to restore the serum potassium above this level prior to study entry)
- Allergies and Adverse Drug Reaction
- Known or suspected history of allergy to brivanib or sorafenib or any agents given in association with this trial
- Prohibited Treatments and/or Therapies
- Prior use of any systemic anti-cancer chemotherapy, immunotherapy or molecular targeted agents for HCC
- Concomitant treatment with rifampin (and its analogues), or St John’s wort
- Prior use of systemic investigational agents for HCC
- Radiotherapy within 4 weeks prior to start of study drug
- Required anticoagulation therapy with an agent such as coumadin, warfarin or heparin
- Required chronic anti-platelet therapy (aspirin at dose ≥ 300 mg/day, clopidogrel at dose ≥ 75 mg/day).
- Prior use of any systemic anti-cancer chemotherapy, immunotherapy or molecular targeted agents for HCC
- Other Exclusion Criteria
- Prisoners or subjects who are involuntarily incarcerated
- Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.
- Prisoners or subjects who are involuntarily incarcerated
Costs for the Patient:
All costs for study drug and study-only tests will be covered by the sponsor and provided free of charge to the patient.
Contact persons:
Sherry Fu at 734-647-3635 (e-mail: sherryfu@med.umich.edu) or Carrie Manwaring at 734-763-7997 (e-mail: cmanwar@med.umich.edu) or Dr. Jorge Marrero at jmarrero@med.umich.edu.
A randomized, double-blind, multi-center phase III study of brivanib plus best supportive care (BSC) versus placebo plus BSC in subjects with advanced hepatocellular carcinoma (HCC) who have failed or are intolerant to sorafenib ( BRISK PS Study)
Primary Objective:
The main purpose of this study is to determine if patients who have liver cancer and who have already received the drug sorafenib live longer when given the investigational drug brivanib alaninate (also known as brivanib) compared to those who receive placebo (a tablet that looks like brivanib, but has no active ingredient).
Study Design:
- This is a multicenter, double-blinded, placebo-controlled, randomized Phase III study in subjects with advanced HCC who have failed or are intolerant to sorafenib therapy.
- After screening for eligibility and signing of informed consent, qualified subjects will be randomized in a 2:1 ratio to receive brivanib plus BSC (Arm 1) or placebo plus BSC (Arm 2).
- Randomization will be stratified by site, ECOG PS (0 vs 1 & 2), progression vs intolerance to sorafenib (which must be documented on the CRF) and extrahepatic spread and/or vascular invastion (yes or no).
- Treatment assignments will remain blinded throughout the study.
- Subjects randomized to treatment arm 1 will take orally brivanib 800 mg once daily.
- Subjects randomized to treatment arm 2 will take orally matched placebo once daily.
Main Inclusion Criteria:
- Signed Written Informed Consent
- Target Population:
- Histologic or cytologic confirmed diagnosis of HCC.
- Advanced HCC defined as
- disease not eligible for surgical or locoregional therapy or
- disease progressive after surgical or locoregional therapy
- disease not eligible for surgical or locoregional therapy or
- Patient has failed ≥ 14 days of sorafenib treatment
- Cirrhotic status of Child-Pugh Class A or B with a score of 7
- ECOG performance status 0, 1, 2
- Subjects who have a life expectancy of at least 8 weeks.
- Accessible for treatment and follow-up.
- Locoregional therapy must be completed at least 3 weeks prior to the baseline scan; previously treated lesions are not selected as index lesions.
- Histologic or cytologic confirmed diagnosis of HCC.
- Physical and Laboratory Test Finding
- Adequate hematologic function with absolute neutrophil counts ≥1,500/mm3, platelet count ≥60 x 109/L, and hemoglobin ≥ 8.5 g/dl
- Adequate hepatic function with serum total bilirubin ≤ 3 mg/dl, serum albumin ≥ 2.8 g/dL and ALT and AST ≤ 5 times the institutional upper limits of normal.
- Amylase and lipase < 1.5 times the institutional upper limit of normal.
- Adequate renal function with serum creatinine ≤ 2.0 mg/dl.
- International normalized ratio (INR) ≤ 2.3 or Prothrombin Time (PT) ≤ 6
seconds above control.
- Left ventricular ejection fraction (LVEF) ≥ 50% as measured by 2-D echocardiogram.
- Adequate hematologic function with absolute neutrophil counts ≥1,500/mm3, platelet count ≥60 x 109/L, and hemoglobin ≥ 8.5 g/dl
- Age and Sex
- Male or female subjects ≥ 18 years of age
- Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and up to 12 weeks after the last dose of investigational product in such a manner that the risk of pregnancy is minimized
Main Exclusion Criteria:
- Sex and Reproductive Status
- Women who are pregnant or breastfeeding
- Target Disease Exceptions
- Brain metastasis or evidence of leptomeningeal disease
- Known fibrolamellar HCC or mixed cholangiocarcinoma and HCC
- History of encephalopathy
- Ascites
- Evidence of portal hypertension with bleeding esophageal or gastric varices within the past 2 months
- Main portal vein* or vena cava thrombosis or occlusion.
- Brain metastasis or evidence of leptomeningeal disease
- Medical History and Concurrent Diseases
- Previous or concurrent cancer that is distinct in primary site or histology from HCC, except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis & T1) (Any cancer curatively treated > 5 years prior to entry is permitted)
- History of active cardiac disease
- Thrombotic or embolic events within the past 6 months, such as a cerebrovascular accident (including transient ischemic attacks), pulmonary embolism
- Any other hemorrhage/bleeding event ≥ CTCAE Grade 3 within 4 weeks except for esophageal or gastric varices
- Active, untreated hepatitis B
- History of non-healing wounds or ulcers, or bone fractures within 3 months of fracture
- Major surgical procedure, open biopsy, or significant traumatic injury less than 3 weeks or those who receive minor surgical procedures (eg core biopsy or fine needle aspiration) within 1 week
- Portal-caval shunts
- Pre-existing thyroid abnormality with thyroid function that cannot be maintained in the normal range with medication
- History of human immunodeficiency virus (HIV) infection
- Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results.
- Any medical condition that is unstable or which could jeopardize the safety of the patient and his/her compliance in the study.
- Previous or concurrent cancer that is distinct in primary site or histology from HCC, except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis & T1) (Any cancer curatively treated > 5 years prior to entry is permitted)
- Physical and Laboratory Test Findings
- Baseline serum sodium < 130 mmol/L
- Baseline serum potassium < 3.5 mmol/L (potassium supplementation may be given to restore the serum potassium above this level prior to study entry)
- Allergies and Adverse Drug Reactions
- Known or suspected history of allergy to brivanib or sorafenib or any agents given in association with this trial
- Prohibited Treatments and/or Therapies
- Prior use of any systemic anti-cancer chemotherapy, immunotherapy, or molecular targeted agents for HCC
- Concomitant treatment with rifampin (and its analogues), or St John’s wort
- Prior use of systemic investigational agents for HCC
- Radiotherapy within 4 weeks prior to start of study drug
- Required anticoagulation therapy with an agent such as coumadin, warfarin, or heparin
- Required chronic anti-platelet therapy (aspirin at dose ≥ 300 mg/day, clopidogrel at dose ≥ 75 mg/day).
- Prior use of any systemic anti-cancer chemotherapy, immunotherapy, or molecular targeted agents for HCC
- Other Exclusion Criteria
- Prisoners or subjects who are involuntarily incarcerated
- Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.
- Prisoners or subjects who are involuntarily incarcerated
Costs for the Patient:
All costs for study drug and study-only tests will be covered by the sponsor and provided free of charge to the patient.
Contact persons:
Sherry Fu at 734-647-3635 (e-mail: sherryfu@med.umich.edu) or Carrie Manwaring at 734-763-7997 (e-mail: cmanwar@med.umich.edu) or Dr. Jorge Marrero at jmarrero@med.umich.edu.
