Adult Primary Liver Cancer, Hepatitis C Infection
Conditions
Brief summary
This randomized phase II trial studies how well S-Adenosyl-L-Methionine Disulphate P-Toluene-Sulfonate (SAMe) works compared to a placebo in preventing liver cancer in patients with chronic hepatitis C infection. Chemoprevention is the use of certain drugs to keep cancer from forming. The use of SAMe may keep cancer from forming in patients with advanced liver disease
Detailed description
PRIMARY OBJECTIVE: I. To determine whether treatment with SAMe for 24 weeks reduces serum level of alpha-fetoprotein (AFP) in patients with advanced liver disease due to chronic hepatitis C. SECONDARY OBJECTIVE: I. To determine whether treatment with SAMe for 24 weeks reduces serum levels of des-gamma carboxyprothrombin (DCP) and alpha-fetoprotein-L3 (AFP-L3) in patients with advanced liver disease due to chronic hepatitis C (hepatocellular carcinoma tumor markers). II. To determine whether treatment with SAMe for 24 weeks alters biochemical markers of liver disease (e.g., serum alanine aminotransferase \[ALT\], aspartate aminotransferase \[AST\], albumin, or bilirubin, etc.) and hepatitis C viral load in patients with advanced liver disease due to chronic hepatitis C (hepatitis C liver disease). III. To determine whether treatment with SAMe for 24 weeks reduces serum levels of tumor necrosis factor-alpha (TNF-alpha), plasma levels of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE) and urine levels of F2-isoprostane in patients with advanced liver disease due to chronic hepatitis C (oxidative stress). IV. To determine whether treatment with SAMe for 24 weeks reduces plasma levels of methionine and homocysteine and increases plasma glutathione (GSH) and SAMe in patients with advanced liver disease due to chronic hepatitis C (SAMe metabolites). V. To determine the safety, tolerability and quality of life of SAMe treatment (up to 2,400 mg/day) for 24 weeks in patients with advanced liver disease due to chronic hepatitis C. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive SAMe orally (PO) twice daily (BID) for 24 weeks in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive placebo PO once daily (QD) for weeks 1-4, PO BID for weeks 5-8, and PO three times daily (TID) for weeks 9-24 in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 6 weeks.
Interventions
OTHERplacebo
Given PO
OTHERlaboratory biomarker analysis
Correlative studies
OTHERimmunoenzyme technique
Correlative studies
OTHERhigh performance liquid chromatography
Correlative studies
Sponsors
National Cancer Institute (NCI)
Chao Family Comprehensive Cancer Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Chronic hepatitis C infection diagnosed by presence of hepatitis C ribonucleic acid (RNA) in serum by test of hepatitis C virus (HCV) RNA * No significant alcohol use (7 or fewer drinks per week) for the past 12 months * Serum AFP (at screening) between 15 and 100 ng/mL (15 ng/mL =\< AFP =\< 100 ng/mL) as measured by the Bayer Advai Centaur chemiluminescence system OR Serum AFP between 10 and 100 ng/mL (10 ng/mL =\< AFP =\<100 ng/mL) as measured by Diagnostic Products Corporation Immulite assay system OR AFP between 12 and 100 ng/mL (12 ng/mL =\< AFP =\< 100 ng/mL) as measured by Ortho ECiQ assay system * Evidence of advanced liver disease based on one or more of the following: * Platelet count less than 150,000/mm\^3 * Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio \> 0.75 * Liver biopsy demonstrating bridging fibrosis or cirrhosis * No treatment with interferon (recombinant interferon alfa), peginterferon (PEG-interferon alfa-2b), or ribavirin for at least 4 months, and not anticipated to start specific treatment for hepatitis C during the study (30 weeks) * Ultrasound (or adequate computed tomography \[CT\] or magnetic resonance imaging \[MRI\]) examination of the liver within 6 months prior to randomization revealing no masses in the liver suggestive of hepatocellular carcinoma * Willing to refrain from consuming over-the-counter SAMe and vitamin pills containing B-vitamins while participating in this study (30 weeks) * Eastern Cooperative Oncology Group (ECOG) performance status 0-2 * Leukocytes \> 1,000/ mm\^3 * Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately * Ability to understand and the willingness to sign a written informed consent document
Exclusion criteria
* Liver disease other than from hepatitis C (e.g., hepatitis B, hemochromatosis, fat in more than 33% of hepatocytes, if liver biopsy has been performed., etc.); subjects with a past history of alcohol use can be enrolled into the study provided they have consumed less than 7 drinks/week for the past 12 months * Evidence of mass in liver by radiologic examination that is suggestive of hepatocellular carcinoma within 6 months prior to randomization * Model for End-Stage Liver Disease (MELD) score greater than 15 within 60 days prior to enrollment * Ascites which is clinically detectable * Use of SAMe during 4 months prior to randomization * Hospitalization within the past 5 years for mania or for bipolar disease * Concurrent use of monoamine oxidase inhibitors (MAO) or other drugs that increase the concentration of serotonin * Participants may not be receiving any other investigational agents * History of allergic reactions attributed to compounds of similar chemical or biologic composition to SAMe * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements * Children are excluded from this study but will be eligible for future pediatric trials, if applicable * Pregnant women are excluded from this study; serum pregnancy must be performed and be negative in all women of child bearing potential within 2 weeks prior to enrollment; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with SAMe, breastfeeding should be discontinued if the mother is treated with SAMe * Subjects with any medical psychosocial condition that, in the opinion of the investigator, could jeopardize the subject's participation in and compliance with the study criteria
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Serum AFP Levels | Baseline to week 24 | Measured using an Food and Drug Administration (FDA)-approved assay. Mean change over time for the SAMe and placebo groups will be estimated. Differences in the change over time between the treated and control groups will be tested using a two-group repeated measures analysis of variance model. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Treatment-related Changes in Serum AFP-L3 (Expressed as the Percentage of Total AFTP) for Hepatocellular Carcinoma | Baseline to week 24 | AFP-L3 assay will be performed by Wako Laboratories using their LiBASys platform. |
| SAMe | Baseline to week 24 | Change in SAMe levels |
| Change in SAMe Metabolites - S-adenosylhomocysteine (SAH) | Baseline to week 24 | S-adenosylhomocysteine (SAH) |
| Change in SAMe Metabolites - Methionine | Baseline to week 24 | Methionine will be measured using HPLC with fluorescence detection. |
| Change in SAMe Metabolites - Total Homocysteine (tHcy) | Baseline to week 24 | Total homocysteine (tHcy) |
| Change in SAMe Metabolites - Plasma GSH | Baseline to week 24 | Plasma GSH will be measured using HPLC with fluorescence detection. |
| Treatment-related Changes in Serum DCP for Hepatocellular Carcinoma | Baseline to week 24 | To determine whether treatment with SAMe for 24 weeks reduces serum levels of des-gamma carboxyprothrombin (DCP) in patients with advanced liver disease due to chronic hepatitis C (hepatocellular carcinoma tumor markers). |
| Change in SAMe Metabolites - 4-hydroxynonenal (4-HNE) | Baseline to week 24 | Serum marker of oxidative stress. One mechanism by which SAMe is hypothesized to be beneficial is by reducing oxidative stress. |
| Change in Markers of Liver Disease - AST | Baseline to week 24 | AST measurements will be performed in a College of American Pathologists (CAP)-certified lab using FDA-approved assays. |
| Change in Markers of Liver Disease - ALT | Baseline to week 24 | ALT measurements will be performed in a College of American Pathologists (CAP)-certified lab using FDA-approved assays. |
| HCV RNA | Baseline to week 24 | Change in HCV RNA levels. Serum level of HVC RNA was measured using COBAS TaqMan HCV test (Roche Molecular Systems). |
| Changes in Quality of Life - Physical Score | Baseline to week 24 | Change from Baseline to Week 24 in Quality of life as as assessed with Short Form (SF)-36 Physical Component Scores. Measured quality of life using the SF-36, a widely used and general questionnaire of quality of life. Possible scores range from 0 and 100. High scores reflect good QOL and low scores reflect bad QOL. Change in QOL = (Week 24 score - Baseline score). |
| Changes in Quality of Life - Mental Score | Baseline to week 24 | Change from Baseline to Week 24 in Quality of life as as assessed with Short Form (SF)-36 Mental Component Scores. Measured quality of life using the SF-36, a widely used and general questionnaire of quality of life. Possible scores range from 0 and 100. High scores reflect good QOL and low scores reflect bad QOL. Change = (Week 24 score - Baseline score). |
| Change in SAMe Metabolites - Malondialdehyde (MDA) | Baseline to week 24 | malondialdehyde |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I (SAMe) Patients receive SAMe PO QD for weeks 1-4, PO BID for weeks 5-8, and PO TID for weeks 9-24 in the absence of disease progression or unacceptable toxicity.
S-adenosyl-L-methionine disulfate p-toluene-sulfonate: Given PO
laboratory biomarker analysis: Correlative studies
immunoenzyme technique: Correlative studies
high performance liquid chromatography: Correlative studies | 57 |
| Arm II (Placebo) Patients receive placebo PO QD for weeks 1-4, PO BID for weeks 5-8, and PO TID for weeks 9-24 in the absence of disease progression or unacceptable toxicity.
placebo: Given PO
laboratory biomarker analysis: Correlative studies
immunoenzyme technique: Correlative studies
high performance liquid chromatography: Correlative studies | 53 |
| Total | 110 |
Baseline characteristics
| Characteristic | Arm I (SAMe) | Arm II (Placebo) | Total |
|---|---|---|---|
| Age, Continuous | 58.5 years STANDARD_DEVIATION 4.9 | 57.2 years STANDARD_DEVIATION 5.8 | 57.88 years STANDARD_DEVIATION 5.33 |
| Sex: Female, Male Female | 9 Participants | 6 Participants | 15 Participants |
| Sex: Female, Male Male | 48 Participants | 47 Participants | 95 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 51 / 57 | 46 / 53 |
| serious Total, serious adverse events | 5 / 57 | 3 / 53 |
Outcome results
Primary
Change in Serum AFP Levels
Measured using an Food and Drug Administration (FDA)-approved assay. Mean change over time for the SAMe and placebo groups will be estimated. Differences in the change over time between the treated and control groups will be tested using a two-group repeated measures analysis of variance model.
Time frame: Baseline to week 24
Population: All subjects who completed the week 24 visit as planned were included in the data anlysis. The number of subjects in each analysis differed slightly because the number of subjects with data at both time points (i.e., week 0 and week 24) varied depending on the outcome measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (SAMe) | Change in Serum AFP Levels | -1.928 ng/mL | Standard Deviation 20.304 |
| Arm II (Placebo) | Change in Serum AFP Levels | 5.855 ng/mL | Standard Deviation 29.207 |
p-value: 0.16Wilcoxon (Mann-Whitney)
Secondary
Change in Markers of Liver Disease - ALT
ALT measurements will be performed in a College of American Pathologists (CAP)-certified lab using FDA-approved assays.
Time frame: Baseline to week 24
Population: All subjects who completed the week 24 visit as planned were included in the data analysis. The number of subjects in each analysis differed slightly because the number of subjects with data at both time points (i.e., week 0 and week 24) varied depending on the outcome measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (SAMe) | Change in Markers of Liver Disease - ALT | -9.548 IU/L | Standard Deviation 34.786 |
| Arm II (Placebo) | Change in Markers of Liver Disease - ALT | 0.019 IU/L | Standard Deviation 41.165 |
Secondary
Change in Markers of Liver Disease - AST
AST measurements will be performed in a College of American Pathologists (CAP)-certified lab using FDA-approved assays.
Time frame: Baseline to week 24
Population: All subjects who completed the week 24 visit as planned were included in the data analysis. The number of subjects in each analysis differed slightly because the number of subjects with data at both time points (i.e., week 0 and week 24) varied depending on the outcome measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (SAMe) | Change in Markers of Liver Disease - AST | -0.755 IU/L | Standard Deviation 37.531 |
| Arm II (Placebo) | Change in Markers of Liver Disease - AST | 1.723 IU/L | Standard Deviation 40.709 |
Secondary
Change in SAMe Metabolites - 4-hydroxynonenal (4-HNE)
Serum marker of oxidative stress. One mechanism by which SAMe is hypothesized to be beneficial is by reducing oxidative stress.
Time frame: Baseline to week 24
Population: All subjects who completed the week 24 visit as planned were included in the data analysis. The number of subjects in each analysis differed slightly because the number of subjects with data at both time points (i.e., week 0 and week 24) varied depending on the outcome measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (SAMe) | Change in SAMe Metabolites - 4-hydroxynonenal (4-HNE) | -0.185 µg/mL | Standard Deviation 0.716 |
| Arm II (Placebo) | Change in SAMe Metabolites - 4-hydroxynonenal (4-HNE) | -0.032 µg/mL | Standard Deviation 0.448 |
Secondary
Change in SAMe Metabolites - Malondialdehyde (MDA)
malondialdehyde
Time frame: Baseline to week 24
Population: All subjects who completed the week 24 visit as planned were included in the data analysis. The number of subjects in each analysis differed slightly because the number of subjects with data at both time points (i.e., week 0 and week 24) varied depending on the outcome measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (SAMe) | Change in SAMe Metabolites - Malondialdehyde (MDA) | -0.007 µmol/L | Standard Deviation 0.848 |
| Arm II (Placebo) | Change in SAMe Metabolites - Malondialdehyde (MDA) | -0.002 µmol/L | Standard Deviation 1.162 |
Secondary
Change in SAMe Metabolites - Methionine
Methionine will be measured using HPLC with fluorescence detection.
Time frame: Baseline to week 24
Population: All subjects who completed the week 24 visit as planned were included in the data analysis. The number of subjects in each analysis differed slightly because the number of subjects with data at both time points (i.e., week 0 and week 24) varied depending on the outcome measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (SAMe) | Change in SAMe Metabolites - Methionine | 0.421 µmol/L | Standard Deviation 18.794 |
| Arm II (Placebo) | Change in SAMe Metabolites - Methionine | -2.894 µmol/L | Standard Deviation 23.669 |
Secondary
Change in SAMe Metabolites - Plasma GSH
Plasma GSH will be measured using HPLC with fluorescence detection.
Time frame: Baseline to week 24
Population: All subjects who completed the week 24 visit as planned were included in the data analysis. The number of subjects in each analysis differed slightly because the number of subjects with data at both time points (i.e., week 0 and week 24) varied depending on the outcome measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (SAMe) | Change in SAMe Metabolites - Plasma GSH | 0.455 µmol/L | Standard Deviation 1.425 |
| Arm II (Placebo) | Change in SAMe Metabolites - Plasma GSH | 0.285 µmol/L | Standard Deviation 1.23 |
Secondary
Change in SAMe Metabolites - S-adenosylhomocysteine (SAH)
S-adenosylhomocysteine (SAH)
Time frame: Baseline to week 24
Population: All subjects who completed the week 24 visit as planned were included in the data analysis. The number of subjects in each analysis differed slightly because the number of subjects with data at both time points (i.e., week 0 and week 24) varied depending on the outcome measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (SAMe) | Change in SAMe Metabolites - S-adenosylhomocysteine (SAH) | 16.326 nmol/L | Standard Deviation 28.212 |
| Arm II (Placebo) | Change in SAMe Metabolites - S-adenosylhomocysteine (SAH) | -3.456 nmol/L | Standard Deviation 13.104 |
Secondary
Change in SAMe Metabolites - Total Homocysteine (tHcy)
Total homocysteine (tHcy)
Time frame: Baseline to week 24
Population: All subjects who completed the week 24 visit as planned were included in the data analysis. The number of subjects in each analysis differed slightly because the number of subjects with data at both time points (i.e., week 0 and week 24) varied depending on the outcome measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (SAMe) | Change in SAMe Metabolites - Total Homocysteine (tHcy) | 0.266 µmol/L | Standard Deviation 2.394 |
| Arm II (Placebo) | Change in SAMe Metabolites - Total Homocysteine (tHcy) | -0.677 µmol/L | Standard Deviation 2.478 |
Secondary
Changes in Quality of Life - Mental Score
Change from Baseline to Week 24 in Quality of life as as assessed with Short Form (SF)-36 Mental Component Scores. Measured quality of life using the SF-36, a widely used and general questionnaire of quality of life. Possible scores range from 0 and 100. High scores reflect good QOL and low scores reflect bad QOL. Change = (Week 24 score - Baseline score).
Time frame: Baseline to week 24
Population: All subjects who completed the week 24 visit as planned were included in the data analysis. The number of subjects in each analysis differed slightly because the number of subjects with data at both time points (i.e., week 0 and week 24) varied depending on the outcome measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (SAMe) | Changes in Quality of Life - Mental Score | 0.83 scores on a scale | Standard Deviation 15.06 |
| Arm II (Placebo) | Changes in Quality of Life - Mental Score | -2.83 scores on a scale | Standard Deviation 11.76 |
p-value: 0.212Two-Group t-test
Secondary
Changes in Quality of Life - Physical Score
Change from Baseline to Week 24 in Quality of life as as assessed with Short Form (SF)-36 Physical Component Scores. Measured quality of life using the SF-36, a widely used and general questionnaire of quality of life. Possible scores range from 0 and 100. High scores reflect good QOL and low scores reflect bad QOL. Change in QOL = (Week 24 score - Baseline score).
Time frame: Baseline to week 24
Population: All subjects who completed the week 24 visit as planned were included in the data analysis. The number of subjects in each analysis differed slightly because the number of subjects with data at both time points (i.e., week 0 and week 24) varied depending on the outcome measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (SAMe) | Changes in Quality of Life - Physical Score | -0.4 units on a scale | Standard Deviation 11.73 |
| Arm II (Placebo) | Changes in Quality of Life - Physical Score | 0.03 units on a scale | Standard Deviation 13.6 |
p-value: 0.878Two-Group t-test
Secondary
HCV RNA
Change in HCV RNA levels. Serum level of HVC RNA was measured using COBAS TaqMan HCV test (Roche Molecular Systems).
Time frame: Baseline to week 24
Population: All subjects who completed the week 24 visit as planned were included in the data analysis. The number of subjects in each analysis differed slightly because the number of subjects with data at both time points (i.e., week 0 and week 24) varied depending on the outcome measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (SAMe) | HCV RNA | -259327.69 IU/mL | Standard Deviation 3084015.42 |
| Arm II (Placebo) | HCV RNA | -19968.89 IU/mL | Standard Deviation 2425010.48 |
Secondary
SAMe
Change in SAMe levels
Time frame: Baseline to week 24
Population: All subjects who completed the week 24 visit as planned were included in the data analysis. The number of subjects in each analysis differed slightly because the number of subjects with data at both time points (i.e., week 0 and week 24) varied depending on the outcome measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (SAMe) | SAMe | 414.242 nmol/L | Standard Deviation 744.373 |
| Arm II (Placebo) | SAMe | -9.085 nmol/L | Standard Deviation 54.621 |
Secondary
Treatment-related Changes in Serum AFP-L3 (Expressed as the Percentage of Total AFTP) for Hepatocellular Carcinoma
AFP-L3 assay will be performed by Wako Laboratories using their LiBASys platform.
Time frame: Baseline to week 24
Population: All subjects who completed the week 24 visit as planned were included in the data analysis. The number of subjects in each analysis differed slightly because the number of subjects with data at both time points (i.e., week 0 and week 24) varied depending on the outcome measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (SAMe) | Treatment-related Changes in Serum AFP-L3 (Expressed as the Percentage of Total AFTP) for Hepatocellular Carcinoma | 0.144 percentage of AFP-L3/AFP | Standard Deviation 1.146 |
| Arm II (Placebo) | Treatment-related Changes in Serum AFP-L3 (Expressed as the Percentage of Total AFTP) for Hepatocellular Carcinoma | 0.335 percentage of AFP-L3/AFP | Standard Deviation 3.486 |
Secondary
Treatment-related Changes in Serum DCP for Hepatocellular Carcinoma
To determine whether treatment with SAMe for 24 weeks reduces serum levels of des-gamma carboxyprothrombin (DCP) in patients with advanced liver disease due to chronic hepatitis C (hepatocellular carcinoma tumor markers).
Time frame: Baseline to week 24
Population: All subjects who completed the week 24 visit as planned were included in the data analysis. The number of subjects in each analysis differed slightly because the number of subjects with data at both time points (i.e., week 0 and week 24) varied depending on the outcome measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (SAMe) | Treatment-related Changes in Serum DCP for Hepatocellular Carcinoma | 0.259 ng/mL | Standard Deviation 0.976 |
| Arm II (Placebo) | Treatment-related Changes in Serum DCP for Hepatocellular Carcinoma | 0.647 ng/mL | Standard Deviation 1.491 |