Infections

All Conditions

Symptoms and General Pathology

Digestive System Diseases

Neoplasms

Rare Diseases

Communicable Diseases

Hepatitis A

Hepatitis C

Hepatitis

Liver Neoplasms

Liver Diseases

Gastrointestinal Diseases

Hepatitis, Viral, Human

Virus Diseases

RNA Virus Infections

Blood-Borne Infections

Flaviviridae Infections

Gastrointestinal Neoplasms

Digestive System Neoplasms

Chronic Graft Versus Host Disease

Primary Liver Cancer

Hematinics

All Drugs and Chemicals

Amino Acids

Liver Extracts

Methionine

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.

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.

S-adenosyl-L-methionine disulfate p-toluene-sulfonate

placebo

laboratory biomarker analysis

immunoenzyme technique

high performance liquid chromatography

John Hoefs

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

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.

Liver Cancer Prevention Trial in Patients With Chronic Hep C Infection

A Phase II, Randomized, Controlled Trial of The Safety and Efficacy of S-Adenosyl-L-Methionine Disulphate P-Toluene-Sulfonate (SAMe) in Reducing Serum Alpha-Fetoprotein (AFP) in Patients With Hepatitis C and Moderately Elevated AFP

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.

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).

AFP-L3 assay will be performed by Wako Laboratories using their LiBASys platform.

Methionine will be measured using HPLC with fluorescence detection.

Plasma GSH will be measured using HPLC with fluorescence detection.

Serum marker of oxidative stress. One mechanism by which SAMe is hypothesized to be beneficial is by reducing oxidative stress.

AST measurements will be performed in a College of American Pathologists (CAP)-certified lab using FDA-approved assays.

ALT measurements will be performed in a College of American Pathologists (CAP)-certified lab using FDA-approved assays.

Change in HCV RNA levels. Serum level of HVC RNA was measured using COBAS TaqMan HCV test (Roche Molecular Systems).

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).

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).

National Cancer Institute (NCI)

Chao Family Comprehensive Cancer Center

Cancer Center

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

Arm I (SAMe)

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

Arm II (Placebo)

Total

Age, Continuous

Sex: Female, Male

Dr. Timothy R. Morgan

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.

Change in Serum AFP Levels

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.

Treatment-related Changes in Serum DCP for Hepatocellular Carcinoma

Treatment-related Changes in Serum AFP-L3 (Expressed as the Percentage of Total AFTP) for Hepatocellular Carcinoma

SAMe

Change in SAMe Metabolites - S-adenosylhomocysteine (SAH)

Change in SAMe Metabolites - Methionine

Change in SAMe Metabolites - Total Homocysteine (tHcy)

Change in SAMe Metabolites - Plasma GSH

Change in SAMe Metabolites - Malondialdehyde (MDA)

Change in SAMe Metabolites - 4-hydroxynonenal (4-HNE)

Change in Markers of Liver Disease - AST

Change in Markers of Liver Disease - ALT

HCV RNA

Changes in Quality of Life - Physical Score

Changes in Quality of Life - Mental Score

Overall Study

Carcinoma

Carcinoma, Hepatocellular

Recurrence

Liver Cirrhosis

Hepatitis B

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Disease Attributes

Enterovirus Infections

Picornaviridae Infections

Adenocarcinoma

Hepadnaviridae Infections

DNA Virus Infections

Antineoplastic Agents

Sorafenib

Navitoclax

Protein Kinase Inhibitors

Enzyme Inhibitors

Patients receive navitoclax PO QD on days 1-21 (days 1-28 cycle of 1 only) and sorafenib tosylate PO BID on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis

Pharmacological Study

Sorafenib Tosylate

Brian A Costello

This phase I trial studies the side effects and the best dose of navitoclax when given together with sorafenib tosylate in treating patients with solid tumors that have returned (relapsed) or do not respond to treatment (refractory). Navitoclax and sorafenib tosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of the combination of navitoclax and sorafenib tosylate (sorafenib) in patients with advanced solid tumors. (Dose escalation cohort) II. To better characterize the toxicity profile of the combination of navitoclax and sorafenib. (Dose expansion cohort)

SECONDARY OBJECTIVES:

I. To identify any activity of this treatment combination in patients with metastatic cancer. (Dose escalation cohort) II. To seek preliminary evidence of activity of this treatment combination in patients with hepatoma. (Dose expansion cohort)

CORRELATIVE OBJECTIVES:

I. To determine whether the combination of navitoclax and sorafenib induces apoptosis that can be detected by peripheral blood biomarker analysis. (Dose escalation cohort) II. To assess peripheral blood biomarkers and pharmacokinetics in a more homogenous population. (Dose expansion cohort) III. To determine whether treatment is associated with Mcl-1 down regulation in hepatocellular carcinoma (HCC) at the maximum tolerated dose (MTD). (Dose expansion cohort) IV. To assess in a preliminary fashion whether pretreatment tumor cell levels of Mcl-1 predict response to this regimen through serial biopsies. (Dose expansion cohort)

OUTLINE: This is a dose-escalation study of navitoclax.

Patients receive navitoclax orally (PO) once daily (QD) on days 1-21 (days 1-28 cycle of 1 only) and sorafenib tosylate PO twice daily (BID) on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Navitoclax and Sorafenib Tosylate in Treating Patients With Relapsed or Refractory Solid Tumors

A Phase I Trial of ABT-263 (Navitoclax), a Bcl-2 Inhibitor, and Sorafenib (Nexavar) in Patients With Relapsed or Refractory Solid Organ Tumors

To assess changes in each antigen, dot plots will be constructed with H-score on the Y axis and pre-or post-treatment status on the X axis, looking for patterns of change that emerge. To assess whether changes occur predominantly in one direction, a sign test will be applied.

Will be assessed by immunohistochemistry. The relationship between pretreatment Mcl-1 expression and clinical response will be examined in a post hoc and exploratory fashion. To assess the relationship between Mcl-1 and response the H score (0-300) vs. response will be graphed. Chi-squared tests will be used to assess significance of relationships between these dichotomous variables and response. In addition, associations between molecular markers and time-to-event variables (progression-free-survival \[PFS\]) will be illustrated graphically using Kaplan-Meier curves and log-rank tests in an exploratory fashion.

Will be assessed by enzyme-linked immunosorbent assay (ELISA). Will be summarized descriptively and plotted along time by dose levels and as a whole. The changes of the serum levels of cleaved and total CK18 at each time point against pre-treatment baseline will be correlated with toxicity and clinical endpoints. The relationships between cleaved and total CK18, caspase 3 and cytochrome c at various time points and dose levels will be explored in longitudinal data analysis. Tissue expression of Mcl-1 will be correlated with serum levels of cleaved and total CK18 at different time points and clinical toxicity and tumor response.

Will be defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least one-third of patients (at least 2 of a maximum of 6 new patients) per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 4.0.

Will be graded per NCI CTCAE v. 4.0. The number and severity of all adverse events (overall, by dose-level, and by tumor group) will be tabulated and summarized in this patient population. The grade 3+ adverse events will also be described and summarized in a similar fashion.

Will be assessed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline version 1.1. Response will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease. The waterfall plot may be used to display best tumor response. Exploratory analysis of the relationship between response and other clinical endpoints may be performed.

The data on time-related variables will be summarized descriptively.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Liver Cancer Prevention Trial in Patients With Chronic Hep C Infection	NCT00513461	Adult Primary L... Hepatitis C Inf...	S-adenosyl-L-me... placebo laboratory biom... immunoenzyme te... high performanc...	18 Years -	University of California, Irvine
Navitoclax and Sorafenib Tosylate in Treating Patients With Relapsed or Refractory Solid Tumors	NCT02143401	Cirrhosis Hepatitis B Inf... Hepatitis C Inf... Metastatic Mali... Recurrent Hepat... Recurrent Malig... Refractory Mali... Stage IV Hepato... Unresectable So...	Laboratory Biom... Navitoclax Pharmacological... Sorafenib Sorafenib Tosyl...	18 Years -	National Cancer Institute (NCI)
Navitoclax and Sorafenib Tosylate in Treating Patients With Relapsed or Refractory Solid Tumors	NCT02143401	Cirrhosis Hepatitis B Inf... Hepatitis C Inf... Metastatic Mali... Recurrent Hepat... Recurrent Malig... Refractory Mali... Stage IV Hepato... Unresectable So...	Laboratory Biom... Navitoclax Pharmacological... Sorafenib Sorafenib Tosyl...	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for hepatitis c infection