Siliphos in Advanced Hepatocellular Carcinoma

Phase I Trial of Siliphos in Patients With Advanced Hepatocellular Carcinoma

Milk thistle is an herbal drug that may have some liver protection properties and may reduce inflammation in the liver. It may also have anticancer effects. However milk thistle is not approved by the Food and Drug Administration for any medical purpose in the United States.

It has not been used in patients with liver cancer previously, to our knowledge, but there have been many studies of its use in patients with hepatitis and cirrhosis. Some of these studies have shown that milk thistle may help reduce elevated liver function tests.

Siliphos is a derivative of milk thistle that can be absorbed better than some other types of milk thistle. The investigators would like to perform a study to identify doses of siliphos that are safe to take in advanced liver cancer and to identify positive or negative side effects this compound may have. The investigators will be using this information in future studies to see if siliphos can be used as a therapy in patients with advanced liver cancer to reduce elevated liver function tests.

Study Overview

• Status: Completed
• Conditions: Advanced Hepatocellular Carcinoma
• Intervention / Treatment: Drug: Silybin

Detailed Description

Milk thistle (MT) has been historically used to treat patients with liver diseases, and has been shown to have antioxidant, anti inflammatory, and hepatoprotective properties. It may also have direct anticancer effects through inhibition of growth factors and promotion of cell cycle arrest. MT has been shown to improve LFTs in several studies of patients with cirrhosis. To our knowledge, there have been no published trials evaluating the clinical efficacy of MT in advanced HCC. We therefore propose a phase I study to identify the maximum tolerated dose (MTD) of silybinphosphatidylcholine (a commercially available preparation with increased bioavailability), in patients with advanced HCC. We will use a traditional dose escalation, open label design with a study intervention period of 3 months, followed by one year of observation, with a maximum total of 30 subjects, evaluating a dose range between 1 to 12 gm Siliphos. The data obtained from this study will be utilized in the future to evaluate MT efficacy in reducing liver function tests in advanced HCC, which will have significant implications in its use as a potential adjunctive agent in patients with currently limited treatment options.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age ≥18 years
• ECOG performance score of 0-3
• Expected survival of >12 weeks
• Subjects with advanced HCC or locally advanced, unresectable HCC
• Elevated LFTs (including at least one of the following: TBili >1.5 times the upper limit of normal; serum AST >2.5 times the upper limit of normal
• HCC diagnosed/defined based on either biopsy, or by suggestive radiologic imaging according to the AASLD guidelines (arterial enhancement with venous washout) or an AFP >200 ng/ml
• Subjects must have measurable disease that can be accurately measured in at least one dimension (with at least >20mm diameter in the longest dimension by conventional imaging or >10 mm by helical CT)
• Elevated liver enzymes that are either due to underlying liver disease and/or tumor which is not amenable to stenting after discussion with interventional GI and/or IR
• Subjects must demonstrate an ability to understand the consent process and willingness to sign a written informed consent form
• Subjects must agree to use birth control pills or other active contraception during active study treatment

Exclusion Criteria:

• Pregnant women or women currently breastfeeding will be excluded from this study because the effects of silybin on pregnant women and/or nursing infants are not known
• Subjects must have < grade 4 hepatic toxicity
• Known brain metastases because of poor prognosis and as patients with brain metastases often develop neurological dysfunction that may confound evaluation of neurologic and other adverse side effects
• History of allergic reactions to the study medication
• Uncontrolled concurrent illness including, but not limited to: ongoing active infection (including SBP), symptomatic congestive heart failure, unstable angina, active cardiac arrhythmia, or psychiatric illness that would limit compliance with study requirements

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Siliphos - dose escalation	Drug: Silybin; 4 dose levels of siliphos: 2, 4, 8, and 12 grams daily in three divided doses. This study will follow a standard sequential Phase I dose escalation design.; Other Names: Siliphos; Milk thistle; Advanced hepatocellular carcinoma

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The maximum tolerated dose of siliphos in patients with advanced hepatocellular carcinoma	Weeks 1, 3, 6, 9, and 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean intra-patient percent change in AST, ALT and total serum bilirubin levels	Fasting morning blood samples collected at baseline, weeks 1, 3, 6, 9, and 12	From baseline to 3 months
Quality of life as measured by the FACT-hepatobiliary questionnaire	Questionnaire administered at baseline, weeks 1, 6, and 12	From baseline to 3 months
Plasma concentrations of silybinin, silybinin B, silibinin glucoronide, and silibinin sulfate	Fasting morning blood samples collected at baseline, weeks 1, 3, 6, 9, and 12	From baseline to 3 months
Mean intra-patient percent change in serum concentrations of CRP, IGF-1, and IGFBP-3	Fasting morning blood samples collected at baseline, weeks 1, 3, 6, and 12	From baseline to 3 months
Tumor response as measured by RECIST criteria and AFP concentrations	Fasting blood samples collected at baseline, weeks 1, 3, 6, 9, and 12 for AFP concentrations. MRI of abdomen/pelvis & CT of chest at baseline and week 12	From baseline to 3 months

Collaborators and Investigators

• Sponsor: Abby Siegel
• Collaborators: Lotte & John Hecht Memorial Foundation
• Investigators: Principal Investigator: Abby Siegel, MD, MS, Columbia University

Study record dates

Study Major Dates

• Study Start: February 1, 2010
• Primary Completion (Actual): June 1, 2013
• Study Completion (Actual): June 1, 2013

Study Registration Dates

• First Submitted: April 12, 2010
• First Submitted That Met QC Criteria: May 21, 2010
• First Posted (Estimate): May 24, 2010

Study Record Updates

• Last Update Posted (Estimate): November 25, 2013
• Last Update Submitted That Met QC Criteria: November 21, 2013
• Last Verified: November 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Physiological Effects of Drugs; Antineoplastic Agents; Protective Agents; Antineoplastic Agents, Phytogenic; Silybin
• Other Study ID Numbers: AAAE7604