Study of TAC-101 as Second Line Treatment in Patients With Advanced Hepatocellular Carcinoma Who Received Sorafenib as First Line Therapy

This study has been terminated.
(Terminated due to safety concerns)
Sponsor:
Collaborator:
Quintiles
Information provided by (Responsible Party):
Taiho Oncology, Inc.
ClinicalTrials.gov Identifier:
NCT00687596
First received: May 28, 2008
Last updated: June 4, 2013
Last verified: June 2013
  Purpose

The purpose of this study is to determine whether TAC-101 as a second line therapy for patients who received Sorafenib as first line therapy is effective in slowing tumor activity in patients with advanced hepatocellular carcinoma. The study is also looking at the safety of TAC-101 following treatment with Sorafenib.


Condition Intervention Phase
Hepatocellular Carcinoma
Drug: TAC-101
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Phase 2, Double-blind, Placebo-controlled, Randomized, International, Multicenter Study of Oral TAC 101 as Second Line Treatment in Patients With Advanced Hepatocellular Carcinoma Who Received Sorafenib as First Line Therapy

Resource links provided by NLM:


Further study details as provided by Taiho Oncology, Inc.:

Primary Outcome Measures:
  • Overall survival (OS) [ Time Frame: Obtained at 30-day Safety F/up, every 9 wks during imaging f/up period; following new lesions, pts will be contacted every 12 wks until until death or for at least 3 yrs after randomization of the last pt, whichever is earlier ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Radiologic progression-free survival (PFS) [ Time Frame: Imaging studies of chest and abdomen obtained at Screening; every 6 wks during study treatment; end of treatment; if pt d/c's for reasons other than PD, every 6 wks until PD; every 6 wks folloing PD util death or up to 2yrs after last pt randomized ] [ Designated as safety issue: No ]
  • Time To Progression (TTP) [ Time Frame: Imaging studies of chest and abdomen obtained at Screening; every 6 wks during study treatment; end of treatment; if pt d/c's for reasons other than PD, every 6 wks until PD; every 6 wks folloing PD util death or up to 2yrs after last pt randomized ] [ Designated as safety issue: No ]
  • Adverse event profile and tolerability TAC-101 as second line therapy [ Time Frame: AEs will be reported from the time a patient signs ICF through the period of patient follow-up (30 days after the last dose of study medication) ] [ Designated as safety issue: Yes ]
  • Effects on plasma levels of the tumor marker alpha-fetoprotein (AFP) and AFP-L3 [ Time Frame: Blood samples collected at Screening; Day 1 of each cycle; at end of treatment; if the patient d/c's study treatment for reasons other than PD, every 6 wks until PD; every 6 wks following PD until death or 2 yrs after last pt is randomized ] [ Designated as safety issue: No ]
  • The relationship between the PK of TAC-101 and its metabolites (blood sampling for PK is optional),and safety and efficacy parameters, including hepatic function [ Time Frame: PK blood samples will be collected at 4, 8, and 24 hours postdose on Day 1 of treatment Cycle 1. The 24 hour sample must be collected prior to dosing on Day 2 ] [ Designated as safety issue: No ]
  • The effects on selected RAR-related factors and a selected growth factor [ Time Frame: Collect blood samples at Screening/Baseline; every 6 wks during the treatment period. ] [ Designated as safety issue: No ]
  • To investigate antitumor activity after treatment discontinuation [ Time Frame: Imaging studies of chest and abdomen obtained at Screening; every 6 wks during study treatment; end of treatment; if pt d/c's for reasons other than PD, every 6 wks until PD; every 6 wks folloing PD until death or up to 2yrs after last pt randomized ] [ Designated as safety issue: No ]
  • To investigate the relationship between tumor gene expression (mRNA expression) of co-activators, co-repressors and efficacy parameters [ Time Frame: The assessment of correlative factors should be conducted on tissue removed prior to the study ] [ Designated as safety issue: No ]

Enrollment: 52
Study Start Date: June 2008
Study Completion Date: August 2010
Primary Completion Date: May 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: A
Patients randomized to TAC 101 will receive TAC 101 20 mg (administered as 2 10 mg formulated tablets) PO daily with approximately 240 mL (8 oz) of water under fed conditions (no later than 1 hour after a meal) for 14 days followed by a 7 day recovery period. This cycle will be repeated every 21 days.
Drug: TAC-101
Patients randomized to TAC 101 will receive TAC 101 20 mg (administered as 2 10 mg formulated tablets) PO daily with approximately 240 mL (8 oz) of water under fed conditions (no later than 1 hour after a meal) for 14 days followed by a 7 day recovery period. This cycle will be repeated every 21 days.
Placebo Comparator: B
Patients randomized to placebo will receive 2 placebo tablets (identical in appearance to the TAC 101 tablets) administered PO daily with approximately 240 mL (8 oz) of water under fed conditions (no later than 1 hour after a meal) in a regimen identical to that for TAC 101.
Drug: Placebo
Patients randomized to placebo will receive 2 placebo tablets (identical in appearance to the TAC 101 tablets) administered PO daily with approximately 240 mL (8 oz) of water under fed conditions (no later than 1 hour after a meal) in a regimen identical to that for TAC 101.

Detailed Description:

Advanced metastatic hepatocellular carcinoma (HCC) is not treatable by surgical approaches or locoregional therapies such as hepatic artery hemoembolization or radiofrequency ablation (RFA) which are effective in controlling localized tumors. Currently marketed systemic chemotherapy agents, with the exception of sorafenib, provide marginal benefit. Despite the demonstrated survival benefit from sorafenib, it is still imperative to improve to the effectiveness of systemic therapy in this patient population. Studies of TAC-101, a synthetic retinoid, indicate that although TAC-101 may not induce tumor regression, it appears to have a stabilizing effect, prolonging survival over what was expected historically. This Phase 2, randomized, double-blind, placebo-controlled international, multicenter study is designed to evaluate the efficacy and safety of TAC 101 as second line treatment in patients with advanced HCC following treatment with sorafenib as first-line therapy. Sorafenib has recently been approved as first line treatment for HCC in the EU and the US and is expected to become the standard of care for the first-line treatment of advanced HCC. Aside from best supportive care, there is no second line therapy available for HCC. It is hypothesized that TAC 101 treatment can extend Overall Survival (OS) after discontinuation of sorafenib.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Provide written informed consent prior to performance of any study procedures
  • Is at least 18 years of age
  • Have a diagnosis of advanced unresectable histologically confirmed HCC (excluding fibrolamellar carcinoma)
  • Have discontinued from first line treatment with sorafenib monotherapy for any reason (ie, tumor disease progression, intolerance) at least 14 days prior to planned randomization but have not received any second line treatment for HCC
  • Have recovered from any significant sorafenib-related treatment toxicities prior to randomization (Grade 1)
  • Have at least 1 target lesion that is viable (has vascularization) and can be accurately measured according to RECIST
  • Patients who have received local therapy prior to sorafenib administration (radiation, surgery, hepatic arterial embolization, chemoembolization, RFA, percutaneous ethanol injection [PEI] or cryoablation) are eligible. Local therapy must be completed at least 4 weeks prior to the baseline scan
  • Have ECOG score of 0, 1, or 2
  • Child-Pugh score <8
  • Have adequate organ function defined as:

    • Platelet count great than 50, less than 109/L;
    • Hemoglobin 8.0 g/dL;
    • Total bilirubin 3 mg/dL;
    • Alanine transaminase (ALT) and aspartate aminotransferase (AST) less than or equal to 5 X ULN;
    • Serum creatinine 1.5 X ULN;
    • PT-international normalized ratio (INR) 2.3 or PT 6 seconds above control
    • Total white blood cell (WBC) count 2.0 109/L
  • Is able to take medications orally (eg, no feeding tube)
  • Women of childbearing potential must have a negative pregnancy test (urine or serum) prior to randomization and within 2 days prior to starting the study drug. Females must agree to adequate non-estrogenic birth control if conception is possible during the study; and males must agree to adequate birth control during the study and up to 6 months after the discontinuation of study medication.

Exclusion Criteria:

  • History of DVT, PE, myocardial infarction (MI), CVA, transitory ischemic attack (TIA), or any other significant TE during the last 3 years
  • Have clinically significant symptoms of hepatic encephalopathy or known brain metastasis
  • Patients who have had clinically significant acute gastrointestinal bleeding as a result of portal vein hypertension within 4 weeks prior to randomization are excluded; however, patients with a history of acute gastrointestinal bleeding that have received appropriate treatment, ie, ligation of varices, are eligible
  • Are receiving therapeutic regimens of anticoagulants, with the exception of prophylaxis care of indwelling venous access devices
  • Have received a liver transplant
  • Are taking prohibited medication
  • Have received a previous systemic therapy (including investigational agents) other than sorafenib (see Inclusion Criterion 4) for treatment of HCC. Patients participating in surveys or observational studies are eligible to participate in this study
  • Have had treatment with any of the following within the specified timeframe prior to randomization:

    • Any sorafenib within the 14 days prior to randomization
    • Major surgery within the 4 weeks prior to randomization
    • Any transfusion, treatment with blood component preparation, received erythropoietin , albumin preparation, and granulocyte colony-stimulating factor (G CSF) within the 2 weeks prior to randomization
  • Has a serious illness or medical condition(s) including, but not limited to the following:

    • Known gastrointestinal disorder, including malabsorption, chronic nausea, vomiting, or diarrhea present to the extent that it might interfere with oral intake and absorption of the study medication
    • Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness
    • Previous or concurrent malignancy except for basal cell carcinoma and/or in situ carcinoma of the cervix, or other solid tumor treated curatively and without evidence of recurrence for at least 3 years prior to the study
    • Uncontrolled metabolic disorders or other nonmalignant organ or systemic diseases or secondary effects of cancer that induce a high medical risk and/or make assessment of survival uncertain
    • Has active or uncontrolled clinically serious infection excluding chronic hepatitis
    • Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the Investigator would make the patient inappropriate for entry into this study (eg, active urinary tract infection)
    • Known allergy or hypersensitivity of TAC 101 and any other components used in the TAC 101 tablet.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00687596

Locations
Italy
I.R.C.C.S. San Matteo University Hospital
Golgi, Pavia, Italy, 27100
Sponsors and Collaborators
Taiho Oncology, Inc.
Quintiles
Investigators
Study Director: Fabio Benedetti, MD Taiho Oncology, Inc.
  More Information

No publications provided

Responsible Party: Taiho Oncology, Inc.
ClinicalTrials.gov Identifier: NCT00687596     History of Changes
Other Study ID Numbers: TAC101-202
Study First Received: May 28, 2008
Last Updated: June 4, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Sorafenib
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 28, 2014