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A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of TAC-101 in Combination With Transcatheter Arterial Chemoembolization (TACE) Versus TACE Alone in Japanese Patients With Advanced Hepatocellular Carcinoma

Phase 2
20 Years
Not Enrolling
Advanced Hepatocellular Carcinoma

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Trial Information

A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of TAC-101 in Combination With Transcatheter Arterial Chemoembolization (TACE) Versus TACE Alone in Japanese Patients With Advanced Hepatocellular Carcinoma

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. Transcatheter arterial
chemoembolization (TACE) is the most commonly performed procedure in the treatment of
unresectable liver tumors for selected patients. The TACE procedure delivers highly
concentrated drugs to the tumor itself and arrests blood flow. Most patients will have
intrahepatic recurrence of their tumors following TACE. 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 study is
designed as a randomized, double-blind, placebo-controlled, parallel-group, phase 2 study in
patients with advanced HCC who have undergone a TACE procedure, which will be conducted at
multiple sites in Japan, to determine if administration of TAC-101 will enhance the
benefits of the TACE procedure.

Inclusion Criteria:

- A patient must meet all of the following inclusion criteria to be eligible for
enrollment in this study and before undergoing the first TACE procedure of this

1. Has an HCC diagnosis by histology or by the following non-invasive criteria
observed either at enrollment or in the past.

- One imaging technique (CT scan or magnetic resonance imaging [MRI] both
with unenhanced plus hepatic arterial phase and portal venous phases)
showing characteristic features in a focal lesion > 20 mm with arterial

- Two dynamic imaging techniques (CT scan, MRI with unenhanced plus hepatic
arterial phase and portal venous phases) showing characteristic features
coincidentally in a focal lesion 10-20 mm with arterial vascularization.

2. Is TACE naïve or has received the most recent TACE procedure at least 120 days
before signing ICF.

3. Eligible to receive TACE and being scheduled to receive TACE.

4. Must be ≥ 20 years of age.

5. Is not amenable to treatment with curative surgery, transplant, or percutaneous
ablation, including RFA, percutaneous ethanol injection therapy (PEIT) and
percutaneous microwave coagulation therapy (PMCT).

6. Must have lesions in the liver that are confirmed nodular type with demonstrated
substantial hypervascularity by CT scan or MRI both with unenhanced plus hepatic
arterial phase and portal venous phases performed prior to first TACE in this
study with the following tumor features:

- If there are ≥ 4 intrahepatic lesions, all lesions can be < 30 mm. or,
regardless of the number of lesions, the longest diameter of at least one
intrahepatic lesion is ≥ 30 mm).

- No vascular invasion in main trunk and first order branch of portal vein.

- No extrahepatic tumor spread. The absence of extrahepatic abdominal tumors
must be confirmed.

7. Has adequate organ function as defined by the following criteria: White blood
cell (WBC) count > 3,000/mm3; Platelet count > 60,000/mm3; Hemoglobin > 8.0
grams (g)/deciliter (dL); Aspartate transaminase (AST) < 5 x upper limit of
normal (ULN); Alanine transaminase (ALT) < 5 x ULN; Total bilirubin < 2.0 mg/dL;
Albumin ≥ 2.8 g/dL; Serum creatinine ≤ 1.5 mg/dL; International normalized ratio
(INR) ≤ 2.0; Triglyceride ≤ 2.5 x ULN.

8. Must have a Child-Pugh classification of ≤ 8.

9. Must have a Cancer of the Liver Italian Program (CLIP)60 score of 0, 1, 2 or 3
(Appendix B).

10. Must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0
to 1.

11. Must be willing and able to comply with schedule visits, treatment plans,
laboratory tests, and other study procedures.

12. Must provide written informed consent prior to the implementation of any study
assessment or procedures.

Exclusion Criteria:

- Patients will be excluded from participation in the study if any of the following
conditions are observed before undergoing the first TACE procedure:

1. Patient has longest diameter of intrahepatic lesion ≥ 100 mm.

2. Patient has only infiltration type of HCC.

3. Patient has extrahepatic metastasis of HCC including regional lymph node
metastases (including in lymph nodes and organs).

4. Patient had systemic chemotherapy (eg, sorafenib, doxorubicin), immunotherapy,
or biologic therapy or radiotherapy for HCC, or treatment with TAC-101.

5. Patient received treatment with any of the following within the specified time
frame: Any major surgical procedure within 28 days prior to signing the ICF; Any
transfusion, treatment with blood component preparation, albumin preparation,
and granulocyte colony stimulating factor (G-CSF) within 14 days prior to
signing the ICF; Any local therapy such as alcohol injection,
radiofrequency/ultrasound ablation, intraarterial chemotherapy (transcatheter
arterial injection) for HCC performed within 28 days prior to signing the ICF;
Any investigational agent within 28 days prior to signing the ICF.

6. Patient has ascites, pleural effusions or pericardial fluid refractory to
diuretic therapy.

7. Patient has clinical symptoms of hepatic encephalopathy.

8. Patient has active or uncontrolled clinically serious infection excluding
chronic hepatitis.

9. Patient has a history of gastrointestinal (GI) bleeding in last 3 months.

10. Patient has previous or concurrent malignancy except for 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.

11. Patient has 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.

12. Patient has any history of deep vein thrombosis (DVT), pulmonary embolism (PE),
myocardial infarction (MI), cerebrovascular accident (CVA), transient ischemic
attack (TIA), unstable angina pectoris, or any other significant thromboembolic
event (TE) during the last 3 years.

13. Patient has clinically significant electrocardiogram (ECG) abnormality.

14. Patient has GI disease resulting in an inability to take oral medication.

15. Patient has known allergy or hypersensitivity to TAC-101, doxorubicin,
epirubicin, other anthracyclines, anthracenediones or any of the components used
in the study drug formulations.

16. Patient has known hypersensitivity to iodinated contrast medium.

17. Patient is receiving therapeutic regimens of anticoagulants. However, use of low
dose anticoagulants for prophylactic care of indwelling venous access device is

18. Patient is taking medication known or suspected to predispose patient to an
increased risk of VTE (eg, oral contraceptives, hormone replacement therapy,
megestrol acetate).

19. Patient is taking azoles or tetracyclines, because of the potential for drug

20. Women who intend to become pregnant or are pregnant or lactating and men able to
procreate that refuse to use a highly effective method of birth control during
treatment with study medication and up to 6 months thereafter.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Outcome Measure:

Time to appearance of new lesions (TTNL)

Outcome Time Frame:

Tumor imaging will be conducted at screening/baseline, every 9 weeks during treatment, every 9 weeks during follow-up period until new lesions are observed or the end of study is reached

Safety Issue:


Principal Investigator

Fabio Benedetti, MD

Investigator Role:

Study Director

Investigator Affiliation:

Taiho Pharma USA, Inc.


United States: Food and Drug Administration

Study ID:




Start Date:

April 2008

Completion Date:

April 2010

Related Keywords:

  • Advanced Hepatocellular Carcinoma
  • Carcinoma
  • Carcinoma, Hepatocellular