Phase 2 Study of TAC-101 Combined With Transcatheter Arterial Chemoembolization (TACE) Versus TACE Alone in Japanese Patients With Advanced Hepatocellular Carcinoma

Study Overview
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Brief Summary
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The purpose of this study is to determine whether TAC-101 combined with Transcatheter Arterial Chemoembolization (TACE) is more effective than TACE alone in slowing tumor activity in patients with advanced hepatocellular carcinoma. The study is also looking at the safety of TAC-101 in combination with TACE.

Detailed Description
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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.

Official Title
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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

Conditions
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Advanced Hepatocellular Carcinoma

Intervention / Treatment
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* Drug: TAC-101
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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 study: 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 vascularization. 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. Is TACE naïve or has received the most recent TACE procedure at least 120 days before signing ICF. Eligible to receive TACE and being scheduled to receive TACE. Must be ≥ 20 years of age. 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). 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. 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. Must have a Child-Pugh classification of ≤ 8. Must have a Cancer of the Liver Italian Program (CLIP)60 score of 0, 1, 2 or 3 (Appendix B). Must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Must be willing and able to comply with schedule visits, treatment plans, laboratory tests, and other study procedures. 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: Patient has longest diameter of intrahepatic lesion ≥ 100 mm. Patient has only infiltration type of HCC. Patient has extrahepatic metastasis of HCC including regional lymph node metastases (including in lymph nodes and organs). Patient had systemic chemotherapy (eg, sorafenib, doxorubicin), immunotherapy, or biologic therapy or radiotherapy for HCC, or treatment with TAC-101. 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. Patient has ascites, pleural effusions or pericardial fluid refractory to diuretic therapy. Patient has clinical symptoms of hepatic encephalopathy. Patient has active or uncontrolled clinically serious infection excluding chronic hepatitis. Patient has a history of gastrointestinal (GI) bleeding in last 3 months. 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. 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. 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. Patient has clinically significant electrocardiogram (ECG) abnormality. Patient has GI disease resulting in an inability to take oral medication. 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. Patient has known hypersensitivity to iodinated contrast medium. Patient is receiving therapeutic regimens of anticoagulants. However, use of low dose anticoagulants for prophylactic care of indwelling venous access device is permitted. Patient is taking medication known or suspected to predispose patient to an increased risk of VTE (eg, oral contraceptives, hormone replacement therapy, megestrol acetate). Patient is taking azoles or tetracyclines, because of the potential for drug interactions. 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.

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants were administered with placebo tablets matching to TAC-101 orally, every day on the first 14 days (Days 1 to 14) followed by a 7-day (Days 15 to 21) treatment recovery period. Repeated every 21 days cycle up to new lesions were observed or the participant met a treatment discontinuation criterion. | Drug: Placebo<br>* Participants received placebo (two matching tablets) at same frequency and duration of active treatment.<br>|
| Experimental: TAC-101<br>Participants were administered with TAC-101 tablets, 20 milligram per day (mg/day) orally for every day on the first 14 days (Days 1 to 14) followed by a 7-day (Days 15 to 21) recovery period (21-day Cycle). Repeated every 21 days cycle up to new lesions were observed or the participant met a treatment discontinuation criterion. | Drug: TAC-101<br>* Participants received TAC-101 20 mg (2 x 10-mg formulated tablets) administered orally every day with approximately 8 oz. water within 1 hour following a morning meal for 14 days followed by a 7-day recovery period, repeated every 21 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Appearance of New Lesions (TTNL) | TTNL was defined as the time from the date of randomization to the date of appearance of a new lesion. Participants who had no appearance of new lesions had their TTNL censored at the date of their last tumor assessment. | From randomization (within 14 days prior to first TACE) assessed every 9 weeks after first TACE to date of appearance of a new lesion or until cut-off date (22-Dec-2009) (up to approximately 20 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS was defined as the time from date of randomization to date of death. Participants who were still alive at the time of analysis had their survival time censored at the last date known to be alive. | From randomization (within 14 days prior to first TACE) assessed every 9 weeks after first TACE until cut-off date of 22 Dec 2009 (up to approximately 20 months) | 
| Progression-Free Survival (PFS) | PFS was defined as the time from date of randomization to the date of disease progression (radiological, only). | From randomization (within 14 days prior to first TACE) assessed every 9 weeks after first TACE until cut-off date of 22 Dec 2009 (up to approximately 20 months) | 
| Objective Tumor Response Rate (ORR) | ORR was defined as the percentage of participants with objective evidence of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to less than (<)10 millimeters (mm). PR was defined as at least a 30 percent decrease in the sum of diameters of the target lesions, taking as a reference the baseline sum diameters. | From randomization (within 14 days prior to first TACE) assessed every 9 weeks after first TACE until cut-off date of 22 Dec 2009 (up to approximately 20 months) | 
| Change From Baseline in Plasma Levels of Tumor Marker Alpha-fetoprotein (AFP) | AFP was known as a tumor marker for advanced hepatocellular carcinoma (HCC) and was recognized as useful for following the course of HCC. Changes in serum AFP parallel the clinical course of HCC, where elevations can precede clinical deterioration and tumor recurrence. | Baseline, End of treatment (last dose of study medication, i.e., approximately 7 months) | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | Any untoward medical condition that occurs in a participants while participating in a clinical study and does not necessarily have a causal relationship with the use of the study drug was considered an adverse event (AE). A serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. TEAEs: AEs that occur from the initiation of any study treatment administration, and do not necessarily have a causal relationship to the use of the study drug. | From first dose of study drug up to 30 days after last dose of study drug or until the start of new anti-tumor therapy, whichever was earlier (up to approximately 8.5 months) |