T-ACE Oil by TAE/TACE in Patients With Hepatocellular Carcinoma

The phase I/II, double-blind, randomized study will investigate the efficacy and safety of TACE/TAE treatment with T-ACE Oil in patients with unresectable hepatocellular carcinoma.

Subjects with HCC that meet all eligibility criteria will be admitted to hospital, and TAE or TACE treatment are performed during the hospitalization period; after embolization, subjects are observed in the ward for 1 to 7 days, and evaluated by physician before being discharged. Subjects will be followed up for 7 weeks after treatment for safety and efficacy evaluation.

Phase I part:

12 evaluable subjects will be enrolled sequentially in Phase I part. The first 3 subjects will receive TAE treatment (whether or not they are contraindicated to Doxorubicin) and the following 3 subjects (4th to 6th subjects) will receive TACE treatment. The remaining subjects may receive TAE or TACE treatment. Subjects will be enrolled sequentially in Phase I. For the first six subjects in Phase I, after the subject completes TAE or TACE treatment and is followed for 2 weeks, safety and tolerability data during this period will be reviewed by the safety review committee (SRC); only approved by the SRC, the next subject may start the TAE or TACE treatment. For the 7th to 12th subjects in Phase I, after the subject completes TAE or TACE treatment and is followed until discharge from hospitalization, safety and tolerability data during this period will be reviewed by the safety review committee (SRC); only approved by the SRC, the next subject may start the TAE or TACE treatment. After data for all 12 evaluable subjects are reviewed by SRC and approval is given by the SRC, the study may proceed to Phase II part.

Phase II part:

70 evaluable subjects will be randomized in a 1:1 ratio to receive TAE/TACE treatment by T-ACE Oil or Lipiodol for safety and efficacy evaluation.

Eligibility Criteria:
Inclusion Criteria:

1. Age of over 20 years (or according to local legal definition of majority).
2. Patients diagnosed of HCC (Meet at least ONE of the following criteria):

   A. Diagnosed via tumor biopsy by pathologists and confirmed by on-service physician.

   B. High risk patients (viral hepatitis B or C or cirrhotic) with typical liver cancer image appeared on MRI or CT scan.
3. In very early stage to intermediate stage by BCLC staging (2018 AASLD), HCC tumor numbers ≦ 10, HCC tumor size ≦ 15 centimeters (determined by CT, MRI or ultrasound), with liver function at Child-Pugh score\[1\] ≦ 8.
4. Disease can be treated by trans-arterial chemoembolization, and can be evaluated by Magnetic resonance imaging (MRI), or computed tomography (CT).
5. Patients who only require a single TAE/TACE treatment to treat all HCC tumors at once.
6. Target HCC tumors should have at least 1 tumor that is larger than 1 cm in diameter (determined by CT, MRI or ultrasound) and non-treated before.
7. May have received local therapy such as TAE, TACE, radiofrequency ablation (RFA) or surgery and remain eligible for study provided the prior therapy was within the following timeframes and the subject has fully recovered from prior therapy:

   A. TAE/TACE: more than 8 weeks since completion of prior therapy B. RFA: After PI confirm subject is fully recovered from prior therapy based on screening visit physical examination and liver function laboratory tests results.

   C. Surgery: After PI confirm subject is fully recovered from prior therapy based on screening visit physical examination and liver function laboratory tests results.
8. Patients able to understand, willing to accept and cooperate with all clinical trial practices.
9. Willing to sign a written informed consent form.

Exclusion Criteria:

1. Major branch of portal vein has been invaded by HCC, extrahepatic metastasis or other malignant tumors (current active malignancy or active malignancy within the past 5 years).
2. Eligible for curative surgery or transplant as judged by PI.
3. Evidences of decompensation (Meet at least ONE of the following criteria):

   * Total Bilirubin \> 2 mg/dL
   * INR \> 1.7
   * Child-Pugh score \> 8
   * refractory ascites
   * active bleeding
   * hepatic encephalopathy
   * severe infection
4. Any of the following findings (but not limit to):

   * Heart failure (NYHA Class III or IV), COPD (Stage III or IV).
   * A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval \>480 milliseconds (ms) (CTCAE grade 1) using Fridericia's QT correction formula.
   * A history of risk factors for torsades de pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome) or use of concomitant medications that prolong the QT/QTc interval (e.g., class Ia, Ic or III antiarrhythmic drugs, tricyclic antidepressants or phenothiazines)
   * Bronchial asthma that may increase the risk associated with study participation, or may interfere with compliance of the protocol as judged by the PI.
   * Renal dysfunction (eGFR \< 50 ml/min/1.73m2 and/or creatinine \> 1.5x ULN), or patients is planned to accept any renal replacement therapy during treatment visits.
   * Diagnosed with hyperthyroidism or receiving treatment for hyperthyroidism. Has unstable thyroid function as judged by the PI (e.g. TSH \> 5.0 mIU/L).
   * Traumatic injuries, clinically significant hemorrhage/bleeding, or clinically significant gastrointestinal bleeding within 8 weeks.
   * Major cardiovascular disease, including stroke and transient ischemic attack (TIA).
   * Known homocystinuria.
5. Any of the following laboratory findings:

   * Absolute Neutrophil Count \< 1000/μL
   * Platelets \< 50,000/μL
   * Hgb \< 8.5 g/dL
   * AST \> 5x ULN
   * ALT \> 5x ULN
6. Performance status Eastern Cooperative Oncology Group (ECOG) of 2 or more.
7. Patients whose blood vessel are too difficult to perform TACE procedure as judged by PI.
8. TACE procedure would be performed in areas of the liver where bile ducts are dilated as judged by PI.
9. Prominent Hepatic arteriovenous (AV) shunt, as judged by PI.
10. Non-targeted area may be endangered during TACE procedure, as judged by PI.
11. Patients, who have ever accepted TACE therapy, and cannot gain extra benefits from further embolization treatment.
12. Number of HCC tumors more than 10.
13. Allergy or contraindication to iodine, Lipiodol, allowed contrast agents, allowed Gelfoam suppositories or allowed artery hemostats.
14. Pregnant females or lactating females.
15. Male or female subjects with fertility who are unwilling to perform highly effective contraception method.
16. Subjects who, in the opinion of the investigator, are not suitable to participate in the trial for whatever reason.