Hepatocellular Carcinoma
Conditions
Keywords
TAE, TACE, Hepatocellular Carcinoma, T-ACE Oil, TACE-OHEP-001
Brief summary
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.
Detailed description
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.
Interventions
DRUGT-ACE Oil
TAE/TACE treatment was performed with T-ACE Oil. The volume of T-ACE Oil injected will be 1-1.5 mL/cm based on the diameter (cm) of the treated tumor, with room for adjustment per subject's condition or Investigator's judgement. The maximum dose of T-ACE Oil is 0.25 mL/kg/day but not over 15 mL for each treatment. The maximum dose of doxorubicin for a single TACE will be based on standard practice at each site with a maximum of 50 mg. Doxorubicin will be constituted according to labeling and site procedures at a concentration of 10 mg/mL. The emulsion to be injected will have a recommended v/v ratio of 2:1 to 2.5:1 (study product : saline with Doxorubicin dissolved within it). If more than the maximum dose of doxorubicin would be needed to form an emulsion with T-ACE Oil, the remaining volume administered will be study product only.
DRUGLipiodol
TAE/TACE treatment was performed with Lipiodol®. The volume of Lipiodol® injected will be 1-1.5 mL/cm based on the diameter (cm) of the treated tumor, with room for adjustment per subject's condition or Investigator's judgement. The maximum dose of T-ACE Oil is 0.25 mL/kg/day but not over 15 mL for each treatment. The maximum dose of doxorubicin for a single TACE will be based on standard practice at each site with a maximum of 50 mg. Doxorubicin will be constituted according to labeling and site procedures at a concentration of 10 mg/mL. The emulsion to be injected will have a recommended v/v ratio of 2:1 to 2.5:1 (study product : saline with Doxorubicin dissolved within it). If more than the maximum dose of doxorubicin would be needed to form an emulsion with Lipiodol®, the remaining volume administered will be study product only.
Sponsors
T-ACE Medical Co., Ltd
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Phase I/II, interventional study; competitive enrollment, multi study center * Phase I part: Open label, single arm, sequential enrollment * Phase II part: Randomized, double-blind, active controlled
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age of over 18 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, largest HCC tumor size \< 7 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). Subjects who have experienced on Lipiodol®-based TAE or TACE treatments are fine to recruit. 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, or the patient has extrahepatic metastasis or other current malignant tumors. 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 \>500 milliseconds (ms) (CTCAE grade 3) 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 \< 30 ml/min/1.73m2 and/or creatinine \> 2.0x ULN), or patients who do not accept suitable hemodialysis therapy or who are planned to accept any renal replacement therapy during treatment visits. (Note: Patients receiving appropriate hemodialysis therapy may be considered for recruitment at the discretion of PI.) * 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. Allergy or contraindication to iodine, Lipiodol®, allowed contrast agents, allowed Gelfoam suppositories or allowed artery hemostats. 13. Pregnant females or lactating females. 14. Male or female subjects with fertility who are unwilling to perform highly effective contraception method. 15. Subjects who, in the opinion of the investigator, are not suitable to participate in the trial for whatever reason.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I part: Adverse Events as Assessed by CTCAE v5.0 | Up to 12 weeks | All Adverse Events (AEs) occurring while on study must be documented appropriately regardless of relationship. All AEs will be followed to adequate resolution. Pre-existing conditions will be recorded as baseline on the "Medical History" of CRF. If the pre-existing condition does not change, it does not have to be reported as an AE on subsequent cycles. However, if it deteriorates at any time during the study, it will be recorded as an AE. |
| Phase I part: Adverse Events of Special Interest (AESIs) | Up to 12 weeks after treatment | Pulmonary embolism and cerebral embolism will be considered adverse events of special interest (AESIs). AESIs will be analyzed as a safety endpoint. |
| Phase I part: Incidence of all serious adverse events (SAEs) after TAE/TACE treatment with T-ACE Oil | 7 weeks after treatment | — |
| Phase I part: Safety variables evaluation - Blood pressures | Pre-intervention (V1)(-28 to -1 days) | Blood pressures (including SBP and DBP, unit: mmHg)of subjects will be measured. |
| Phase I part: Safety variables evaluation - pulse rate | Pre-intervention (V1)(-28 to -1 days) | Pulse rate (beats/min) of subjects will be measured. |
| Phase I part: Safety variables evaluation - Body weight. | Pre-intervention (V1)(-28 to -1 days) | Body weight (kilograms) of subjects will be measured. |
| Phase I part: Safety variables evaluation - Respiratory rate | Pre-intervention (V1)(-28 to -1 days) | Respiratory rate (times/min) of subjects will be measured. |
| Phase I part: Safety variables evaluation - Body temperature. | Pre-intervention (V1)(-28 to -1 days) | Body temperature (oC) of subjects will be measured. |
| Phase I part: Safety variables evaluation - WBC | Pre-intervention (V1)(-28 to -1 days) | WBC (1000/uL) of subjects will be measured. |
| Phase I part: Safety variables evaluation - Platelet count | Pre-intervention (V1)(-28 to -1 days) | Platelet count (1000/uL) of subjects will be measured. |
| Phase I part: Safety variables evaluation - Hb | Pre-intervention (V1)(-28 to -1 days) | Hb (g/dL) of subjects will be measured. |
| Phase I part: Safety variables evaluation - blood urea nitrogen test | Pre-intervention (V1)(-28 to -1 days) | BUN (mg/dL) of subjects will be measured. |
| Phase I part: Safety variables evaluation - Bilirubin | Pre-intervention (V1)(-28 to -1 days) | Bilirubin-T and Bilirubin-D (mg/dL) of subjects will be measured. |
| Phase I part: Safety variables evaluation - Renal function | Pre-intervention (V1)(-28 to -1 days) | Creatinine (mg/dL) of subjects will be measured. |
| Phase I part: Safety variables evaluation - Liver function | Pre-intervention (V1)(-28 to -1 days) | AST and ALT (U/L) of subjects will be measured. |
| Phase I part: Safety variables evaluation - Coagulation function | Pre-intervention (V1)(-28 to -1 days) | Prothrombin time and APTT (seconds) of subjects will be measured. |
| Phase I part: Safety variables evaluation - Thyroid function (T3) | Pre-intervention (V1)(-28 to -1 days) | T3 (ng/dL) of subjects will be measured. |
| Phase I part: Safety variables evaluation - Thyroid function (Free T4) | Pre-intervention (V1)(-28 to -1 days) | T4 (ng/dL) of subjects will be measured. |
| Phase I part: Safety variables evaluation - Thyroid function (TSH) | Pre-intervention (V1)(-28 to -1 days) | TSH (uIU/ml) of subjects will be measured. |
| Phase I part: Safety variables evaluation - ECG test | Pre-intervention (V1)(-28 to -1 days) | Electrocardiogram (ECG) of subjects will be measured. The participants with treatment-related adverse events will be assessed by CTCAE v5.0 |
| Phase II part: T-ACE Oil or Lipiodol deposition type on CT scan after TAE/TACE treatment. | 72 hours after treatment | CT or MRI image should be taken at the screening visit, after the TAE or TACE procedure and visit 4 (6 weeks after TAE or TACE procedure). No additional contrast will be administered for the CT after TAE or TACE procedure. V1 and V4 image evaluation will be performed by MRI. V2 image evaluation method will be performed by CT scan. If the subject has had an MRI examination within 28 days before TAE/TACE treatment, the V1 MRI can be skipped. |
| Phase II part: mRECIST overall response at 6 weeks after TAE/TACE treatment. | 6 weeks after treatment. | mRECIST (modified Response Evaluation Criteria in Solid Tumors) overall response and mRECIST target lesion response will be evaluated based on the image taken at the screening visit and at visit 4 (6 weeks after TAE or TACE procedure). mRECIST overall response for each patient will be categorized: Complete response (CR), Partial response (PR), Stable disease (SD), and Progressive disease (PD). mRECIST overall response is based on target lesions and non-target lesions responses and appearance of new lesions and/or extra-hepatic disease. |
| Phase II part: target lesion response at 6 weeks after TAE/TACE treatment. | 6 weeks after treatment. | target lesion response will be evaluated based on the image |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase I part: T-ACE Oil deposition type on CT scan after TAE/TACE treatment with T-ACE Oil. | 72 hours after treatment | CT or MRI image should be taken at the screening visit, after the TAE or TACE procedure and visit 4 (6 weeks after TAE or TACE procedure). No additional contrast will be administered for the CT after TAE or TACE procedure. V1 and V4 image evaluation will be performed by MRI. V2 image evaluation method will be performed by CT scan. If the subject has had an MRI examination within 28 days before TAE/TACE treatment, the V1 MRI can be skipped. |
| Phase I part: mRECIST overall response at 6 weeks after TAE/TACE treatment with T-ACE Oil. | 6 weeks after treatment. | mRECIST (modified Response Evaluation Criteria in Solid Tumors) overall response and mRECIST target lesion response will be evaluated based on the image taken at the screening visit and at visit 4 (6 weeks after TAE or TACE procedure). mRECIST overall response for each patient will be categorized: Complete response (CR), Partial response (PR), Stable disease (SD), and Progressive disease (PD). mRECIST overall response is based on target lesions and non-target lesions responses and appearance of new lesions and/or extra-hepatic disease. |
| Phase I part: target lesion response at 6 weeks after TAE/TACE treatment with T-ACE Oil. | 6 weeks after treatment. | target lesion response will be evaluated based on the image |
| Phase II part: Incidence of all adverse events (AEs) after TAE/TACE treatment with T-ACE Oil or Lipiodol. | 7 weeks after treatment | — |
| Phase II part: Incidence of adverse events of special interest (AESIs) after TAE/TACE treatment with T-ACE Oil or Lipiodol. | 7 weeks after treatment | — |
| Phase II part: Incidence of all serious adverse events (SAEs) after TAE/TACE treatment with T-ACE Oil or Lipiodol. | 7 weeks after treatment | — |
| Phase II part: Safety variables evaluation - Blood pressures | Pre-intervention (V1)(-28 to -1 days) | Blood pressures (including SBP and DBP, unit: mmHg) of subjects will be measured. |
| Phase II part: Safety variables evaluation - Pulse rate | Pre-intervention (V1)(-28 to -1 days) | Pulse rate (beats/min) of subjects will be measured. |
| Phase II part: Safety variables evaluation - Body weight. | Pre-intervention (V1)(-28 to -1 days) | Body weight (kilograms) of subjects will be measured. |
| Phase II part: Safety variables evaluation - Body temperature. | Pre-intervention (V1)(-28 to -1 days) | Body temperature (oC) of subjects will be measured. |
| Phase II part: Safety variables evaluation - WBC | Pre-intervention (V1)(-28 to -1 days) | WBC (1000/uL) of subjects will be measured. |
| Phase II part: Safety variables evaluation - Platelet count | Pre-intervention (V1)(-28 to -1 days) | Platelet count (1000/uL) of subjects will be measured. |
| Phase II part: Safety variables evaluation - Hb | Pre-intervention (V1)(-28 to -1 days) | Hb (g/dL) of subjects will be measured. |
| Phase II part: Safety variables evaluation - blood urea nitrogen test | Pre-intervention (V1)(-28 to -1 days) | BUN (mg/dL) of subjects will be measured. |
| Phase II part: Safety variables evaluation - Bilirubin | Pre-intervention (V1)(-28 to -1 days) | Bilirubin-T and Bilirubin-D (mg/dL) of subjects will be measured. |
| Phase II part: Safety variables evaluation - Renal function | Pre-intervention (V1)(-28 to -1 days) | Creatinine (mg/dL) of subjects will be measured. |
| Phase II part: Safety variables evaluation - Liver function | Pre-intervention (V1)(-28 to -1 days) | AST and ALT (U/L) of subjects will be measured. |
| Phase II part: Safety variables evaluation - Coagulation function | Pre-intervention (V1)(-28 to -1 days) | Prothrombin time and APTT (seconds) of subjects will be measured. |
| Phase II part: Safety variables evaluation - Thyroid function (T3) | Pre-intervention (V1)(-28 to -1 days) | T3 (ng/dL) of subjects will be measured. |
| Phase II part: Safety variables evaluation - Thyroid function (Free T4) | Pre-intervention (V1)(-28 to -1 days) | T4 (ng/dL) of subjects will be measured. |
| Phase II part: Safety variables evaluation - Thyroid function (TSH) | Pre-intervention (V1)(-28 to -1 days) | TSH (uIU/ml) of subjects will be measured. |
| Phase II part: Safety variables evaluation - ECG test | Pre-intervention (V1)(-28 to -1 days) | each component of Electrocardiogram (ECG) of subjects will be measured. The participants with treatment-related adverse events will be assessed by CTCAE v5.0 |
Countries
Taiwan
Contacts
PRINCIPAL_INVESTIGATORPo-Chin Liang, PhD, MD
National Taiwan University Hospital
STUDY_CHAIRXi-Zhang Lin, MD
T-ACE Medical Co., Ltd
Outcome results
None listed