A Study of PTX-9908 Injection for Non-resectable HCC with TACE

This is a multicenter, Phase I/II study in patients with non-resectable hepatocellular carcinoma following TACE treatment.

Phase I (Open-label dose escalation)

This study will be an open-label study with an Accelerated Phase and a Standard Phase. For the Accelerated Phase of the study, one patient per dose level (1 mg/kg, and 2 mg/kg) is planned. For the dose levels in the standard phase (4 mg/kg, 8 mg/kg and 16 mg/kg), it will follow the Fibonacci's rule of 3 + 3 design. All eligible patients who have received TACE treatment and recovered well, will be administrated PTX-9908 Injection intravenously one dose per day for 5 days on Week 1 (excludes weekends and public holidays), and one dose per week (on Day 8, Day 15, and Day 22) for 3 consecutive weeks. The 4-week treatment period, will be followed by a 2-week follow-up period.

Phase II (Randomized placebo controlled dose expansion)

The objective of phase II is to further evaluate the safety, tolerability and antitumor activity of PTX-9908 Injection for patients with non-resectable hepatocellular carcinoma following TACE treatment. Approximately 24 eligible patients who have received TACE treatment and recovered, will be randomized to PTX-9908 Injection using the predetermined dose in phase I or the vehicle placebo in a 2:1 ratio. PTX-9908 Injection or placebo will be administered intravenously one dose per day for 5 days in Week 1 (excludes weekends and public holidays), and one dose per week till Week 12 (Day 78). The 12-week treatment period, will be followed by a 2-week follow-up period.


Eligibility Criteria:
Inclusion Criteria:

1. Unresectable hepatocellular carcinoma and at intermediate-stage HCC (BCLC stage B or Child-Pugh class A/B with large or multifocal HCC, no vascular invasion, or extrahepatic spread) with completed TACE procedure in 4 weeks before day 1 of study intervention infusion.
2. Recovered from TACE treatment and procedure related toxicities including ALT/AST and bilirubin within normal limit or reference numeric value (reference value is defined as the test value before TACE procedure).
3. ECOG (Eastern Cooperative Oncology Group) performance status \< 2.
4. Have adequate organ and marrow function as defined below:

   1. Absolute neutrophil count \> 1,200/µL
   2. Hemoglobin \> 9 g/dL
   3. Platelets \> 100,000/µL
   4. Total bilirubin \< 2 X ULN
5. Have adequate kidney function as estimated glomerular filtration rate (eGFR) \> 60 mL/min/1.73m2
6. A negative pregnancy test at screening. This applies to any female patient with childbearing potential.
7. Agree to use adequate contraception after signing informed consent form, during the duration of study participation and for at least 4-weeks after completion or withdrawal from the study. This applies to any female patient with childbearing potential and any male patient whose female partner has childbearing potential.

   Acceptable contraceptive methods include:
   1. Established use of oral, injected or implanted hormonal methods of contraception
   2. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
   3. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) \>=20 years of age. (Note: In Taiwan, age of majority recognized in law is 20 years of age)
8. \>=20 years of age. (Note: In Taiwan, age of majority recognized in law is 20 years of age)
9. Anticipated life expectancy of \>= 6 months at assessment during screening.
10. Ability to understand and have signed a written informed consent document.

Exclusion Criteria:

1. 1. Patient with Child-Pugh B8-9.
2. Patient who has had anti-cancer therapy including surgery, radiotherapy, immunotherapy, or chemotherapy (except in TACE regimen) within 4 weeks prior to the screening visit.
3. Patient who has received any other investigational agents within 4 weeks prior to the screening visit.
4. Patient who has not recovered from the side effects of the earlier investigational agent or had anti-cancer therapy including surgery, radiotherapy, immunotherapy, or chemotherapy.
5. Patient with known brain metastases, leptomeningeal or epidural metastases (unless treated and well controlled for \>= 3 months).
6. Patient with prior history of co-malignancies, except for adequately treated carcinoma in situ of the cervix, ductal carcinoma in situ (DCIS) of the breast, and basal cell/squamous cell skin cancer.
7. Patient with history of myocardial infarction or uncontrolled cardiac dysfunction, or unstable arrhythmia or symptomatic peripheral arterial vascular disease.
8. Patient with history of positive serology for human immunodeficiency virus (HIV).
9. Patient with active, uncontrolled bacterial, viral, or fungal infections, which require systemic therapy.
10. Patient with poor liver function as indicated by serum bilirubin \> 2 mg/dL, Child-Pugh Class C, severe coagulopathy (INR \> 2) not correctable with vitamin K, or active hepatic encephalopathy.
11. Patient with known allergic reactions to biological agent or polypeptides similar to PTX-9908 Injection.
12. Woman who is pregnant or nursing.
13. Patient with concomitant disease or condition that could interfere with the conduct of the study, or that would, in the opinion of the investigator, pose an unacceptable risk to the patient in this study.
14. Patient with unwillingness or inability to comply with the study protocol for any reason.
15. A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval \>480 milliseconds (ms) (CTCAE grade 1) using Frederica's QT correction formula
16. A history of additional risk factors for torsades de pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome)
17. The use of concomitant medications that prolong the QT/QTc interval