Safety, Tolerability and Pharmacokinetics Characteristics of Recombinant Oncolytic Vaccinia Virus Injection T601 as a Single Drug or in Combination With Oral Flucytosine (5-FC), in Patients With Advanced Malignant Solid Tumors

This open, dose-escalation and extended PhI/IIa clinical trial aims to evaluate the safety, tolerability of T601 as a single-agent as well as combined with prodrug 5-FC to treat patients with advanced malignant solid tumors and to explore the pharmacokinetic characteristics of T601, 5-FC, 5-FU, FBAL, which includes PhI study of dose-escalation study and Ph IIa study of extending study.

Preclinical studies have confirmed that the combination of T601 and 5-FC can not only enhance the anti-tumor effect, but also reduce the toxicity of T601. Considering the risks and benefits of participants of the clinical trial, the protocol design is divided into 4 parts:

Part 1: dose-escalation study of single-dose of T601 to evaluate the safety and tolerability of T601 and to determine the MTD;

Part 2: dose-escalation study of single-dose of T601 combined with predrug 5-FC, to evaluate the safety and tolerability of the treatment of single dose of T601 combined with predrug 5-FC and to determine the MTD of single dose of T601 when combing with 5-FC;

Part 3: dose-escalation study of multiple-dose of T601 combined with predrug 5-FC, to explore the safety and tolerability of the treatment of multiple dose of T601 combined with predrug 5-FC and to determine the MTD of multiple dose of T601 when combing with 5-FC, also to determine the RP2D (recommended dose for Phase II Trial);

Part 4: extending study of multiple-dose of T601 combined with predrug 5-FC, to evaluate the efficacy of the treatment of multiple-dose of T601 combined with predrug 5-FC in patients with various specific tumors and to evaluate the ORR, DCR and PFS according to the RECIST v1.1.

Eligibility Criteria:
Inclusion Criteria:

1. Male or female, aged ≥18 years and ≤ 75;
2. Part1-Part3: histological or cytological confirmed advanced malignant solid tumors patients who have received standard therapeutic options in previous treatment and now there's no standard therapy available; Part4: patients with gastric cancer, pancreatic cancer and hepatocellular carcinoma will be enrolled in Phase IIa Clinical Trial;
3. Eastern Cooperative Oncology Group (ECOG) performance status 0-1;
4. Expected survival of at least 3 months;
5. Patient presenting with at least one evaluable lesion according to RECIST 1.1 in Part1-Part3; patient presenting with at least one measurable lesion according to RECIST 1.1 in Part4;
6. Adequate blood system function, liver function and kidney function:

   1. ANC≥1.5×109/L，PLT≥80×109/L，Hb≥90 g/L;
   2. TBIL≤1.5×ULN，ALT≤3×ULN，AST≤3×ULN (Patients with liver metastasis or liver cancer ALT≤5×ULN，AST≤5×ULN);
   3. Cr≤1.5×ULN, creatinine clearance\>50mL/min (calculate according to Cockcroft-Gault Formula);
   4. APTT≤1.5×ULN，PT≤1.5×ULN，INR≤1.5×ULN.
7. Fertile eligible patients (male and female) must agree to use highly effective method of contraception (i.e. hormone or barrier method or abstinence) during clinical trial and for a minimum of 12 weeks after the last administration of T601; negative blood pregnancy test for women of childbearing potential (WOCBP) within 7 days before enrollment ;
8. Give informed consent to the study prior to the test and voluntarily sign a written informed consent.

Exclusion Criteria:

1. Received chemotherapy, radiation, biotherapy, endocrine therapy, immunotherapy and other anti-tumor treatments within 4 weeks prior to T601 treatment initiation, except for the following items:

   Received nitrosourea or mitomycin C within 6 weeks before T601 treatment initiation; Orally taken fluorouracil and small-molecule targeted drugs within 2 weeks before T601 treatment initiation or within 5 half-lives of the above drugs (subject to whichever is longer); Received the Chinese medicines with anti-tumor indications within 2 weeks before T601 treatment initiation;
2. Prior participation in another clinical study involving an IMP with last intake within 4 weeks prior to T601 treatment initiation;
3. Received major organ surgery (excluding needle biopsy) or severe trauma within 4 weeks prior to T601 treatment initiation;
4. The adverse reactions of previous anti-tumor therapy have not yet returned to CTCAE 5.0 ≤1 (except the toxicity that the investigator judged as no safety risk, such as hair loss);
5. With clinical symptoms of brain metastasis, spinal cord compression, and cancerous meningitis, or other evidence indicates that the metastasis of the patient's brain and spinal cord has not been controlled, and the investigator judged that the patient was not suitable for inclusion. Patients with clinical symptoms suspected of cerebral or pia mater disease should be excluded by CT/MRI examination;
6. Uncontrolled bacterial, viral or fungal infections requiring systematic treatment;
7. History of immunodeficiency, including positive HIV antibody test;
8. Active chronic hepatitis B (HBV-DNA higher than the lower limit of detection), hepatitis C antibody positive;
9. Patients who are unable to swallow oral drugs;
10. History of serious cardiovascular and cerebrovascular diseases:

    1. Ventricular arrhythmias requiring clinical intervention;
    2. Acute coronary syndrome, congestive heart failure, stroke or other class III or above cardiovascular events within 6 months;
    3. New York Heart Association (NYHA) cardiac function grade ≥II or Left Ventricular Ejection Fraction (LVEF) \<50%;
    4. Hypertension uncontrolled by standard treatment;
11. Skin diseases that need systematic treatment;
12. Patients who need long-term use of glucocorticoids (prednisone\>10 mg/d or equivalent dose of the same drug) or other immunosuppressive agents during the study period or within 14 days before initiation of T601; Exceptions: local, ocular, intra-articular, intranasal, and inhaled glucocorticoid therapy; Short-term use of glucocorticoids for preventive treatment (e.g. prevention of contrast agent allergy);
13. History of severe systemic reaction or side-effect after vaccinia vaccine injection;
14. Known hypersensitivity to 5-FC or intolerance to 5-FC treatment;
15. Known alcohol or drug dependence;
16. Mental disorders or patients unable or unwilling to comply with the protocol requirements;
17. Pregnant or lactating female patients;
18. Patients who, as determined by the investigator, have other serious systemic diseases or laboratory abnormalities or other reasons, are not eligible to participate in this clinical trial.