Study on the Safety and Efficacy of Intratumoral Administration of IDOV-SAFETM in the Treatment of Advanced Solid Tumors

This is an open-label, dose escalation, phase I study to evaluate safety tolerability, MTD, pharmacokinetic profile, immunogenicity, and pharmacodynamic profile of intratumoral Administration of IDOV-SAFETM in patients with advanced solid tumors.

The therapeutic dose for mice was 1x10\^8 PFU, and the maximum starting dose for humans was 2.67x10\^9 PFU based on the Guidelines for Estimating the Maximum Recommended Starting Dose for the First Clinical Trial of Healthy Adult Volunteers.

Dose escalation phase:

At this stage, the investigators plan to enroll about 13-25 patients with advanced malignant solid tumors confirmed by histology or cytology after failure of standard treatment or without standard treatment in China for intratumoral injection of IDOV-SAFETM.

This phase consisted of five dose groups: 1x10\^8 PFU, 3x10\^8 PFU, 7x10\^8 PFU, 1x10\^9 PFU and 3x10\^9 PFU. The first dose group included 1 subject, and the other dose groups were increased by "3+3", with 3-6 subjects in each group. Each patient received intratumoral injection on the first day, 14 days as a course of treatment. The follow-up investigator decided whether to continue the second (D14) and third (D28) course of administration according to the comprehensive assessment of the subjects' conditions; All subjects in each dose group may be incremented to the next dose group after completing a safety assessment 21 days after the first dose.

The dose escalation or setting may be adjusted as determined by the Safety Committee (SMC).

Dose expansion phase:

According to the results of the phase I trial, one dose was selected for dose expansion, and the selected dose level was extended to 5\~18 patients. Each patient received intratumoral injection on the first day, and 14 days was a course of treatment. The subsequent investigators decided whether to continue the administration of the second (D14) and third (D28) courses according to the comprehensive evaluation of the subjects' conditions. Each patient was treated for at least one course of treatment (14 days).

Based on the preliminary clinical trial data, the number of injections and the interval time of administration can be adjusted during the dose expansion phase after the decision of the Safety Committee (SMC).

Duration of administration:

In both phases, safety and efficacy were evaluated 42 days after initial dosing. If CT evaluation suspects false progression, puncture and pathology examination are required.

After SMC's decision, it is determined that the benefits of continued treatment outweigh the risks of the subject, and if the subject wishes to continue treatment, the subject may continue to receive the experimental drug. The specific course of treatment will be determined by the SMC based on preliminary clinical trial data.

The safety and efficacy of the investigational drug will be evaluated periodically during continued dosing, and the risk and benefit of continuing treatment will be determined by the SMC. If benefit \> risk is no longer satisfied, the long-term safety and survival follow-up period is entered.

Long-term safety and survival follow-up:

Adverse events occurring throughout the study from the first dosing of each subject in both phases will be collected, and long-term safety and survival follow-up will continue up to 2 years after the last dosing (site visits every 8 weeks from the DLT observation period until patients meet end-of-treatment criteria or the end of survival follow-up date, whichever arrives first).

Eligibility Criteria:
Inclusion Criteria:

1. 18 \~75 years old, gender is not limited;
2. During screening, patients with advanced malignant solid tumors confirmed by histology or cytology (mainly including breast cancer (triple-negative priority), melanoma, head and neck tumors, and gastrointestinal cancers such as colorectal cancer, cholangiocarcinoma, pancreatic cancer, and liver cancer with intratumoral injection conditions).
3. At the time of screening, the disease has progressed after or during standard treatment; Or subjects with advanced malignant solid tumors who currently have no standard treatment available or are intolerant to chemotherapy.
4. Tumor lesions and/or metastases with at least one evaluable lesion that is subcutaneously accessible or can be injected under imaging guidance, according to the solid tumor response criteria (RECIST version 1.1).
5. When screening, the ECOG score of physical strength score is 0 or 1.
6. Life expectancy assessed by the investigator at the time of screening was ≥3 months.
7. Subjects had adequate organ function at baseline:

   a) Bone marrow function (no growth factor support therapy or component transfusion within 14 days prior to screening) : i. Neutrophil absolute value (ANC) ≥1.5×10\^9/L; ii. Hemoglobin (HB) ≥90g/L; iii. Platelet count (PLT) ≥75×10\^9/L; b) Liver function: i. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 1.5 times the upper limit of normal (ULN) (ALT and AST≤ 3 times ULN for liver metastasis or hepatocellular carcinoma); ii. Blood total bilirubin ≤1.5 ULN (in subjects with liver metastasis or hepatocellular carcinoma or Gilbert syndrome or familial benign nonbinding hyperbilirubinemia, the acceptable range of this indicator is ≤2.5 ULN); c) Renal function: serum creatinine ≤ 1.5x ULN or creatinine clearance ≥50mL/min; d) left ventricular ejection fraction (LVEF) ≥ 45%. e) Coagulation function: activated partial thromboplastin time (APTT) ≤1.5×ULN, International Standardized ratio (INR) ≤1.5×ULN.
8. Fertile female subjects must have negative blood beta-HCG test results within 7 days prior to enrollment.
9. Subjects must agree to use highly effective contraception for at least 90 days from the start of the ICF to the end of the study.
10. Be fully informed of this study and voluntarily sign ICF.

Exclusion Criteria:

1. At the time of screening, advanced malignant tumors have a chance of being cured by radical treatment.
2. Asymptomatic brain metastases such as untreated ones at the time of screening; Subjects with symptomatic central nervous system (CNS) metastatic or cancerous meningitis; Or there was other evidence of uncontrolled central nervous system or meningeal metastases in subjects who were judged by the investigator to be unsuitable for enrollment.
3. Prior to enrollment, there was severe chronic or active infection: active hepatitis B (HbsAg positive, HBV DNA test value greater than the upper limit of normal); Active hepatitis C (those with positive anti-HCV antibodies are further tested positive for HCV RNA); A known history of immunodeficiency virus (HIV) disease or a positive HIV antibody test; Other conditions requiring systemic anti-infective treatment in the 4 weeks prior to initial use of the investigational drug include, but are not limited to, hospitalization for infectious complications, bacteremia, severe pneumonia, or active tuberculosis.
4. At the time of screening, patients had a history of active autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, vasculitis, etc., or were receiving long-term systemic steroids (prednisone \>10mg/ day or equivalent doses of the same drug) or any other form of immunosuppressant therapy within 4 weeks prior to the first use of the study drug.
5. Patients with received allogeneic tissue or solid organ transplantation.
6. There is evidence of clinically significant immunodeficiency, such as primary immunodeficiency status, such as severe combined immunodeficiency disease (SCID); Combined with opportunistic infections.
7. Anticoagulants or antiplatelet drugs should be used before injection and should not be interrupted, including: aspirin should not be stopped within 7 days before injection; Coumarin that cannot be stopped within 7 days prior to injection; Direct thrombin inhibitors (such as dabigatrun) or direct factor Xa inhibitors (such as rivaroxaban, apixaban, and neperoxaban) that cannot be discontinued within 4 days prior to injection; Low molecular weight heparin (LMWH) should not be stopped within 24 hours before injection, and ordinary heparin (UFH) should not be stopped more than 4 hours before injection.
8. Patients with a history of severe cardiovascular and cerebrovascular disease, including but not limited to: congestive heart failure ≥II heart function grade of the New York Heart Association (NYHA); Left ventricular ejection fraction (LVEF) \<50%; QT interval (QTcF) \>470ms as corrected by the Fridericia method or prolonged QT interval syndrome; Acute coronary syndrome, aortic dissection, severe arrhythmia, stroke, or other grade 3 or higher cardiovascular and cerebrovascular events occurred within 6 months before first administration; The presence of uncontrolled hypertension (systolic blood pressure \>140mmHg or diastolic blood pressure \>90mmHg). Subjects with a history of hypertension are admitted to the study if their blood pressure is controlled below this standard and maintained with antihypertensive therapy.
9. Patients with received treatment with other methods, including but not limited to chemotherapy, radiotherapy, biotherapy, endocrine therapy, immunotherapy, etc., within 4 weeks prior to the first use of the investigational drug.
10. Other diseases or abnormalities assessed by the investigator as unsuitable for participation in the study.
11. Vaccination against smallpox or monkeypox within 10 years.