A Clinical Study on Evaluating Intravenous Administration of IDOV-SAFE

Subjects were Chinese patients with histologically or cytologically confirmed advanced malignant solid tumors (mainly focused on MSS type colon and rectal cancer) who had failed standard systemic therapy and were inoperable.

The first stage was the dose escalation stage, which was divided into 4 dose groups according to the "3+3" dose escalation principle. One patient was enrolled in the first dose group, and 3-6 patients were enrolled in each of the latter three dose groups, with a total of 10-19 patients enrolled.

The second stage is the security extension stage, which is selected by SMC 1-2 dose cohorts were expanded for safety and divided into three cohorts in total(IIA, IIB, IIC) to explore the safety of sequential or combined administration modes with immune targeted therapy. Each cohort included 6-12 subjects at different dose levels, and three cohorts could be carried out at the same time.

The third stage is the dose expansion stage. According to the safety, PK and clinical data of the three cohorts in the second stage, 1-2 cohorts were selected by SMC for dose expansion. The sample size of each cohort was expanded to 20 cases on the original basis. The estimated ORR of the trial drug was 24%, and the ORR of the standard treatment was 5%. When the type I error was one-sided 0.025, and the power was 80%, the sample size was estimated by the normal approximation method. So each dose expansion phase A minimum of 20 subjects were required to be enrolled in the cohort.

Overview of clinical trial The therapeutic dose in mice was 1x108 PFU, and the maximum starting dose in humans was 2.67x10\^9 PFU according to the "Guidelines for the estimation of the maximum recommended starting dose of drugs in the First clinical trial of Healthy Adult Volunteers".

Phase 1: Dose escalation phase:

We plan to enroll 10 to 19 patients in China with histologically or cytologically confirmed advanced solid tumors who have failed to respond to standard treatment or have no standard treatment options for IDOV-SAFETM intravenous administration. Patients with MSS colorectal cancer were included in this stage.

This phase included four dose groups of 1x10\^9 PFU, 3x10\^9 PFU, 1x10\^10 PFU and 3x10\^10 PFU. One subject was enrolled in the first dose group, and the other dose groups were increased by a "3+3" method, with 3-6 subjects in each group. All participants in each dose arm could not be escalated to the next dose arm until they had completed the 21-day safety assessment.

Dose escalation or Settings may be adjusted at the discretion of the Safety Committee (SMC).

Phase 2: Security Extension Phase:

One or two dose levels determined by MTD or SMC were selected for expansion. This phase was divided into three cohorts, the first cohort included 18 cases, and the latter two cohorts included 6-12 patients in each group:

Cohort IIA: Patients with MSS colorectal cancer who progressed after IDOV-SAFETM monotherapy were treated with IDOV-SAFETM+ toripalimab-furoquininib combination therapy

IIA1: Approximately 6 subjects were included in the first dose group. IIA2: About 12 subjects were included in the second dose group;

Cohort IIB: Patients with cholangiocarcinoma, gastric cancer, esophageal squamous cell carcinoma, liver cancer and other digestive system tumors were enrolled.

Enroll 6-12 subjects in the second dose group;

Cohort IIC: patients with MSS colorectal cancer were enrolled. After 2 cycles of IDOV-SAFETM treatment, the subjects were treated with IDOV-SAFETM, toripalimab and fuquinitinib combination therapy.

Enroll 6-12 subjects in the second dose arm.

Phase III: Dose expansion phase:

According to the safety, PK and clinical data of the three cohorts in the second phase, one or two cohorts were selected by SMC for dose expansion, and the sample size of each cohort was expanded to 20 cases.

After completing the first cycle of dosing, all subjects received subsequent cycles of dosing after 21 days of safety assessment. The course of treatment, related examinations and tumor efficacy evaluation were consistent between the monotherapy phase and the combination phase. The patients were treated with intravenous injection on D1, 3 and 5 of each course of treatment according to every 3 weeks (21 days) as a course of treatment. Safety checks were performed for each cycle. Tumor efficacy was evaluated every 2 cycles (every 6 weeks) according to RECIST1.1 and iRECIST standards. Pharmacodynamic tests (including tumor markers, T cell subsets, cytokines, viral load in tumor tissue, etc.), viral distribution detection, and TCR-Seq detection were performed regularly.

When the subject met the 9.1 criteria for the end of treatment for the subject, the treatment period ended and the subject entered the long-term safety and survival follow-up period.

Long-term SAFETY AND SURVIVAL FOLLOW-UP:

Adverse events that occurred in each subject from the first dose of the study were collected throughout the course of the study, and long-term safety and survival follow-up was to continue for 2 years after the last dose (visits were performed every 8 weeks until death or loss to follow-up or the end of survival follow-up). Before the subjects started a new antineoplastic therapy, they were examined accordingly according to the "6.9 Clinical Trial Schedule". Survival was confirmed by telephone visits after the initiation of a new antineoplastic therapy.

Other medications:

If, according to the investigator's judgment during the trial, the patient is considered to be safe but not effective at the current dose, the subject needs to withdraw from the trial, and the trial SMC meeting has decided and the next (higher) dose group has been initiated. At the discretion of the investigator, the higher dose of the trial drug could be administered to the subject who was withdrawing from the trial.

In order to ensure the interests of the subjects to the greatest extent, after the end of the treatment, if the subjects are evaluated by the investigators and the subjects agree, this clinical trial can provide "compensatory medication", and provide IDOV-SAFETM to the subjects for free. At the same time, the patients need to sign the informed consent for the use of "compensatory medication".

Eligibility Criteria:
Inclusion Criteria:

1. Be fully aware of this study and voluntarily sign ICF. 2. Age range from 18 to 70 years old at the time of screening, gender is not limited.

3. At the time of screening, patients with advanced malignant digestive system tumors confirmed by histology or cytology, including MSS type colorectal cancer, bile duct cancer, stomach cancer, esophageal cancer, liver cancer, etc.

4. At the time of screening, the disease has progressed after or during standard treatment; Subjects with advanced malignant digestive system tumors with no standard treatment currently available, intolerance to chemotherapy, or greater than or equal to progression after 2-line system therapy.

1. Be fully aware of this study and voluntarily sign ICF.
2. Age range from 18 to 70 years old at the time of screening, gender is not limited.
3. At the time of screening, patients with advanced malignant digestive system tumors confirmed by histology or cytology, including MSS type colorectal cancer, bile duct cancer, stomach cancer, esophageal cancer, liver cancer, etc.
4. At the time of screening, the disease has progressed after or during standard treatment; Subjects with advanced malignant digestive system tumors with no standard treatment currently available, intolerance to chemotherapy, or greater than or equal to progression after 2-line system therapy.
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) ≥1.5×109/L; ii. Hemoglobin (HB) ≥90g/L; iii. Platelet count (PLT) ≥75×109/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. Total blood 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;
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. At least one measurable lesion according to RECIST v1.1 criteria, The target lesion had not been treated with radiotherapy or had definite radiographic progression after previous radiotherapy.

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 14 days prior to the first use of the study drug.
5. Have 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. Have 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. 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 before the first use of study drug.
12. Allergy to macromolecular antibody drugs or small molecule TKI drugs.