A Clinical Study on Evaluating Intravenous Administration of IDOV-SAFE

Summary

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.

Eligibility

Inclusion Criteria:

1\. Be fully aware of this study and voluntarily sign ICF. 2. Age range from 18 to 75 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.

Conditions2

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