Safety, Tolerability, and Preliminary Antitumor Activity of Non-Cationic Peptide-CD47 siRNA in Advanced Solid Tumors

A Clinical Trial of Non-cationic Peptide-CD47 siRNA for Safety, Tolerability, and Preliminary Antitumor Activity in Patients With Advanced Malignant Solid Tumors

This study evaluates a non-cationic peptide-CD47 siRNA nanocomplex for refractory advanced solid tumors. The candidate blocks the CD47-SIRPα "don't eat me" signal, repolarizes tumor-associated macrophages, and restores antitumor immunity. Using a 3+3 dose-escalation design (25, 50, 100 μg), the investigators aim to define the MTD and RP2D, providing a novel therapeutic approach and clinical evidence for siRNA drug development.

This is a single-arm, open-label, non-randomized, single-center, prospective phase 1 clinical study conducted to evaluate the safety, tolerability, and preliminary antitumor activity of intratumorally injected NCP-CD47 siRNA in participants with advanced solid tumors. The primary objective is to assess the safety and tolerability of the NCP-CD47 siRNA formulation, and the secondary objective is to evaluate its preliminary antitumor activity. Safety refers to the frequency and severity of adverse events induced by NCP-CD47 siRNA, mainly assessed by the incidence of dose-limiting toxicities (DLTs), adverse events graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, and routine laboratory examinations including hematological and biochemical indicators. Tolerability reflects participants' ability to tolerate adverse events related to the study drug, mainly assessed by the number of treatment discontinuations due to treatment-related adverse reactions, as well as changes in physiological and biochemical parameters, body weight, and adverse event reports (CTCAE 5.0). The primary endpoint is the incidence of DLTs and the number of treatment discontinuations due to treatment-related adverse reactions during the first treatment cycle of NCP-CD47 siRNA administration. The secondary endpoints include objective response rate (ORR), disease control rate (DCR), time to first complete response (CR) or partial response (PR), duration of response (DOR, defined as the interval from the first confirmed CR or PR to the first disease progression or death from any cause), duration of stable disease (SD, defined as the interval from the first confirmed SD to the first disease progression or death from any cause), progression-free survival (PFS, defined as the interval from the first administration of NCP-CD47 siRNA to the first disease progression or death from any cause), and overall survival (OS, defined as the interval from the first administration of NCP-CD47 siRNA to death from any cause). The study plans to enroll 3 to 18 participants with advanced solid tumors who have failed second-line chemotherapy, adopts a standard "3+3" dose-escalation design with three siRNA dose levels (25 μg, 50 μg, and 100 μg) and 3 participants enrolled in each dose cohort, administers the NCP-CD47 siRNA formulation via intratumoral injection, and ensures that the formulation is manufactured under GMP-compliant conditions, then aliquoted and reserved for clinical use in accordance with the clinical administration protocol.

Inclusion Criteria:

• Male or female patients aged ≥18 years and ≤70 years.
• Histopathologically confirmed advanced recurrent/metastatic malignant solid tumors that are refractory to second-line treatment and have no available standard clinical therapeutic options (e.g., advanced soft tissue sarcoma, advanced head and neck squamous cell carcinoma, malignant melanoma, etc.).
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1.
• Expected overall survival ≥3 months.
• Interval from the last chemotherapy, radiotherapy, or surgery ≥28 days.
• Interval from the last use of nitrosourea or mitomycin C ≥6 weeks.
• Adequate organ function, defined by the following laboratory parameters within 14 days prior to enrollment:
• Hemoglobin ≥90 g/L (no blood transfusion within 14 days).
• Absolute neutrophil count >1.5 × 10⁹/L.
• Platelet count ≥80 × 10⁹/L.
• Total bilirubin ≤1.5 × upper limit of normal (ULN).
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤2.5 × ULN (≤5 × ULN in case of liver metastasis).
• Creatinine clearance ≥60 mL/min (calculated by Cockcroft-Gault formula).
• Left ventricular ejection fraction (LVEF) ≥50%.
• Signed written informed consent.

Exclusion Criteria:

• Participation in another investigational drug clinical trial within 4 weeks.
• Tumor located adjacent to major blood vessels or trachea.
• Uncontrolled cardiac clinical symptoms or diseases, including New York Heart -Association (NYHA) Class ≥2 heart failure, unstable angina, myocardial infarction within 1 year, or clinically significant supraventricular/ventricular arrhythmias requiring treatment or intervention.
• Female patients who are pregnant or lactating.
• Active pulmonary tuberculosis, bacterial or fungal infection (≥Grade 2 per NCI-CTCAE version 5.0), active human immunodeficiency virus (HIV) infection, active hepatitis B virus (HBV) infection, or hepatitis C virus (HCV) infection.
• History of uncontrollable psychoactive substance abuse or presence of mental disorders.
• Any active autoimmune disease or history of autoimmune disease, including but not limited to uveitis, enteritis, hypophysitis, nephritis, hyperthyroidism, and hypothyroidism. Subjects with vitiligo or childhood asthma in complete remission (no adult intervention required) are eligible; subjects with asthma requiring bronchodilator therapy are excluded.
• Receiving immunosuppressive therapy.
• History of drug abuse or known medical, psychological, or social conditions that interfere with study compliance (e.g., alcoholism or illicit drug addiction).
• Known hypersensitivity, allergy, or intolerance to the study drug NCP-CD47 siRNA (including any excipients), or history of severe allergic reactions to any drugs, foods, or vaccines (e.g., anaphylactic shock, allergic laryngeal edema, allergic dyspnea, allergic purpura, thrombocytopenic purpura, local Arthus reaction, etc.).
• Female subjects planning pregnancy, or male subjects whose partner plans pregnancy, from screening until 12 months after the last study drug injection.
• Any concomitant disease that, in the investigator's judgment, may seriously compromise patient safety or prevent the subject from completing the study.