NK521 in the Treatment of Malignant Ascites Associated With Advanced Solid Tumors

NK521 in the Treatment of Malignant Ascites Associated With Advanced Solid Tumors

Study Population: Adult subjects aged 18-75 years with relapsed/refractory advanced solid tumors (including liver, gastric, colorectal, ovarian cancer, etc.) and malignant ascites confirmed by cytology, who have failed at least 2 lines of standard systemic therapy.

Study Design: This is a dose-escalation, single-center, open-label, prospective Phase 1 study. A total of 18 subjects will be enrolled and assigned to 2 administration groups (9 subjects each):

Group A (Intravenous infusion): For subjects with small-volume malignant ascites.

Group B (Intraperitoneal perfusion): For subjects with large-volume symptomatic malignant ascites.

Each group will follow a conventional "3+3" dose-escalation design with 3 dose levels (1×10⁹, 3×10⁹, 6×10⁹ NK cells per dose), administered once weekly, 3 weeks per cycle, for 2 consecutive cycles.

Primary Objectives: To evaluate the safety and tolerability, and to determine the dose-limiting toxicity (DLT) of NK521 administered intravenously and intraperitoneally.

Secondary Objectives: To assess the preliminary anti-tumor efficacy including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), puncture-free survival (PuFS), and changes in tumor markers, as well as health-related quality of life (HRQoL).

Inclusion Criteria:

• Pathologically diagnosed with relapsed/refractory advanced solid tumors, including but not limited to liver cancer, gastric cancer, colorectal cancer, ovarian cancer, etc.
• Complicated with malignant ascites with identifiable tumor cells in ascites. Patients with advanced solid tumors who have failed at least 2 lines of standard therapy.
• At least one measurable lesion on CT or MRI per RECIST v1.1.
• ECOG performance status 0-2.
• Life expectancy ≥3 months.
• All toxicities from prior antineoplastic therapy have resolved to Grade 1 (CTCAE v5.0) or baseline except alopecia and fatigue; subjects with long-term stable sequelae from prior therapy (e.g., platinum-induced neuropathy) are allowed.
• Women of childbearing potential must be non-lactating with a negative serum pregnancy test within 1 week before enrollment; all subjects must agree to use contraception from signing informed consent until 6 months after the last NK521 infusion.
• Able to comply with the study protocol and follow-up procedures.
• Voluntarily signed and provided written informed consent.

Exclusion Criteria:

• Symptomatic central nervous system (CNS) metastasis and/or carcinomatous meningitis.
• History of other malignancies within the past 3 years.
• Active, known or suspected autoimmune disease, excluding hypothyroidism requiring only hormone replacement therapy, skin diseases not requiring systemic therapy (e.g., vitiligo, psoriasis, alopecia), or diseases not expected to relapse without external triggers.
• History of immunodeficiency, including positive HIV test, other acquired or congenital immunodeficiency diseases, or organ transplantation.
• History of severe cardiovascular and cerebrovascular diseases, including but not limited to: severe cardiac arrhythmia or conduction abnormality requiring clinical intervention (e.g., ventricular arrhythmia, third-degree atrioventricular block); QTc interval >480 ms on 12-lead ECG at rest; acute coronary syndrome, congestive heart failure, aortic dissection, stroke, or other Grade ≥3 cardiovascular/cerebrovascular events within 6 months before enrollment; NYHA Class ≥II heart failure or left ventricular ejection fraction (LVEF) <50%; uncontrolled hypertension.
• Received radical radiotherapy within 4 weeks before enrollment; received local palliative radiotherapy within 2 weeks before enrollment.

Not fully recovered from major surgery or trauma within 2 weeks before enrollment.

-Participated in another investigational drug trial and received investigational therapy or used an investigational device within 4 weeks before enrollment.

Received cellular antineoplastic therapy within 1 year before dosing; received other antineoplastic therapy outside this protocol within 4 weeks before dosing, including but not limited to chemotherapy, molecular targeted therapy, hormonal therapy, immunotherapy, biotherapy, or Chinese herbal patent medicine with antineoplastic indications.

• Received blood transfusion, erythropoietin, granulocyte colony-stimulating factor (G-CSF), or granulocyte-macrophage colony-stimulating factor therapy within 2 weeks before enrollment.

• Received systemic therapy with corticosteroids (prednisone >10 mg/day or equivalent) or other immunomodulatory agents (e.g., thymosin, interleukin-2, interferon) within 2 weeks before enrollment. Inhaled or topical corticosteroids are allowed in subjects without active autoimmune disease.

• Positive virology test for hepatitis B or hepatitis C at screening, meeting any of the following:

  1. HBsAg positive with positive HBV-DNA titer or above upper limit of normal (ULN);
  2. HCV antibody positive.

• Known hypersensitivity or intolerance to PD-1 monoclonal antibody.

Meeting any of the following laboratory criteria:

1. Hematology: Absolute neutrophil count <1.5×10⁹/L; platelet count <75×10⁹/L; hemoglobin <90 g/L.

2. Hepatic function: ALT >3×ULN (≥5×ULN for liver metastasis); AST >3×ULN (≥5×ULN for liver metastasis); TBIL >1.5×ULN, or TBIL >2.5×ULN (3.0 mg/dL) for subjects with Gilbert syndrome.

3. Renal function: Serum creatinine >1.5×ULN or creatinine clearance <50 mL/min.

   • Any uncertain factors affecting subject safety or compliance.
   • Any other severe or uncontrolled medical disease, active infection, abnormal physical examination, abnormal laboratory test, altered mental status, or psychiatric disease that, in the investigator's opinion, increases subject risk or affects study results.