Overview
This is a single-center, open-label, Phase I/II clinical study designed to evaluate the safety, tolerability, and preliminary efficacy of SK-NK Cell Injection administered via intraperitoneal (IP) perfusion in patients with advanced ovarian cancer complicated by massive ascites .
The study focuses on patients who have failed standard therapies and are suffering from severe ascites. The treatment involves the direct infusion of allogeneic, highly activated Natural Killer (NK) cells (SK-NK) into the abdominal cavity .
The study consists of two phases:
Phase I (Dose Escalation): To determine the safety profile and the Recommended Phase 2 Dose (RP2D) using a "3+3" design with three increasing dose levels.
Phase II (Dose Expansion): To further evaluate the efficacy of the treatment in controlling ascites and suppressing tumor growth at the determined RP2D.
Participants will receive the study treatment once weekly for 4 weeks.
Description
Background and Rationale:
Ovarian cancer often presents with malignant ascites in advanced stages, which is associated with poor prognosis and severely reduced quality of life. The peritoneal cavity in these patients is characterized by an immunosuppressive tumor microenvironment. Natural Killer (NK) cells are innate immune effector cells capable of recognizing and killing tumor cells without MHC restriction. "Super Kill-NK" (SK-NK) cells are highly activated allogeneic NK cells derived from healthy donors, characterized by high expression of activation markers (e.g., CD16, NKG2D) and enhanced cytotoxicity. Intraperitoneal delivery allows for direct contact between effector cells and tumor cells within the peritoneal cavity, potentially increasing local therapeutic concentration while minimizing systemic toxicity .
Study Design:
This is an open-label, single-arm, Phase I/II study. Phase I (Dose Escalation): Utilizing a standard "3+3" design to assess safety and identify the Dose-Limiting Toxicity (DLT). Three dose cohorts are planned: 3×10\^8, 6×10\^8, and 9×10\^8 cells per dose. The DLT observation period is 28 days after the first infusion.
Phase II (Dose Expansion): Once the Recommended Phase 2 Dose (RP2D) is determined, additional patients will be enrolled to evaluate efficacy.
- Intervention
Eligible patients will receive SK-NK Cell Injection via intraperitoneal perfusion. The treatment schedule consists of one infusion every week for a total of 4 doses (Days 1, 8, 15, and 22).
- Objectives
Primary: To evaluate safety, tolerability, and determine the RP2D. Secondary: To assess the Ascites Response Rate, Objective Response Rate (ORR), Duration of Relief (DoR), and 1-year Overall Survival (OS). Pharmacokinetics (PK) and pharmacodynamics (PD) will also be evaluated by monitoring SK-NK cell persistence and cytokine levels in peripheral blood and ascites .
Exploratory: To investigate the mechanism of action of NK cell therapy in the malignant ascites microenvironment.
Eligibility
Inclusion Criteria:
Voluntarily sign the written Informed Consent Form (ICF) and be able to comply with study procedures and follow-up.
Female, aged 18 to 75 years. ECOG performance status of 0 to 2. Histologically or cytologically confirmed advanced ovarian cancer. Participants must have failed at least two lines of standard therapy (disease progression or intolerance), have no standard therapy available, or be unable to receive standard therapy for other reasons .
Complicated by massive malignant ascites, defined as a volume of ≥ 2000 mL indicated by Ultrasound or CT.
Expected survival time ≥ 3 months.
Adequate organ function (no blood transfusion, cell growth factors, etc., within 14 days prior to enrollment), defined as:
Neutrophils (ANC) ≥ 1.0×10\^9/L Platelets (PLT) ≥ 80×10\^9/L Hemoglobin (Hb) ≥ 80 g/L Total Bilirubin (TBIL) ≤ 1.5×ULN (≤ 3×ULN for Gilbert's syndrome or liver metastasis) ALT and AST ≤ 2.5×ULN (≤ 5×ULN if liver metastasis is present) INR ≤ 1.5×ULN and APTT ≤ 1.5×ULN (unless on anticoagulant therapy) Creatinine clearance ≥ 60 mL/min (calculated by Cockcroft-Gault formula) Toxicities from prior therapies must have recovered to ≤ Grade 1 (except for alopecia and ≤ Grade 2 neurotoxicity caused by chemotherapy) .
Exclusion Criteria:
Prior receipt of other cell therapies. Presence of loculated (septated) ascites indicated by CT or Ultrasound. Receipt of any systemic anti-tumor therapy (including chemotherapy, targeted therapy, etc.) within 3 weeks prior to intraperitoneal perfusion.
Receipt of Traditional Chinese Medicine (herbal) with anti-tumor indications within 3 weeks prior to intraperitoneal perfusion.
Receipt of systemic corticosteroids (≥ 10 mg/day prednisone or equivalent) or other immunosuppressive medications within 2 weeks prior to intraperitoneal perfusion (inhaled, topical, or physiologic replacement doses are allowed).
Major surgery within 4 weeks prior to screening or planned major surgery during the study period.
History of other malignancies within 5 years (except for cured local tumors with low risk of recurrence, such as non-melanoma skin cancer).
History of active or suspected autoimmune or inflammatory disease. History of organ transplantation or hematopoietic stem cell transplantation.
Presence of active infection, including:
Active Hepatitis B (HBsAg positive and HBV-DNA \> 1000 copies/mL) Active Hepatitis C (HCV antibody positive and HCV-RNA detected) Systemic active infection requiring antibiotic treatment Congenital or acquired immunodeficiency (e.g., HIV infection) Vaccination with live or attenuated vaccines within 4 weeks prior to intraperitoneal perfusion.
Severe cardiovascular diseases, including:
Uncontrolled hypertension (SBP \> 160 mmHg and/or DBP \> 100 mmHg) History of hypertensive crisis or hypertensive encephalopathy Cardiovascular accident, TIA, myocardial infarction, unstable angina, or significant vascular disease within 6 months NYHA Class ≥ II heart failure or LVEF \< 50% Severe arrhythmia uncontrolled by medication (QTc ≥ 450 ms for males, ≥ 470 ms for females), or congenital Long QT syndrome Severe respiratory disease (e.g., history of severe interstitial lung disease, severe COPD), FEV1 \< 2L, or DLCO \< 40%.
History of clear neurological or psychiatric disorders, including epilepsy or dementia.
Other conditions considered unsuitable for the study by the investigator (e.g., prior Grade ≥ 3 adverse events from immunotherapy).
