An Open-label, Single-arm Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetic Profile, and Preliminary Efficacy of KT032 Cell Injection in Patients With Mesothelin-positive Advanced Solid Tumors.
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 24
- 主要终点
- Dose-Limiting Toxicity（DLT）
研究概览
简要总结
An Open-label, Single-arm Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetic Profile, and Preliminary Efficacy of KT032 Cell Injection in Patients With Mesothelin-positive Advanced Solid Tumors.
详细描述
This is a single-arm, single-center, open-label, dose-escalation and expansion study to investigate the safety and tolerability, pharmacokinetics, and preliminary efficacy of the investigational product administered via intraperitoneal injection in adult patients with advanced solid tumors.
Dose-Escalation Phase： After providing informed consent, subjects will be screened for eligibility based on inclusion/exclusion criteria. Eligible subjects will receive KT032 treatment. Dose escalation will follow the "3+3" principle across three dose cohorts: 1.0×10⁶, 2.0×10⁶, and 3.0×10⁶ CAR-T cells/kg (for the highest dose cohort, dosing will be calculated based on 70 kg for subjects weighing >70 kg). Given the special nature of the cellular product, a ±20% variance in the actual administered dose is permitted for each cohort. This phase plans to enroll 12-18 subjects with single-dose administration.
Dose-Expansion Phase： Based on data from the dose-escalation phase, one optimal dose cohort will be selected to expand with 6 additional subjects. The specific expansion study plan and sample size will be determined according to preliminary safety, PK, and efficacy data obtained during the dose-escalation phase.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Aged 18 to 75 years (inclusive), any gender;
- •Histopathologically confirmed diagnosis of advanced solid tumors (including but not limited to ovarian cancer, mesothelioma, colon cancer, etc.), with peritoneal or intraperitoneal metastasis as the primary disease manifestation;
- •Progression or intolerance to prior systemic standard-of-care treatment according to guidelines (systemic therapy includes but is not limited to systemic chemotherapy, molecular targeted therapy, etc.), and unsuitable for surgery or local treatment (including ablation therapy, interventional therapy, and radiotherapy); specifically: Ovarian cancer: Recurrence during or within 6 months after second-line or later platinum-based chemotherapy; Mesothelioma: Failure of, intolerance to, or ineligibility for at least first-line therapy; Colon cancer: Failure of, intolerance to, or ineligibility for at least third-line therapy;
- •Ovarian cancer: Progression, intolerance, or ineligibility after second-line standard therapy including carboplatin ± paclitaxel/albumin-bound paclitaxel/docetaxel/pegylated liposomal doxorubicin;
- •Advanced colon cancer: Progression, intolerance, or ineligibility after third-line standard therapy including cetuximab ± irinotecan/regorafenib/fruquintinib/trifluridine/tipiracil;
- •Mesothelioma: Progression, intolerance, or ineligibility after first-line standard therapy with pemetrexed combined with cisplatin/carboplatin;
- •Presence of at least one measurable lesion per RECIST 1.1 criteria;
- •MSLN expression positivity in tumor tissue detected by immunohistochemistry (IHC), defined as IHC ≥2+ (i.e., ≥26% positive tumor cells stained); subjects must undergo fresh tumor tissue biopsy; if biopsy is not feasible, at least 5 archived tumor tissue slides collected within one year must be provided (if multiple tumor tissue collections exist, the most recent sample is preferred);
- •ECOG performance status 0-1 (see Appendix 1) and estimated life expectancy >12 weeks;
- •Adequate organ function with all following laboratory results prior to enrollment:
- •Hematology: Absolute neutrophil count (ANC) ≥1.5×10⁹/L (growth factor support allowed, but must not have received within 7 days prior to laboratory testing); Absolute lymphocyte count (ALC) ≥0.7×10⁹/L; Platelets ≥100×10⁹/L (no transfusion support within 7 days prior to laboratory testing); Hemoglobin ≥90 g/L (no RBC transfusion within 7 days prior to laboratory testing; recombinant human erythropoietin allowed); Hepatic function: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×upper limit of normal (ULN); Total serum bilirubin ≤2×ULN; ALT and AST may be extended to ≤5×ULN if abnormalities are determined by the investigator to be due to disease (e.g., hepatic metastases or biliary obstruction) or Gilbert's syndrome; Renal function: Creatinine clearance (CrCl) ≥50 mL/min calculated by Cockcroft-Gault formula; Coagulation function: Fibrinogen ≥1.0 g/L; Activated partial thromboplastin time ≤1.5×ULN; Prothrombin time (PT) ≤1.5×ULN; Oxygen saturation >91% (on room air); Left ventricular ejection fraction (LVEF) ≥50%;
- •Recovery from all toxicities related to prior treatment to acceptable baseline status, or recovery to normal or Grade 1 per NCI CTCAE 5.0, as determined by the investigator; except for toxicities not expected to increase safety risk of subsequent investigational product infusion, such as alopecia, vitiligo, etc.;
- •Agreement by subjects and their partners to use effective contraceptive methods (excluding rhythm method) from the time of informed consent signature until one year after CAR-T cell infusion;
- •Written informed consent on IRB/IEC-approved consent form obtained personally from the subject prior to initiation of any screening procedures.
排除标准
- •Other malignancies within 5 years prior to screening, except adequately treated cervical carcinoma in situ, basal cell or squamous cell skin cancer, or ductal carcinoma in situ of the breast after radical surgery;
- •Hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) positive with peripheral blood hepatitis B virus (HBV) DNA titer above the lower limit of detection of the quantitative assay at the study site; Hepatitis C virus (HCV) antibody positive with peripheral blood HCV RNA above the lower limit of detection of the quantitative assay at the study site; Human immunodeficiency virus (HIV) antibody positive; Positive syphilis test;
- •Patients with central nervous system metastases and/or other unstable central nervous system diseases (hemorrhage, active infarction, infection, etc.);
- •Receipt of live attenuated vaccine within 4 weeks prior to cell injection;
- •History of hypersensitivity to prior immunotherapy, allergy or intolerance to fludarabine, cyclophosphamide, albumin-bound paclitaxel conditioning regimen drugs, or tocilizumab, or allergy to components of the investigational product formulation, or history of other severe allergic reactions;
- •Poorly controlled hypertension (systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg) or clinically significant (e.g., active) cardiovascular disease, such as cerebrovascular accident (within 6 months prior to main informed consent signature), myocardial infarction (within 6 months prior to main informed consent signature), unstable angina, New York Heart Association (NYHA) Class II or greater congestive heart failure, or serious arrhythmia not controlled by medication or potentially affecting study treatment; Clinically significant abnormalities on ECG in 3 consecutive readings (at least 5 minutes apart each) or mean QTcB ≥450 ms;
- •Other severe organic diseases or psychiatric disorders;
- •Chronic obstructive pulmonary disease, interstitial lung disease, or clinically significant abnormal pulmonary function test results;
- •Autoimmune diseases: History of autoimmune disease deemed unsuitable for this study by the investigator, such as systemic lupus erythematosus, vasculitis, infiltrative lung disease (subjects with vitiligo are excluded from this exclusion criterion);
- •Systemic corticosteroids (topical use allowed), hydroxyurea, immunomodulatory agents (e.g., α or γ interferon, GM-CSF, mTOR inhibitors, cyclosporine, thymosin, etc.) within 2 weeks prior to screening or planned use during the study (if long-term use exists);
- •Chemotherapy within 2 weeks prior to cell injection, immunotherapy within 4 weeks, radiotherapy within 12 weeks prior to infusion, or other antineoplastic agents with insufficient washout period of less than 5 half-lives;
- •Pregnant or lactating women, and female subjects planning pregnancy within 1 year after cell infusion;
- •Subjects with any concurrent medical condition or disease that the investigator determines may interfere with study conduct;
- •Receipt of other cellular or gene therapy products within 3 months prior to cell injection, or patients deemed unsuitable for enrollment by the investigator;
- •Patients whom the investigator determines will have difficulty completing all study visits or procedures (including follow-up period), or with insufficient compliance; or patients deemed unsuitable for enrollment by the investigator.
研究组 & 干预措施
KT032：1.0×10⁶ CAR-T cells/kg
干预措施: KT032(anti-MSLN chimeric antigen receptor autologous T cell injection) (Biological)
KT032：2.0×10⁶ CAR-T cells/kg
干预措施: KT032(anti-MSLN chimeric antigen receptor autologous T cell injection) (Biological)
KT032：3.0×10⁶ CAR-T cells/kg
干预措施: KT032(anti-MSLN chimeric antigen receptor autologous T cell injection) (Biological)
结局指标
主要结局
Dose-Limiting Toxicity（DLT）
时间窗: 28 days
Safety
Maximal Tolerable Dose（MTD）
时间窗: 28 days
tolerability evaluation
Adverse Event（AE）
时间窗: Disease progression, withdrawal from the study, death, or 2 years following cell administration, whichever occurs first
Incidence rate
Serious Adverse Event（SAE）
时间窗: Disease progression, withdrawal from the study, death, or 2 years following cell administration, whichever occurs first
Incidence rate
Adverse Event of Special Interest （ AESI）
时间窗: Disease progression, withdrawal from the study, death, or 2 years following cell administration, whichever occurs first
Incidence rate
次要结局
- Overall Survival (OS)(2 years)
- PK(2 years)
- Antitumor efficacy-Objective response rate (ORR)(2 years)
- Disease Control Rate (DCR)(2 years)
- Duration of Response (DOR)(2 years)
- Progression-Free Survival (PFS)(2 years)
研究者
Weijia Fang, MD
Director,Principal Investigator
Zhejiang University