An Open-label, Single-arm, Phase I Clinical Trial to Evaluate the Safety and Efficacy of TX103 CAR-T Cells in Participants With Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 85
- 试验地点
- 2
- 主要终点
- Safety#Incidence and severity of adverse events (AEs)
研究概览
简要总结
This is a single-arm, open-label, Phase I study to evaluate the safety, tolerability, and antitumor activity of TX103 CAR-T cells in subjects with TX103-positive advanced solid tumors. The study also aims to explore the maximum tolerated dose (MTD) and determine the recommended Phase II dose (RP2D) of TX103 CAR-T cell therapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 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
- •1. Voluntary participation: Subjects must voluntarily participate in this clinical trial, fully understand and sign the informed consent form (ICF), and be willing and able to comply with all study procedures.
- •2. Age: Male or female patients aged ≥18 years and <75 years at the time of signing the ICF.
- •3. Diagnosis: Subjects must have B7-H3/CD276-positive advanced solid tumors confirmed by pathology, who have failed standard therapy or are intolerant to standard treatment.
- •Intraperitoneal infusion cohort: limited to subjects with recurrent or metastatic ovarian cancer, fallopian tube cancer, primary peritoneal cancer, or other advanced solid tumors with peritoneal metastases confined to the peritoneal cavity.
- •Intravenous infusion cohort: subjects with advanced solid tumors regardless of peritoneal metastasis, preferably including head and neck squamous cell carcinoma, esophageal cancer, lung malignancies, triple-negative breast cancer, colorectal cancer, and mesenchymal-derived malignancies.
- •4. B7-H3/CD276 expression: Tumor tissue immunohistochemistry (IHC) results show B7-H3/CD276 positivity ≥20%, defined as the percentage of viable tumor cells with positive membrane expression of B7-H3/CD276 in non-necrotic tumor tissue.
- •5. Measurable/evaluable disease:
- •Intraperitoneal infusion cohort, Phase Ia: at least one evaluable lesion per RECIST 1.1;
- •Intravenous infusion cohorts (Ia and Ib) and intraperitoneal infusion cohort (Ib): at least one measurable lesion per RECIST 1.
- •6. Performance status: Eastern Cooperative Oncology Group (ECOG) performance status of 0-
- •7. Life expectancy: Expected survival of >6 months.
- •Apheresis capability: Adequate venous access for leukapheresis and no contraindications to the procedure.
- •9. Adequate organ function (per NCI CTCAE v5.0) within screening period:
- •Hematologic: WBC ≥ 3.0×10⁹/L; hemoglobin ≥ 8.0 g/dL; absolute neutrophil count ≥ 1.5×10⁹/L; platelet count ≥ 75.0×10⁹/L. No transfusions or supportive treatments (e.g., G-CSF, erythropoietin, TPO agonists, IL-11) within 14 days before testing.
- •Renal: Serum creatinine ≤ 1.5× upper limit of normal (ULN) and estimated glomerular filtration rate (eGFR) or creatinine clearance (CrCl, per Cockcroft-Gault formula) > 50 mL/min.
- •Hepatic: ALT and AST ≤ 2.5× ULN (≤ 5.0× ULN for patients with liver metastases).
- •Bilirubin: Total bilirubin ≤ 2.0× ULN (except for patients with Gilbert's syndrome).
- •Coagulation: PT, APTT, or INR ≤ 1.5× ULN (without anticoagulant therapy).
- •Cardiac function: Left ventricular ejection fraction (LVEF) ≥ 50% within 1 month before enrollment.
- •Pregnancy test: Negative serum pregnancy test for women of childbearing potential.
- •Contraception: Subjects with reproductive potential must agree to use effective contraception from the date of informed consent signing until 365 days after the last infusion.
排除标准
- •1. Pregnant or lactating women.
- •Viral infections:
- •Positive for HIV antibody or syphilis serologic test;
- •Positive for HBsAg or HBcAb with HBV DNA ≥ 2000 IU/mL;
- •Positive for HCV antibody with detectable HCV RNA;
- •Presence of other active viremia.
- •Known hypersensitivity, allergy, intolerance, or contraindication to TX103 CAR-T or any component of the study drugs (including fludarabine, cyclophosphamide, or tocilizumab), or history of severe allergic reactions.
- •4. Active autoimmune diseases, including but not limited to autoimmune hepatitis, interstitial pneumonitis, uveitis, enteritis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, or hypothyroidism.
- •Subjects with vitiligo or childhood asthma that has resolved and requires no intervention may be included.
- •Subjects requiring medical intervention for asthma (e.g., bronchodilators) are excluded.
- •5. Receiving systemic immunosuppressive therapy, or judged by the investigator to require long-term immunosuppressants during the study. Topical, inhaled, or intranasal corticosteroids are permitted.
- •6. Prior exposure to any gene-engineered T-cell therapy (including CAR-T or TCR-T) or any other gene therapy.
- •7. History of organ transplantation.
- •Untreated or symptomatic central nervous system (CNS) metastases or leptomeningeal metastases.
- •Subjects previously treated for brain/leptomeningeal metastases may be eligible if neurologically stable for ≥1 month (MRI) and off systemic corticosteroids for >2 weeks.
- •9. Imaging (CT/MRI) showing tumor invasion of major blood vessels (e.g., aorta, pulmonary arteries/veins, vena cava) or indistinct vascular margins.
- •10. History of epilepsy or seizure-provoking disorders within 1 year prior to infusion.
- •11. Unresolved toxicities from prior anticancer therapy not recovered to CTCAE v5.0 Grade ≤1, except for investigator-judged non-safety-risk toxicities (e.g., alopecia, Grade 2 peripheral neuropathy, stable hypothyroidism with replacement therapy).
- •12. Major surgery or significant trauma within 1 month prior to leukapheresis.
- •Any severe, acute, or chronic medical or psychiatric condition, or laboratory abnormality that may increase risk or interfere with study results, including but not limited to:
- •Active infection requiring systemic therapy prior to lymphodepletion;
- •Uncontrolled cardiac disease: unstable angina, myocardial infarction within 1 year, heart failure (NYHA class ≥ II), or clinically significant arrhythmia requiring treatment/intervention;
- •Poorly controlled hypertension (SBP ≥ 160 mmHg or DBP ≥ 100 mmHg despite therapy);
- •Clinically significant bleeding (e.g., GI bleeding, bleeding ulcers, stool occult blood ++ or above, vasculitis) within 3 months before first infusion;
- •Arterial/venous thrombotic events (e.g., stroke, TIA, intracerebral hemorrhage, DVT, pulmonary embolism) within 6 months before first infusion;
- •Clinically significant pleural, pericardial, or peritoneal effusions not controllable by drainage or other means;
- •Severe cirrhosis, hepatic atrophy, or severe portal hypertension;
- •Complete intestinal obstruction.
- •History of or concurrent malignancy within the past 3 years, except for adequately treated non-melanoma skin cancer or carcinoma in situ (e.g., cervix, bladder, or breast).
研究组 & 干预措施
IV Dose-Escalation Cohort
Subjects in this arm will receive TX103 CAR-T cells via intravenous infusion. A standard 3+3 dose-escalation design will be used to evaluate safety, tolerability, and preliminary antitumor activity. The planned dose levels are as follows:Dose Level 1: 1.0 × 10⁸ CAR-T cells;Dose Level 2: 3.0 × 10⁸ CAR-T cells;Dose Level 3: 9.0 × 10⁸ CAR-T cells;Dose Level 4: 2.0 × 10⁹ CAR-T cells.
干预措施: Anti-B7-H3 Chimeric Antigen Receptor T-Cell (CAR-T Cell) Injection/TX103 (Biological)
IP Dose-Escalation Cohort
Subjects in this arm will receive TX103 CAR-T cells via intraperitoneal (IP) infusion. This cohort will be initiated sequentially after the IV dose-escalation cohort. The starting dose for the IP cohort will be based on the safe and potentially efficacious dose identified in the IV cohort. Further dose escalation will be determined by the Safety Science Committee based on accumulated safety and efficacy data. The planned dose levels are as follows:Dose Level 1: 1.0 × 10⁸ CAR-T cells;Dose Level 2: 3.0 × 10⁸ CAR-T cells;Dose Level 3: 9.0 × 10⁸ CAR-T cells;Dose Level 4: 2.0 × 10⁹ CAR-T cells;Dose Level 5: 4.0 × 10⁹ CAR-T cells.
Dose escalation will proceed sequentially, with safety evaluation at each dose level before escalation.
干预措施: Anti-B7-H3 Chimeric Antigen Receptor T-Cell (CAR-T Cell) Injection/TX103 (Biological)
Expansion Cohort (Phase Ib)
Subjects in this arm will receive TX103 CAR-T cells at the dose determined to be safe and potentially efficacious in the Phase Ia dose-escalation cohorts. The expansion cohort will focus on tumor types that showed preliminary signs of antitumor activity in Phase Ia, and selection will also consider clinical needs and other relevant factors. The purpose of this cohort is to further evaluate the safety, tolerability, and preliminary efficacy of TX103 CAR-T therapy in these selected tumor types.
干预措施: Anti-B7-H3 Chimeric Antigen Receptor T-Cell (CAR-T Cell) Injection/TX103 (Biological)
结局指标
主要结局
Safety#Incidence and severity of adverse events (AEs)
时间窗: 1 year post CAR-T cells infusion
To evaluate the possible adverse events after TX103 infusion, including the incidence, and severity of AEs.
Safety#Incidence of Dose Limiting Toxicity (DLT)
时间窗: 28 days after the first TX103 infusion
Type, incidence, and severity of dose limiting toxicities (DLTs) within 28 days after the first TX103 infusion.
The maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of TX103
时间窗: From first dose of TX103 until the end of Dose Limiting Toxicity (DLT) observation period (typically 28 days post-infusion for each dose).
次要结局
- Progression Free Survival (PFS)(1 year post CAR-T cells infusion)
- Disease Control Rate (DCR)(1 year post CAR-T cells infusion.)
- Overall survival (OS)(6 and 12 months post CAR-T cells infusion)
- Objective response rate (ORR)(1 year post CAR-T cells infusion)
- Time to Remission (TTR)(1 year post CAR-T cells infusion.)
- Duration of Response (DOR)(1 year post CAR-T cells infusion.)
- Duration of disease control (DDC)(1 year post CAR-T cells infusion.)