Phase I/II Clinical Trial of CD73/AXL Targeted HypoSti.CAR-T Cells in Treating Patients With CD73/AXL Positive Advanced/Metastatic Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Phase 1: RP2D
研究概览
简要总结
In this single-center, single-arm,prospective, open-label, phase 1/2 study, the safety and efficacy of novel autologous hypoxia-activated CAR-T cell therapy targeting CD73 and AXL ( CD73/AXL.HypoSti.CAR-T) will be evaluated in patients with CD73/AXL antigen positive advanced/metastatic solid tumors. In this clinical trial, at least 12 eligible patients in dose escalation period will be enrolled to receive 3 doses Of CD73/AXL.HypoSti.CAR-T cell therapy according to the "3+3" principle. In dose expansion period, additional at most 21 eligible patients will be enrolled to receive CD73/AXL.HypoSti.CAR-T cell therapy at dose of recommended phase 2 dose(RP2D).
详细描述
Currently, CAR T-cell therapy still faces significant challenges in its application to solid tumors due to multiple obstacles, including the lack of tumor-specific antigens, the complex immunosuppressive tumor microenvironment (TME), tumor heterogeneity, and on targeted/non-targeted (OTOT) toxicity. Previous studies have found that intratumoral hypoxic microenvironment facilitated the development and metastasis of tumor cells. Meanwhile, cytotoxic T cells, including CAR-T cells, struggle to survive and proliferate in this low-oxygen microenvironment.
CD73 (also known as 5'-nucleotidase) and AXL (a receptor tyrosine kinase) are both overexpressed in multiple solid tumors, but less so in normal tissues. They are both involved in regulating tumorigenesis, development, metastasis processes, correlating with inferior prognosis.Dual targeting of CD73 and AXL can effectively address antigen escape and tumor heterogeneity, representing a promising novel immunotherapy strategy.
In this study, combining hypoxia-activated precision with dual-targeting synergy,Investigators have developed a novel CD73/AXL.HypoSti.CAR-T that could effectively expand and survive in hypoxic TME ,offering enhanced efficacy and safety for solid tumors in animal models. Further clinical development is warranted to validate these promising preclinical results. So we conduct this clinical trial in order to test the the safety profiles and anti-tumor activities of CD73/AXL.HypoSti.CAR-T cell in vivo. In dose escalation period, at least 12 eligible patients will be enrolled and receive 3 doses of CD73/AXL.HypoSti.CAR-T cell therapy (1 × 10^6 cells/ kg, 3 × 10^6 cells/kg, 1 × 10^7 cells/kg) according to the "3+3" principle. In dose expansion period, additional at most 21 eligible patients will be enrolled to receive CD73/AXL.HypoSti.CAR-T cell infusion at RP2D, which is determined by data from dose escalation period, including occurrence of dose limiting toxicities (DLT), pharmacokinetics/pharmacodynamics, efficacy and other parameters, to furtherly evaluate the safety and efficacy profiles of CD73/AXL.HypoSti.CAR-T cell therapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 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
- •Age 18-75 (inclusive).
- •The Eastern Cooperative Oncology Group (ECOG) score ≤2 and Estimated life expectancy of more than 3 months.
- •Histopathological confirmed advanced or metastatic solid tumors failed to at least first-line treatment or initially diagnosed advanced/metastatic solid tumors that have no National Comprehensive Cancer Network (NCCN) guideline recommended standard firstline therapy. Tumor types include but are not limited to:biliary malignancies, pancreatic cancer, lung cancer, breast cancer, head and neck malignancies, gynecological tumors, etc.
- •The expression of CD73 or AXL antigen is≥50%.
- •At least one measurable lesion at baseline per RECIST version 1.
- •Fresh solid tumor samples or formalin-fixed paraffin embedded tumor archival samples within 6 months are necessary; Fresh tumor samples are preferred. Subjects are willing to accept tumor rebiopsy in the process of this study.
- •Adequate organ function as defined by the following criteria:
- •Absolute neutrophil count (ANC) ≥ 1 x 10^9/L, Platelet count ≥75 x 10^9/ L, hemoglobin (Hgb) ≥ 90g/L ;
- •Serum creatinine≤1.5 upper limit of normal (ULN) or creatinine clearance (as estimated by Cockcroft Gault) ≥60 mL/min;
- •Serum aspartate amino transferase (AST) and alanine aminotransferase (ALT), ≤3.0 x ULN (≤5 x ULN for patients with liver cancer or metastases); Total serum bilirubin ≤1.5 x ULN(≤3 x ULN for patients with liver cancer or metastases);
- •Cardiac ejection fraction ≥ 50%, no evidence of pericardial effusion as determined by an echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG) findings;
- •International Normalized Ratio (INR) ≤ 1.5 times the upper limit of normal (ULN), and Activated Partial Thromboplastin Time (APTT) ≤ 1.5 times ULN;
- •Baseline oxygen saturation >91% on room air.
- •Previous treatment must be completed for more than 4 weeks prior to the enrollment of this study, and subjects have recovered to <= grade 1 toxicity (except for hematological toxicities and clinically non-significant toxicities such as alopecia).
- •Pregnancy tests for women of childbearing age shall be negative; Both men and women agreed to use effective contraception during treatment and during the subsequent 1 year.
- •Ability to understand and sign a written informed consent document.
排除标准
- •Subjects are being treated with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of enrollment.
- •Received cytotoxic chemicals, monoclonal antibodies, immunotherapy, targeted therapy or other anti-tumor therapy within 4 weeks or 5 half-lives before enrollment.
- •Pregnant, lactating, or breastfeeding females.
- •Known positive test result for human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS);Active infection of hepatitis B virus (HBV), or hepatitis C virus (HCV).
- •History of allergy or intolerance to study drug components.
- •Prior organ allograft transplantations or allogeneic hematopoietic stem cell transplantation.
- •Major surgery or trauma occurred within 28 days prior to enrollment, or major side effects have not been recovered.
- •Known brain metastases or active central nervous system (CNS).Subjects with CNS metastases who were treated with radiotherapy for at least 3 months prior to enrollment, have no central nervous symptoms and are off corticosteroids, are eligible for enrollment, but require a brain MRI screening.
- •Previous or concurrent cancer within 5 years prior to treatment start except for curatively treated cervical cancer in situ, non-melanoma skin cancer, superficial bladder tumors.
- •Uncontrolled intercurrent illness, including ongoing or active systemic infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia (excluding insignificant sinus bradycardia and sinus tachycardia) or psychiatric illness/social situations and any other illness that would limit compliance with study requirements and jeopardize the safety of the patient.
- •Active bleeding or known hemorrhagic tendency.
- •Vaccination within 30 days of study enrollment.
- •Being participating any other trials or withdraw within 4 weeks.
- •Researchers believe that other reasons are not suitable for clinical trials.
研究组 & 干预措施
CD73/AXL.HypoSti.CAR-T cells
Enrolled participants will be given a preconditioning regimen consisted of albumin-bound paclitaxel, cyclophosphamide and fludarabine before the infusion of CD73/AXL.HypoSti.CAR-T cells.
Enrolled patients in this arm will be administered CD73/AXL.HypoSti.CAR-T cells in "3+3" based escalation manner.
干预措施: CD73/AXL.HypoSti.CAR-T cells (Biological)
CD73/AXL.HypoSti.CAR-T cells
Enrolled participants will be given a preconditioning regimen consisted of albumin-bound paclitaxel, cyclophosphamide and fludarabine before the infusion of CD73/AXL.HypoSti.CAR-T cells.
Enrolled patients in this arm will be administered CD73/AXL.HypoSti.CAR-T cells in "3+3" based escalation manner.
干预措施: Albumin-Bound Paclitaxel (Drug)
CD73/AXL.HypoSti.CAR-T cells
Enrolled participants will be given a preconditioning regimen consisted of albumin-bound paclitaxel, cyclophosphamide and fludarabine before the infusion of CD73/AXL.HypoSti.CAR-T cells.
Enrolled patients in this arm will be administered CD73/AXL.HypoSti.CAR-T cells in "3+3" based escalation manner.
干预措施: Cyclophosphamide (Drug)
CD73/AXL.HypoSti.CAR-T cells
Enrolled participants will be given a preconditioning regimen consisted of albumin-bound paclitaxel, cyclophosphamide and fludarabine before the infusion of CD73/AXL.HypoSti.CAR-T cells.
Enrolled patients in this arm will be administered CD73/AXL.HypoSti.CAR-T cells in "3+3" based escalation manner.
干预措施: Fludarabine (Drug)
结局指标
主要结局
Phase 1: RP2D
时间窗: Up to 12 months.
The recommended dose for phase 2 was determined through phase 1 study.
Phase 2: Objective response rate (ORR) .
时间窗: Up to 3 years.
ORR includes complete response(CR) and partial response (PR), as defined by investigators according to investigators Response Evaluation Criteria in Solid Tumours 1.1 (RECIST 1.1) or Immune Response Evaluation Criteria in Solid Tumours (iRECIST) criteria.
Phase 1: Incidence of treatment related adverse events (TRAEs).
时间窗: Up to 12 months
TRAEs are defined as any medical events since the initiation of CD73/AXL.HypoSti.CAR-T cell therapy . Cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome (ICANS) will be evaluated according to the standards released by American Society for Transplantation and Cellular Therapy (ASTCT) criteria in 2019, and the others will be graded by common terminology criteria for adverse events (CTCAE) V5.0.
Phase 1:Incidence of dose limiting toxicities (DLTs).
时间窗: Up to 28 days after infusion.
DLTs are defined as CD73/AXL.HypoSti.CAR-T cell therapy related adverse events within the first 28 days that meet the following criteria: * Grade 4 CRS or grade 3 CRS that is not resolved to grade 2 or lower within 2 weeks; * Grade 3 ICANS lasting for ≥7 days or Grade 4 ICANS; * Any other Grade ≥4 and Grade 3 AEs related to the CD73/AXL.HypoSti.CAR-T infusion that lasts for ≥14 days, except hematology toxicity.
次要结局
- Phase 2:Overall Survival (OS)(Up to 3 years.)
- Phase 1 and phase 2: Pharmacodynamics: Peak level of cytokines in serum.(Up to 28 days after infusion.)
- Phase 2:Progression Free Survival (PFS)(Up to 3 years.)
- Phase 2:Duration of response (DOR) .(Up to 3 years.)
- Phase 1 and phase 2: Pharmacokinetics:Number and copy number of CD73/AXL.HypoSti.CAR-T cells .(Up to 12 months.)
- Phase 2:Time to response (TTR).(Up to 3 years.)
研究者
Han weidong
Director of Biotherapeutic Department
Chinese PLA General Hospital