A Phase I Dose-Escalation and Phase II Study of Nanobody-Based CD5-Targeted CAR-T Cells in Relapsed or Refractory T-Cell Acute Lymphoblastic Leukemia and T-Cell Lymphoma (T-ALL/NHL): The CONQUER Trial
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- DLT (Dose-Limiting Toxicity)
研究概览
简要总结
To observe the safety and efficacy of Nanobody-Based CD5-targeted chimeric antigen receptor T cells in the treatment of refractory or relapsed T-ALL/NHL
详细描述
This Phase I/II study aims to evaluate the safety, tolerability, and efficacy of Nanobody-Based CD5 Chimeric Antigen Receptor (CAR) T-cell therapy in patients with relapsed or refractory (R/R) T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoma (T-NHL).
In the Phase I portion, a 3+3 dose-escalation design will be utilized to assess the safety profile and determine the optimal dose of Nanobody-Based CD5 CAR-T cells. The recommended Phase II dose (RP2D) will be established based on safety data, dose-limiting toxicities (DLTs), and preliminary efficacy outcomes.
The Phase II portion will then evaluate the efficacy of Nanobody-Based CD5 CAR-T therapy at the RP2D. The primary and secondary endpoints will include:
Overall response rate (ORR) Disease-free survival (DFS) Overall survival (OS) Comprehensive safety assessments will be conducted throughout the study, with a particular focus on cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).
By investigating Nanobody-Based CD5 CAR-T therapy, this study aims to address the significant unmet clinical need for effective treatment options in patients with R/R T-ALL/NHL and provide insights into its potential as a novel immunotherapeutic approach.
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
- 3 Years 至 70 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •The subject or guardian understands and voluntarily signs the informed consent form (ICF).
- •Male or female, aged 3-70 years at the time of signing the ICF (inclusive).
- •Expected survival of at least 12 weeks.
- •ECOG performance status of 0-2 at the time of ICF signing.
- •Diagnosis of relapsed/refractory T-cell lymphoblastic leukemia/lymphoma (R/R T-ALL/NHL) confirmed at screening and meeting at least one of the following criteria:
- •Bone marrow involvement: Morphologic examination shows ≥5% lymphoblasts, and/or
- •Cerebrospinal fluid (CSF) involvement: Tumor cells detected in CSF, and/or
- •Extramedullary disease: Presence of measurable lesions (lymph node/mass ≥1.5 cm in axial diameter or extranodal lesion ≥1 cm in axial diameter).
- •CD5 expression: Tumor cells in bone marrow, peripheral blood, or CSF are CD5-positive by flow cytometry, and/or lymph node/mass or extranodal lesions are CD5-positive by pathology.
- •Adequate major organ function, defined as:
- •AST and ALT ≤5× upper limit of normal (ULN).
- •Total bilirubin ≤2× ULN.
- •Renal function: Serum creatinine clearance ≥60 mL/min (Cockcroft-Gault formula) or creatinine ≤1.5× ULN.
- •Blood oxygen saturation >92%.
- •Reproductive health requirements:
- •Fertile men and women of childbearing potential must agree to use effective contraception from ICF signing until 2 years after study drug administration.
- •Women of childbearing potential (pre-menopausal or within 2 years post-menopause) must have a negative blood pregnancy test at screening.
排除标准
- •History of central nervous system (CNS) diseases, including but not limited to:
- •Paralysis
- •Severe brain injury
- •Parkinson's disease
- •Neuropathy
- •History of autoimmune diseases requiring systemic immunosuppressive therapy within 2 years prior to signing the ICF, including but not limited to:
- •Crohn's disease
- •Rheumatoid arthritis
- •Systemic lupus erythematosus (SLE)
- •Systemic sclerosis
- •Inflammatory bowel disease (IBD)
- •Vasculitis
- •Psoriasis
- •Presence of any uncontrolled active infection at the time of signing the ICF or within 4 weeks prior to apheresis that requires antibiotic, antiviral, or antifungal treatment.
- •Positive virological or infectious disease markers, including:
- •Hepatitis B virus (HBV): Subjects with positive HBsAg or HBcAb-positive at screening must have undetectable HBV DNA in peripheral blood to be eligible; otherwise, they should be excluded.
- •Hepatitis C virus (HCV): Subjects with positive HCV antibodies and detectable HCV RNA should be excluded.
- •Human immunodeficiency virus (HIV) antibody-positive subjects should be excluded.
- •Cytomegalovirus (CMV) DNA test-positive subjects should be excluded.
- •Epstein-Barr virus (EBV) DNA test-positive subjects should be excluded.
- •Positive serological or non-specific antibodies for Treponema pallidum (syphilis).
- •Clinically significant cardiovascular diseases, including any of the following:
- •QTc interval ≥480 ms (Fridericia correction formula)
- •New York Heart Association (NYHA) Class II or higher heart failure
- •Unstable angina or acute myocardial infarction within 6 months prior to signing the ICF
- •Left ventricular ejection fraction (LVEF) <50%
- •Poorly controlled hypertension (as determined by the investigator)
- •Clinically significant arrhythmias or those requiring antiarrhythmic treatment, including:
- •Persistent ventricular tachycardia
- •Ventricular fibrillation
- •Torsades de pointes
- •Complete left bundle branch block
- •History of severe hypersensitivity or allergy to any components of the study drug.
- •Receipt of any investigational drug therapy or other systemic antitumor therapy within 4 weeks before apheresis (or 5 half-lives of the drug, whichever is longer, as determined by the investigator).
- •Receipt of extensive radiotherapy within 4 weeks prior to signing the ICF, except for palliative radiotherapy for non-target lesions within 2 weeks before signing the ICF or as expected during the study.
- •Unresolved toxicity from prior antitumor therapy that has not returned to Grade 1 or baseline levels at the time of signing the ICF, except for hair loss and pigmentation (per NCI-CTCAE v5.0).
- •Requirement for systemic corticosteroids or other immunosuppressive therapy (≥10 mg/day prednisone or equivalent) within 3 days prior to apheresis or during the study period, except for:
- •Intranasal, inhaled, or topical steroids, or localized steroid injections (e.g., intra-articular injections)
- •Systemic corticosteroids ≤10 mg/day prednisone (or equivalent physiological dose)
- •Steroids as prophylaxis for allergic reactions (e.g., pre-medication before contrast-enhanced CT)
- •Steroids used for symptomatic treatment of transfusion-related reactions
- •Major surgery within 4 weeks prior to signing the ICF (excluding routine biopsy procedures) or planned major surgery during the study period.
- •History of active tuberculosis infection within 1 year prior to signing the ICF, except for subjects with a history of tuberculosis more than 1 year ago, provided that the investigator determines there is no evidence of active tuberculosis.
- •History of other primary malignancies within 5 years prior to signing the ICF, except for:
- •Adequately treated carcinoma in situ of the cervix
- •Localized basal cell carcinoma or squamous cell carcinoma of the skin
- •Receipt of live-attenuated or inactivated vaccines within 4 weeks before signing the ICF or planned vaccination during the screening period.
- •Any other condition or complication that, in the investigator's judgment, may affect adherence to the study protocol or make the subject unsuitable for participation.
- •Pregnancy or lactation.
研究组 & 干预措施
CD5-targeted CAR-T cells
Eligible patients will receive a single infusion of CD5-targeted CAR-T cells at 3+3 dose-escalation design.
Phase II: Patients will receive CD5-targeted CAR-T cells at the RP2D.
干预措施: CD5-targeted CAR-T cells (Biological)
结局指标
主要结局
DLT (Dose-Limiting Toxicity)
时间窗: Day28 after CAR-T cell infusion
CRS and ICANS will be assessed per ASTCT (2019), while other AEs follow CTCAE v5.0. DLTs are CAR-T-related AEs that occur within 28 days post-infusion and meet the following criteria: Grade 4+ CRS, or Grade 3 CRS unresolved to ≤ Grade 2 within 7 days. Grade 3+ non-hematologic toxicity unresolved to ≤ Grade 2 within 7 days. Grade 4+ ICANS, or Grade 3 ICANS unresolved to ≤ Grade 2 within 3 days. Grade 3+ hypersensitivity reaction. Any unexpected toxicity requiring study discontinuation. Exemptions: Rapid hypersensitivity resolving to ≤ Grade 2 in 2 hours. Reversible Grade 3 AEs lasting ≤7 days. Transient CRS-related organ dysfunction, resolving in ≤7 days per SRC. All DLTs are reviewed by the Safety Review Committee (SRC).
Overall Response Rate (ORR)
时间窗: Within 3 months after CAR-T cell infusion
ORR is defined as the proportion of patients achieving Complete Remission (CR), Complete Remission with Incomplete Hematologic Recovery (CRi), or Morphologic Leukemia-Free State (MLFS) per European LeukemiaNet (ELN) 2022 for T-ALL and Lugano/Lyric 2016 for T-NHL. CR: \<5% blasts in bone marrow, no circulating blasts/extramedullary disease, ANC \>1.0 × 10⁹/L, platelets \>100 × 10⁹/L, MRD-negative. CRi: Meets CR but lacks full hematologic recovery. MLFS: \<5% blasts, no hematologic recovery required. Lugano 2016 (T-NHL): CR = complete metabolic response on PET-CT; PR = ≥50% tumor reduction.
次要结局
- Overall Survival (OS)(Within 2-year after CAR-T cell infusion)
- Progression-Free Survival (PFS)(Within 2-year after CAR-T cell infusion)
研究者
Xiangyu Zhao
Deputy Hospital Director
Peking University People's Hospital