A Phase I Dose-Escalation and Phase II Study of Nanobody-Based CD19/CD22 Tandem Dual Chimeric Antigen Receptor (CAR) T-cell Therapy in Patients With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- Dose-Limiting Toxicity (DLT)
研究概览
简要总结
To evaluate the efficacy and safety of Nanobody-Based CD19/CD22 Tandem Dual Chimeric Antigen Receptor (CAR) T-cell therapy in patients with relapsed or refractory B-ALL
详细描述
This Phase I/II study aims to evaluate the safety, tolerability, and efficacy of Nanobody-Based CD19/CD22 Tandem Dual CAR-T-cell therapy in patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL), particularly those who have failed or relapsed after CD19- or CD22-targeted CAR-T or antibody-based immunotherapy.
In the Phase I portion of the study, a 3+3 dose-escalation design will be employed to evaluate safety and determine the optimal dose of Nanobody-Based CD19-22 Tandem CAR-T cells. Three dose levels will be tested: 0.3 × 10⁶ cells/kg, 1.0 × 10⁶ cells/kg, and 2.0 × 10⁶ cells/kg. 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 focus on evaluating the efficacy of nanobody-based CD19/CD22 tandem dual CAR-T therapy at the RP2D in patients with R/R B-ALL who are refractory to or have relapsed after prior immunotherapies, including blinatumomab, inotuzumab ozogamicin, or prior single-target CAR-T therapy, with key endpoints including overall response rate (ORR), duration of response (DOR), disease-free survival (DFS), and overall survival (OS).Safety assessments will include cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), immune effector cell-associated hemophagocytic syndrome (IEC-HS), and immune effector cell-associated hematotoxicity (ICAHT) will also be conducted throughout the study.
This study seeks to address the unmet clinical need for effective treatment options in patients with R/R B-ALL, particularly those who have exhausted prior CD19- or CD22-directed therapies.
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
- 12 Years 至 65 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •The subject or their legally authorized representative (guardian) understands the study and voluntarily signs the informed consent form (ICF).
- •Male or female, aged 12 to 65 years at the time of signing the ICF (inclusive of the cutoff values).
- •Expected survival of at least 12 weeks. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 at the time of signing the ICF.
- •At the time of signing the ICF, the patient must be diagnosed with R/R B-ALL and meet the following criteria:
- •Bone marrow morphological examination at screening shows >5% blasts in the bone marrow, and/or cerebrospinal fluid (CSF) analysis detects leukemic cells, and/or the presence of measurable extramedullary lesions, defined as:
- •Any lymph node or mass with an axial diameter >1.5 cm Any extranodal lesion with an axial diameter >1.0 cm
- •Flow cytometry confirms CD19 or CD22 positivity in tumor cells from bone marrow, peripheral blood, or cerebrospinal fluid, or pathology confirms CD19 or CD22 positivity in lymph nodes/masses or extranodal lesions.
- •Eligibility for Phase II (RP2D) is restricted to patients with R/R B-ALL who have failed prior immunotherapies, including blinatumomab, inotuzumab ozogamicin, or prior single-target CAR-T therapy.
- •Adequate organ function, meeting the following laboratory criteria:
- •Liver function:
- •Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤5× upper limit of normal (ULN) Total bilirubin ≤2× ULN
- •Renal function:
- •Adults: Serum creatinine clearance ≥60 mL/min (using the Cockcroft-Gault formula) or creatinine ≤1.5× ULN
- •Children: Serum creatinine levels must not exceed the following values:
- •10-13 years: ≤1.2 mg/dL Males 13-16 years: ≤1.5 mg/dL Females ≥13 years: ≤1.4 mg/dL Males ≥16 years: ≤1.7 mg/dL Blood oxygen saturation (SpO₂) >92% on room air. Fertile male and female subjects of reproductive potential must agree to use effective contraception from the time of informed consent until 2 years after administration of the study drug.
- •Women of childbearing potential (WOCBP) include premenopausal women and those within 2 years post-menopause.
- •A negative blood pregnancy test is required for all female participants of childbearing potential at screening.
排除标准
- •Subjects who meet any of the following criteria will be excluded from the study:
- •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
CD19/CD22 Tandem Dual CAR-T
Eligible patients will be treated with Nanobody-Based CD19/CD22 Tandem Dual CAR-T
干预措施: Nanobody-Based CD19/CD22 Tandem Dual CAR-T (Biological)
结局指标
主要结局
Dose-Limiting Toxicity (DLT)
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 (possibly, likely, or definitely related) 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 4+ hematologic toxicity (excluding lymphopenia) lasting \>28 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.
Overall Response Rate (ORR)
时间窗: Within 3 months after CAR-T cell infusion
Time Frame: Within 3 months after CAR-T cell infusion Definition: 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), as per European LeukemiaNet (ELN) 2022 criteria. Response Criteria (ELN 2022): Complete Remission (CR): \<5% bone marrow blasts Absolute neutrophil count (ANC) ≥1.0 × 10⁹/L Platelet count ≥100 × 10⁹/L No evidence of extramedullary disease Full hematologic recovery Complete Remission with Incomplete Hematologic Recovery (CRi): \<5% bone marrow blasts ANC \<1.0 × 10⁹/L and/or platelet count \<100 × 10⁹/L No evidence of extramedullary disease Morphologic Leukemia-Free State (MLFS): \<5% bone marrow blasts No hematologic recovery required (ANC and platelet counts may remain low) No extramedullary leukemia
次要结局
- Disease-Free Survival (DFS)(2-year)
- Overall Survival (OS)(2-year)
研究者
Xiao-Jun Huang
Director of Peking University Institute of Hematology
Peking University People's Hospital