NCT07451054招募中1 期
Phase 1 Study of Autologous Anti-CD45 CAR T Cells in Combination With CD45 Base Edited HSPCs in Patients With Relapsed or Refractory Hematologic Malignancies
适应症
干预措施
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 42
- 试验地点
- 1
- 主要终点
- Incidence of Adverse Events as assessed by CTCAE v6.0
研究概览
简要总结
This is a phase 1, open-label, dose-finding study to assess the safety, feasibility, pharmacokinetics and preliminary efficacy of autologous base edited anti-CD45 CAR T cells (referred to as "CART-45 cells") following an autologous transplant of CD45 base edited hematopoietic stem and progenitor cells (referred to as "CD45BE-HSPC") in patients with relapsed or refractory hematologic malignancies.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •1. Signed informed consent form
- •Male or females age ≥ 18 years
- •Disease-Specific Criteria
- •a. B-cell Non-Hodgkin Lymphoma (B-cell NHL)- including the following sub-types:
- •i. Patients with any of the following large B-cell lymphoma diagnoses who meet the prior treatment criteria outlined below: Diffuse Large B-cell Lymphoma not otherwise specified (DLBCL NOS); Primary Cutaneous DLBCL; Primary Mediastinal (thymic) Large B-cell Lymphoma; ALK+ Anaplastic Large B-cell Lymphoma; High-Grade B-cell Lymphoma with MYC and BCL2 and/or BCL6 rearrangements (i.e., "Double or Triple Hit"); High-grade B-cell Lymphoma, NOS; T-cell Rich B-cell Lymphoma; Transformed Follicular Lymphoma; or any aggressive B-cell lymphoma arising from indolent lymphoma.
- •1. Patients must have either failed/relapsed after, or be ineligible for, prior commercial CAR T cell therapy; AND
- •Relapsed/refractory disease after at least 2 prior lines of appropriate therapy.
- •ii. Follicular Lymphoma
- •Patients must have either failed/relapsed after, or be ineligible for, prior commercial CAR T cell therapy; AND
- •Relapsed/refractory disease after at least 2 prior lines of systemic therapy (not including a single agent monoclonal antibody therapy).
- •iii. Mantle Cell Lymphoma
- •Patients must have either failed/relapsed after, or be ineligible for, prior commercial CAR T cell therapy; AND
- •Relapsed/refractory disease after at least 2 prior lines of systemic therapy, including a Bruton tyrosine kinase (TKI) inhibitor. Single-agent monoclonal antibody therapy does not count towards prior lines of therapy.
- •iv. Marginal Zone Lymphoma- relapsed/refractory disease after at least 2 prior lines of appropriate therapy, including a Bruton tyrosine kinase (TKI) inhibitor. Note: Single-agent monoclonal antibody therapy does not count towards prior lines of therapy.
- •b. T-cell Non-Hodgkin Lymphoma (T-cell NHL)
- •i. Histologically or cytologically confirmed relapsed or refractory (r/r) mature aggressive T- and NK-cell neoplasms as defined in the 5th edition of the WHO Classification of Hematolymphoid tumors, which includes any of the following diagnoses:
- •Peripheral T-cell Lymphoma, NOS (PTCL-NOS);
- •Nodal T-cell Lymphomas with T Follicular Helper [TFH] Phenotype, including Follicular T cell Lymphoma, Angioimmunoblastic Lymphoma, or Anaplastic Large Cell Lymphoma (ALCL);
- •ALK+ or ALK-, Enteropathy-Associated T-cell Lymphoma (EATL);
- •Monomorphic Epitheliotropic Intestinal T-cell Lymphoma (MEITL);
- •Extranodal NK/T-cell Lymphoma;
- •Primary Cutaneous T-cell Lymphoma (CTCL);
- •Transformed Mycosis Fungoides (tMF) without blood involvement;
- •Primary Cutaneous Aggressive Epidermotropic CD8+ Cytotoxic T-Cell Lymphoma;
- •Subcutaneous Panniculitis-like T-cell Lymphoma.
- •ii. Must have received at least one prior line of systemic therapy for their lymphoma. Additional prior treatment provisions required for the following indications:
- •1. Participants with Anaplastic Large Cell Lymphoma (ALCL) must have received prior Brentuximab vedotin, unless contraindicated.
- •2. Participants with Subcutaneous Panniculitis-like T-cell Lymphoma or Transformed Mycosis Fungoides (tMF) must have received at least 2 prior lines of systemic therapy.
- •c. Hodgkin Lymphoma (HL)
- •i. Patients with histologically proven classical Hodgkin Lymphoma that is CD45 positive by IHC or flow cytometry by a CLIA certified laboratory; AND
- •ii. Relapsed/refractory disease after at least 2 prior lines of therapy which must include the following:
- •Brentuximab vedotin and immune checkpoint inhibitors (unless contraindicated); AND
- •Autologous stem cell transplant (unless patient has chemorefractory disease to salvage treatment) d. Large Cell Transformation of CLL (Richter's Transformation) i. Patients must be primary refractory or received at least 1 prior line of treatment for Richter's Transformation.
- •4. Patients are appropriate candidates for autologous HSCT as per physician-investigator clinical discretion
- •5. Patients with relapsed disease after prior allogeneic SCT must meet the following criteria:
- •a. Have no active GVHD and require no immunosuppression
- •b. Are more than 6 months from transplant at the time of physician-investigator confirmation of eligibility
- •6. Adequate organ function defined as:
- •Serum creatinine ≤ 1.5x ULN or estimated creatinine clearance ≥ 35 mL/min and not on dialysis
- •ALT/AST ≤ 3 x ULN
- •Direct bilirubin ≤ 2.0 mg/dl; for patients with Gilbert's syndrome direct bilirubin must be ≤ 3.0 mg/dl
- •Left Ventricular Ejection Fraction (LVEF) ≥ 40% confirmed by ECHO/MUGA
- •DLCO > 45% predicted value; adjusted for level of hemoglobin
- •Must have minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygen > 92% on room air
- •ECOG Performance Status 0-1
排除标准
- •Active hepatitis B or hepatitis C infection
- •Any active, uncontrolled infection.
- •Class III/IV cardiovascular disability according to the New York Heart Association Classification.
- •Clinically apparent arrhythmia or arrhythmias that are not stable on medical management within two weeks of physician-investigator confirmation of eligibility.
- •Severe, active co-morbidity that, in the opinion of the physician-investigator, would preclude participation in this study.
- •Prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen.
- •Active acute or chronic GVHD requiring systemic therapy.
- •Dependence on systemic steroids or immunosuppressant medications. For additional details regarding use of steroid and immunosuppressant medications.
- •Active CNS involvement. Patients with a history of CNS involvement that was successfully treated are eligible. A CNS evaluation is only required for eligibility if a subject is experiencing signs/symptoms of CNS involvement.
- •Patients with evidence of a circulating T-cell malignancy as measured by flow cytometry.
- •History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40).
- •Active autoimmune disease requiring systemic immunosuppressive treatment equivalent to ≥ 10mg of prednisone. Patients with autoimmune neurologic diseases (such as MS) will be excluded.
- •Pregnant or nursing (lactating) patients. Participants of reproductive potential must agree to use acceptable birth control methods.
研究组 & 干预措施
Cohort B: T-cell Non-Hodgkin Lymphoma (T-cell NHL), Hodgkin Lymphoma (HL)
Experimental
干预措施: CART-45 cells (Biological)
Cohort B: T-cell Non-Hodgkin Lymphoma (T-cell NHL), Hodgkin Lymphoma (HL)
Experimental
干预措施: CD45BE-HSPC (Biological)
Cohort A: B-cell Non-Hodgkin Lymphoma (B-cell NHL), Richter's Transformation (RT)
Experimental
干预措施: CART-45 cells (Biological)
Cohort A: B-cell Non-Hodgkin Lymphoma (B-cell NHL), Richter's Transformation (RT)
Experimental
干预措施: CD45BE-HSPC (Biological)
结局指标
主要结局
Incidence of Adverse Events as assessed by CTCAE v6.0
时间窗: Up to 15 years post infusion
Type, frequency and severity of adverse events as assessed by CTCAE V6.0. Each disease-specific cohort will be analyzed separately.
Occurrence of dose-limiting toxicities (DLTs)
时间窗: 21 days post-CART-45 infusion
Unacceptable toxicity as defined by the protocol. DLTs will be evaluated separately by each disease-specific cohort.
Identification of the maximum tolerated dose (MTD)
时间窗: 21 days post-CART-45 infusion
Selected based on an isotonic regression model. The MTD will be established separately by disease-specific cohort.
Identification of a recommended dose for expansion (RDE)
时间窗: 3 months post-CART-45 infusion
Evaluated by Cohort/dose level using a multi-criteria decision analysis.
次要结局
- Proportion of CD45BE-HSPC products that fail to meet the product release criteria(3 months)
- Proportion of CART-45 products that fail to meet the product release criteria(3 months)
- Proportion of CD45BE-HSPC products that fail to meet the protocol-defined dose(3 months)
- Proportion of CART-45 products that fail to meet the assigned dose.(3 months)
- Evaluate study feasibility(3 months)
- Engraftment of CD45BE-HSPC(28 days after treatment)
- Overall survival (OS)(Up to 15 years after last CART-45 Cells administration)
- Overall Response/Remission Rate (ORR)(Month 3)
- Best Overall Response (BOR)(From Month 3 up to Month 12)
- Duration of Response (DOR)(From Month 3 up to 15 years)
- Progression-Free Survival (PFS)(Up to 15 years)
研究者
研究点 (1)
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