NCT06393335RecruitingEarly Phase 1
Safety and Efficacy of Metabolically Armed CD19 CAR-T Cells (Meta10-19) in the Treatment of Relapsed and/or Refractory CD19-positive B Cell Hematological Malignancies Clinical Research
The Children's Hospital of Zhejiang University School of Medicine1 site in 1 country36 target enrollmentStarted: May 15, 2024Last updated:
Conditions
Interventions
Trial Snapshot
- Phase
- Early Phase 1
- Status
- Recruiting
- Sponsor
- Enrollment
- 36
- Locations
- 1
- Primary Endpoint
- MTD
Study Overview
Brief Summary
A Study of Metabolically Armed CD19 CAR-T Cells Therapy for Patients With Relapsed and/or Refractory CD19-positive B cell Hematological Malignancies
Detailed Description
This is a single arm, open-label study. This study is indicated for relapsed or refractory CD19-positive B cell Hematological Malignancies.
- Main research objectives:
To evaluate the safety and efficacy of metabolically armed CD19 CAR-T Cells in the treatment of r/r CD19-positive B cell Hematological Malignancies 2. Secondary research objectives:
- To evaluate the pharmacokinetic (PK) and pharmacodynamics(PD) characteristics of metabolically armed CD19 CAR-T Cells after infusion.
- To evaluate tumor remission after infusion of metabolically armed CD19 CAR-T Cells.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 6 Months to 18 Years (Child, Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Age range: 6 months to 18 years old, inclusive, for both males and females.
- •The patient or their guardian voluntarily signed the informed consent.
- •Patients with relapsed or refractory CD19-positive B cell hematological malignancies:
- •Relapsed or refractory B-ALL (meeting one of the following conditions):
- •Patients who relapse within 30 months after the initial remission, with >5% primordial cells (lymphoblast and prolymphocyte) in bone marrow morphology, confirmed by flow cytometry.
- •Patients who relapse 30 months after the initial remission and fail to achieve complete remission or show poor response to early treatment after one course of standardized induction therapy.
- •Patients who relapse after allogeneic hematopoietic stem cell transplantation (HSCT) and must undergo screening 3 months post-HSCT .
- •Patients who do not achieve CR after standardized chemotherapy, or have >1% minimal residual disease (MRD) in bone marrow after 3 months of chemotherapy.
- •Philadelphia-chromosome-positive (Ph+) patients who do not achieve CR or relapse after being treated with at least two tyrosine kinase inhibitors (TKI).
- •Patients who are not suitable candidates for allogeneic hematopoietic stem cell transplantation.
- •Relapsed or refractory CD19+ B-NHL (meeting one of the following conditions):
- •Patients who have been treated with CD20 antibodies (such as rituximab) and at least two chemotherapy regiments, one of which should include anthracyclines.
- •After these treatments, patients experienced stable disease (SD) (with SD duration ≤12 months) or disease progression.
- •Patients who relapse after auto/allo-HSCT, or are not eligible for HSCT.
- •Patients with double-hit and triple-hit lymphoma who do not respond to second-line treatment.
- •Positive CD19 expression comfirmed by immunohistochemistry or flow cytometry.
- •For participants who had failed prior CD19-CAR T cell therapy: at least 30-days has elapsed since participant received last CD19-CAR T cell therapy.
- •Presence at least one measurable lesion at baseline, as per the initial assessment, staging and response assessment recommendations for Hodgkin's and non-Hodgkin's lymphoma (2014 edition).
- •Life expectancy ≥ 12 weeks.
- •Organ function:
- •Complete blood count (CBC) test results should meet the following criteria within 24 hours before apheresis (Avoid blood/platelet transfusion, cell growth factors (except recombinant erythropoietin) and other supportive treatments within 7 days prior to the test):
- •Absolute Lymphocyte Count (ALC) ≥ 0.5×10^9 /L (except for those receiving bridging chemotherapy).
- •Platelet (PLT) ≥ 25×10^9 /L.
- •Hemoglobin (Hb) ≥ 70.0 g/L
- •Blood biochemistry:
- •Serum creatinine (Scr) ≤ 1.5× Upper limit of normal (ULN), or Creatinine Clearance (Ccr) ≥ 40 mL/min (calculated using the Cockcroft-Gault formula).
- •Alanine aminotransferase (ALT) ≤ 2.5×ULN.
- •Aspartate aminotransferase (AST) ≤ 2.5×ULN.
- •Total bilirubin (TBIL) ≤ 2×ULN; Patients who with Gilbert-Meulengracht syndrome with TBIL ≤ 3×ULN and Direct Bilirubin (DBIL) ≤1.5×ULN may be included.
- •Amylase (AMY) and Lipase (LPS) ≤ 1.5×ULN.
- •Alkaline phosphatase (ALP) ≤ 2.5×ULN.
- •If bone or liver metastases are present, AST, ALT, ALP ≤ 5×ULN.
- •Prothrombin time (PT) was extended ≤ 4 s, fibrinogen ≥ 1 g/L, activated partial thromboplastin time (APTT) ≤ 1.5×ULN.
- •Pulmonary function: dyspnea ≤ CTCAE grade 1 and blood oxygen saturation (SaO2) ≥ 91% in ambient air.
- •Hemodynamic stability was determined by echocardiography or multichannel radionuclide angiography (MUGA) with a left ventricular ejection fraction (LVEF) ≥ 45％.
- •Patients taking the following medications must meet the following criteria:
- •Steroids: Therapeutic doses of steroids must be discontinued 2 weeks prior to Meta10-19 infusion. However, physiological replacement doses of steroids are permitted, with hydrocortisone or its equivalent < 6-12mg/mm^2/day.
- •Immunosuppressive agents: Any immunosuppressive medication must be stopped ≥ 4 weeks before signing the informed consent.
- •Anti-proliferative therapy other than preconditioning chemotherapy should be ceased within 2 weeks prior to Meta10-19 infusion.
- •Treatment for central nervous system (CNS) diseases must be stopped 1 week before Meta10-19 infusion (e.g., intrathecal methotrexate).
- •As determined by the researchers, patients who have recovered from the toxicity of the previous treatments, that is, the CTCAE toxicity grade is less than 1 (excluding specific toxicity of grade 2 or lower, such as hair loss, deemed irrecoverable in a short timeframe by the researchers) are suitable for receiving pretreatment chemotherapy and CAR-T cell therapy.
- •The patient should have adequate venous access for apheresis or peripheral blood collection, with no other contraindications for blood cell separation.
Exclusion Criteria
- •Patients with a history of central nervous system (CNS) diseases other than CNS leukemia, such as seizures disorders, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement.
- •Patients who had received chemotherapy other than preconditioning chemotherapy within 2 weeks prior to Meta10-19 infusion.
- •Patients who have participated in other clinical trials within 30 days prior to enrollment.
- •Patients with active hepatitis B (defined as positive for hepatitis B surface antigen or hepatitis B core antibody, with concomitant hepatitis B virus DNA level > 1000 copies/ml) or hepatitis C (positive for HCV RNA).
- •Patients who are positive for HIV antibodies or treponema pallidum antibodies.
- •Patients with uncontrolled acute life-threatening bacterial, viral or fungal infections (e.g., positive blood cultures ≤ 72 hours before Meta10-19 infusion).
- •Patients with unstable angina pectoris and/or myocardial infarction within 6 months prior to enrollment..
- •Patients with history of other malignancies may be eligible for enrollment under the following conditions:
- •Adequately treated basal or squamous cell carcinoma (requiring adequate wound healing before signing informed consent).
- •Carcinoma in situ (DCIS) of cervical or breast cancer, which has been treated therapeutically, has shown no signs of recurrence for at least 3 years prior to the signing of the informed consent.
- •The primary malignancy has been completely resected and in complete remission for ≥ 5 years.
- •Patients with active neuroautoimmune or inflammatory conditions (e.g., Guillian-Barre syndrome, amyotrophic lateral sclerosis).
- •Patients with other conditions deemed unsuitable for enrollment in this clinical study by the investigator.
Arms & Interventions
Administration of Metabolically Armed CD19 CAR-T cells
Experimental
Patients undergo leukapheresis. Patients will receive a lymphodepletion chemotherapy with cyclophosphamide and fludarabine before CAR-T cells infusion. A dose of metabolically armed CD19 CAR-T cells will be infused on day 0.
Intervention: Metabolically Armed CD19 CAR-T cells (Drug)
Outcomes
Primary Outcomes
MTD
Time Frame: MTD will be determined based on DLTs observed during the first 28 days of study treatment
Determine the Maximal Tolerable Dose(MTD)
Objective response rate (ORR)
Time Frame: Within 3 months following infusion of Meta10-19
Measure Tumor response rate (including CR and PR)
Secondary Outcomes
- Concentration of CAR-T cells(Up to 12 months after CAR-T treatment)
- Pharmacodynamics of CAR-T cells(Up to 28 days after infusion)
Investigators
Xiaojun Xu
Principal Investigator
The Children's Hospital of Zhejiang University School of Medicine
Study Sites (1)
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