Phase 1a/1b Dose Escalation and Cohort Expansion Study of the Safety and Efficacy of B-Cell Activating Factor Receptor (BAFFR)-Based Chimeric Antigen Receptor T-Cells (MC10029) in Subjects With Relapsed or Refractory BAFFR-Expressing B-Cell Hematologic Malignancies
概览
- 阶段
- 1 期
- 干预措施
- Autologous BAFFR-targeting CAR T Cells
- 疾病 / 适应症
- B-Cell Non-Hodgkin Lymphoma
- 发起方
- Mayo Clinic
- 入组人数
- 27
- 试验地点
- 1
- 主要终点
- Incidence of dose-limiting toxicities (DLT)
- 状态
- 招募中
- 最后更新
- 2个月前
概览
简要总结
This phase I trial tests safety, side effects and best dose of B-cell activating factor receptor (BAFFR)-based chimeric antigen receptor T-cells, with fludarabine and cyclophosphamide lymphodepletion, for the treatment of patients with B-cell hematologic malignancies that has come back after a period of improvement (relapsed) or that does not respond to treatment (refractory). BAFFR-based chimeric antigen receptor T-cells is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's cancer cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. Giving chemotherapy, such as fludarabine and cyclophosphamide, helps ill cancer cells in the body and helps prepare the body to receive the BAFFR based chimeric antigen receptor T-cells. Giving BAFFR based chimeric antigen receptor T-cells with fludarabine and cyclophosphamide for lymphodepletion may work better for the treatment of patients with relapsed or refractory B-cell hematologic malignancies.
详细描述
PRIMARY OBJECTIVES: I. To assess the safety and tolerability of (MC10029) autologous BAFFR-targeting chimeric antigen receptor (CAR) T cells following lymphodepleting (LD) therapy in subjects with relapsed or refractory BAFFR expressing B-cell hematologic malignancies. II. To determine the recommended dose for phase 1b (dose expansion) and recommend phase 2 dose. SECONDARY OBJECTIVES: I. To assess the efficacy and antitumor activity of MC10029 in subjects with relapsed or refractory BAFFR-expressing B-cell hematologic malignancies. II. To determine long-term toxicities in MC10029 recipients. III. To determine feasibility of manufacturing success rate of MC10029. CORRELATIVE RESEARCH OBJECTIVES: I. To evaluate the pharmacokinetics of MC10029 in peripheral blood samples. II. To study the relationship between BAFFR expression and clinical activity of MC10029. OUTLINE: Patients undergo leukapheresis. Patients then receive cyclophosphamide intravenously (IV), over 60 minutes and fludarabine IV over 30 minutes on day -5 to -3 or bendamustine IV over 10 minutes on days -4 and -3. Patients receive BAFFR based chimeric antigen receptor T-cells IV on day 0. Patients undergo echocardiography and magnetic resonance imaging (MRI) at screening, computed tomography (CT) scan, positron emission tomography (PET) scan, bone marrow biopsy/aspirate and blood sample collection throughout the study and tumor biopsy at progression. After completion of study treatment, patients followed up at day 1, 2, 3, 4, 8, 11, 14, 21, 28, 60, 90, 180, 270, 365, 545 and 730 and then periodically for up to 15 years.
研究者
入排标准
入选标准
- •PRE-REGISTRATION: Age ≥ 18 years
- •PRE-REGISTRATION: Confirmed diagnosis of 1 of the following relapsed or refractory B-cell hematologic malignancies: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or large B cell lymphoma (LBCL) including Richter's transformation from CLL/SLL
- •For CD19+ B cell malignancies; relapsed or refractory disease is defined by one of the following histopathology:
- •Biopsy proven SLL or flow cytometry proven CLL; relapsed or refractory disease is defined as:
- •Demonstration of progressive or stable disease by positron emission tomography/computed tomography (PET/CT) or computed tomography (CT) criteria according to the international workshop on chronic lymphocytic leukemia (iwCLL) 2018 criteria
- •Biopsy proven B-cell non-Hodgkin lymphoma (NHL) of any histopathology (including Richter Transformation of CLL); relapsed or refractory disease is defined as:
- •Demonstration of progressive or stable disease by PET/CT or CT criteria as the best response to the most recent chemotherapy regimen according to the revised Lugano Response Criteria for Malignant Lymphoma
- •PRE-REGISTRATION: Disease Specific prior lines of therapies below:
- •For CLL/SLL, patients must have received ≥ two prior lines of therapy, and/or ≥ 6 months of second line prior BTK inhibition (e.g. ibrutinib or other such as acalabrutinib or zanubrutinib) and must have failed to respond to venetoclax or be intolerant. Exception: Patients in stable disease (SD) or partial response (PR) with a known ibrutinib resistance mutation (BTK or phospholipase Cγ2) may be included even if on ibrutinib therapy for less than 6 months
- •These patients may or may not have received prior antibody directed against cluster of differentiation 20 (CD20).
排除标准
- •PRE-REGISTRATION: Prior solid organ transplantation
- •PRE-REGISTRATION: Unstable angina, clinically significant arrhythmia, or myocardial infarction ≤ 6 months of prior to pre-registration, or grade 3 or higher pericardial effusion at the time of pre-registration
- •PRE-REGISTRATION: Prior anti-BAFF-R therapies
- •PRE-REGISTRATION: Known contraindication to lymphodepleting (LD) chemotherapy
- •PRE-REGISTRATION: Use of systemic antitumor therapy or investigational agent ≤ 14 days, prior to pre-registration
- •PRE-REGISTRATION: Receiving any other investigational agent which would be considered as a treatment for the BAFF-R
- •PRE-REGISTRATION: Autologous HCT ≤ 60 days prior to pre-registration
- •PRE-REGISTRATION: Uncontrolled intercurrent non-cardiac illness including, but not limited to:
- •Previous or concurrent malignancy
- •Ongoing or active infection
研究组 & 干预措施
Treatment (BARRF based chimeric antigen receptor T-cells)
Patients undergo leukapheresis. Patients then receive cyclophosphamide IV, over 60 minutes and fludarabine IV over 30 minutes on day -5 to -3 or bendamustine IV over 10 minutes on days -4 and -3. Patients receive BAFFR based chimeric antigen receptor T-cells IV on day 0. Patients undergo echocardiography and MRI at screening, CT scan, PET scan, bone marrow biopsy/aspirate and blood sample collection throughout the study and tumor biopsy at progression.
干预措施: Autologous BAFFR-targeting CAR T Cells
Treatment (BARRF based chimeric antigen receptor T-cells)
Patients undergo leukapheresis. Patients then receive cyclophosphamide IV, over 60 minutes and fludarabine IV over 30 minutes on day -5 to -3 or bendamustine IV over 10 minutes on days -4 and -3. Patients receive BAFFR based chimeric antigen receptor T-cells IV on day 0. Patients undergo echocardiography and MRI at screening, CT scan, PET scan, bone marrow biopsy/aspirate and blood sample collection throughout the study and tumor biopsy at progression.
干预措施: Bendamustine
Treatment (BARRF based chimeric antigen receptor T-cells)
Patients undergo leukapheresis. Patients then receive cyclophosphamide IV, over 60 minutes and fludarabine IV over 30 minutes on day -5 to -3 or bendamustine IV over 10 minutes on days -4 and -3. Patients receive BAFFR based chimeric antigen receptor T-cells IV on day 0. Patients undergo echocardiography and MRI at screening, CT scan, PET scan, bone marrow biopsy/aspirate and blood sample collection throughout the study and tumor biopsy at progression.
干预措施: Biopsy
Treatment (BARRF based chimeric antigen receptor T-cells)
Patients undergo leukapheresis. Patients then receive cyclophosphamide IV, over 60 minutes and fludarabine IV over 30 minutes on day -5 to -3 or bendamustine IV over 10 minutes on days -4 and -3. Patients receive BAFFR based chimeric antigen receptor T-cells IV on day 0. Patients undergo echocardiography and MRI at screening, CT scan, PET scan, bone marrow biopsy/aspirate and blood sample collection throughout the study and tumor biopsy at progression.
干预措施: Biospecimen Collection
Treatment (BARRF based chimeric antigen receptor T-cells)
Patients undergo leukapheresis. Patients then receive cyclophosphamide IV, over 60 minutes and fludarabine IV over 30 minutes on day -5 to -3 or bendamustine IV over 10 minutes on days -4 and -3. Patients receive BAFFR based chimeric antigen receptor T-cells IV on day 0. Patients undergo echocardiography and MRI at screening, CT scan, PET scan, bone marrow biopsy/aspirate and blood sample collection throughout the study and tumor biopsy at progression.
干预措施: Bone Marrow Aspiration and Biopsy
Treatment (BARRF based chimeric antigen receptor T-cells)
Patients undergo leukapheresis. Patients then receive cyclophosphamide IV, over 60 minutes and fludarabine IV over 30 minutes on day -5 to -3 or bendamustine IV over 10 minutes on days -4 and -3. Patients receive BAFFR based chimeric antigen receptor T-cells IV on day 0. Patients undergo echocardiography and MRI at screening, CT scan, PET scan, bone marrow biopsy/aspirate and blood sample collection throughout the study and tumor biopsy at progression.
干预措施: Computed Tomography
Treatment (BARRF based chimeric antigen receptor T-cells)
Patients undergo leukapheresis. Patients then receive cyclophosphamide IV, over 60 minutes and fludarabine IV over 30 minutes on day -5 to -3 or bendamustine IV over 10 minutes on days -4 and -3. Patients receive BAFFR based chimeric antigen receptor T-cells IV on day 0. Patients undergo echocardiography and MRI at screening, CT scan, PET scan, bone marrow biopsy/aspirate and blood sample collection throughout the study and tumor biopsy at progression.
干预措施: Cyclophosphamide
Treatment (BARRF based chimeric antigen receptor T-cells)
Patients undergo leukapheresis. Patients then receive cyclophosphamide IV, over 60 minutes and fludarabine IV over 30 minutes on day -5 to -3 or bendamustine IV over 10 minutes on days -4 and -3. Patients receive BAFFR based chimeric antigen receptor T-cells IV on day 0. Patients undergo echocardiography and MRI at screening, CT scan, PET scan, bone marrow biopsy/aspirate and blood sample collection throughout the study and tumor biopsy at progression.
干预措施: Echocardiography
Treatment (BARRF based chimeric antigen receptor T-cells)
Patients undergo leukapheresis. Patients then receive cyclophosphamide IV, over 60 minutes and fludarabine IV over 30 minutes on day -5 to -3 or bendamustine IV over 10 minutes on days -4 and -3. Patients receive BAFFR based chimeric antigen receptor T-cells IV on day 0. Patients undergo echocardiography and MRI at screening, CT scan, PET scan, bone marrow biopsy/aspirate and blood sample collection throughout the study and tumor biopsy at progression.
干预措施: Fludarabine
Treatment (BARRF based chimeric antigen receptor T-cells)
Patients undergo leukapheresis. Patients then receive cyclophosphamide IV, over 60 minutes and fludarabine IV over 30 minutes on day -5 to -3 or bendamustine IV over 10 minutes on days -4 and -3. Patients receive BAFFR based chimeric antigen receptor T-cells IV on day 0. Patients undergo echocardiography and MRI at screening, CT scan, PET scan, bone marrow biopsy/aspirate and blood sample collection throughout the study and tumor biopsy at progression.
干预措施: Leukapheresis
Treatment (BARRF based chimeric antigen receptor T-cells)
Patients undergo leukapheresis. Patients then receive cyclophosphamide IV, over 60 minutes and fludarabine IV over 30 minutes on day -5 to -3 or bendamustine IV over 10 minutes on days -4 and -3. Patients receive BAFFR based chimeric antigen receptor T-cells IV on day 0. Patients undergo echocardiography and MRI at screening, CT scan, PET scan, bone marrow biopsy/aspirate and blood sample collection throughout the study and tumor biopsy at progression.
干预措施: Magnetic Resonance Imaging
Treatment (BARRF based chimeric antigen receptor T-cells)
Patients undergo leukapheresis. Patients then receive cyclophosphamide IV, over 60 minutes and fludarabine IV over 30 minutes on day -5 to -3 or bendamustine IV over 10 minutes on days -4 and -3. Patients receive BAFFR based chimeric antigen receptor T-cells IV on day 0. Patients undergo echocardiography and MRI at screening, CT scan, PET scan, bone marrow biopsy/aspirate and blood sample collection throughout the study and tumor biopsy at progression.
干预措施: Positron Emission Tomography
结局指标
主要结局
Incidence of dose-limiting toxicities (DLT)
时间窗: Up to 28 days after MC10029 (autologous B-cell activating factor receptor [BAFFR]-targeting chimeric antigen receptor [CAR] T cells product) infusion
DLTs are defined per the protocol and assessed by the number of DLTs that occur during the DLT evaluation period and persist beyond the specified duration (relative to the time of onset, defined as within 28 days).
Incidence and severity of treatment emergent adverse events
时间窗: Up to 15 years
Defined as adverse events (AEs) that occur or worsen in severity on or after MC10029 product infusion.
次要结局
- Overall response rate(Up to 15 years)
- Progression free survival(Up to 15 years)
- Overall survival(Up to 15 years)
- Duration of response(Up to 15 years)
- Number of conforming versus nonconforming products(Up to 15 years)
- Complete response rate(Up to 15 years)