A Phase 1/2 Open-label, Multicenter Study of Lenzilumab and Axicabtagene Ciloleucel in Subjects With Relapsed or Refractory Large B-cell Lymphoma (ZUMA-19)
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 6
- 试验地点
- 10
- 主要终点
- Phase 1: Percentage of Participants Experiencing Adverse Events (AEs) Defined as Dose Limiting Toxicities (DLTs) Related to Sequenced Therapy With Lenzilumab and Axicabtagene
研究概览
简要总结
The primary objectives of this study are:
Phase 1: To evaluate the safety of sequenced therapy with lenzilumab and axicabtagene ciloleucel in participants with relapsed or refractory large B-cell lymphoma and identify the most appropriate dose of lenzilumab for Phase 2.
Phase 2: To evaluate the incidence of neurologic events with sequenced therapy given at the recommended Phase 2 dose (RP2D) of lenzilumab in participants with relapsed or refractory large B-cell lymphoma.
详细描述
This study was intended to be a Phase 1/2, but the planned Phase 2 part has been canceled.
All participants who received an infusion of lenzilumab and axicabtagene ciloleucel will be provided the opportunity to transition to a separate long-term follow-up (LTFU) study, KT-US-982-5968.
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
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Individuals with large B-cell lymphoma, including Diffuse large B-cell lymphoma (DLBCL) not otherwise specified, Primary mediastinal large B-cell lymphoma (PMBCL), High-grade B-cell lymphoma (HGBL), and DLBCL arising from Follicular lymphoma (FL)
- •Individuals must have relapsed disease after 2 or more lines of systemic therapy, or chemorefractory disease defined as the following:
- •No response to first-line therapy, including the following:
- •Progressive disease (PD) as best response to first therapy
- •Stable disease (SD) as best response after ≥ 4 cycles of first-line therapy (eg, 4 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP)), with SD duration no longer than 6 months from the last dose of therapy
- •No response to ≥ 2 lines of therapy, including the following:
- •PD as best response to most recent therapy
- •SD as best response after ≥ 2 cycles of last line of therapy
- •Individuals must have received adequate prior therapy including at a minimum:
- •Anti-CD20 monoclonal antibody unless investigator determines that tumor is CD20 negative, and
- •An anthracycline-containing chemotherapy regimen
- •At least 1 measurable lesion according to the International Working Group Lugano Classification. Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy.
- •Magnetic resonance imaging of the brain showing no evidence of central nervous system (CNS) lymphoma
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- •Individuals with a known medical history of tuberculosis or a risk for tuberculosis exposure require negative tuberculosis testing by either tuberculin skin test or interferon gamma release assay.
- •Adequate bone marrow function as evidenced by:
- •Absolute neutrophil count ≥ 1000/μL
- •Platelets ≥ 75,000/μL
- •Absolute lymphocyte count ≥ 100/μL
- •Adequate renal, hepatic, cardiac, and pulmonary function as evidenced by:
- •Creatinine clearance (Cockcroft-Gault) ≥ 60 mL/min
- •Serum alanine aminotransferase or aspartate aminotransferase ≤ 2.5 upper limit of normal
- •Total bilirubin ≤ 1.5 mg/dL, except in individuals with Gilbert's Syndrome
- •Cardiac ejection fraction ≥ 50% with no evidence of clinically significant pericardial effusion as determined by echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG) findings
- •No clinically significant pleural effusion
- •Baseline oxygen saturation > 92% on room air
排除标准
- •History of Richter's transformation of chronic lymphocytic leukemia
- •Autologous stem cell transplant (SCT) within 6 weeks of planned axicabtagene ciloleucel infusion
- •History of allogeneic stem cell transplantation
- •Prior CD19 targeted therapy or prior CAR T cell therapy
- •History of pulmonary alveolar proteinosis (PAP)
- •History of severe, immediate hypersensitivity reaction attributed to aminoglycosides
- •Known history of human immunodeficiency virus (HIV) infection, hepatitis B (HBsAg positive) or hepatitis C (HCV) (anti-HCV positive) infection. A history of hepatitis B or hepatitis C infection is permitted if the viral load is undetectable per quantitative polymerase chain reaction (PCR) and/or nucleic acid testing.
- •Individuals with detectable Cerebrospinal fluid (CSF) malignant cells, or brain metastases, or with a history of CNS lymphoma, CSF malignant cells or brain metastases
- •History or presence of CNS disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement
- •Note: Other protocol defined Inclusion/Exclusion criteria may apply.
研究组 & 干预措施
Lenzilumab and Axicabtagene Ciloleucel
Phase 1: Participants will receive cyclophosphamide and fludarabine lymphodepleting chemotherapy followed by sequenced therapy of lenzilumab and axicabtagene ciloleucel on Day 0 to determine a recommended Phase 2 dose (RP2D) of lenzilumab. Phase 2: Participants will receive cyclophosphamide and fludarabine lymphodepleting chemotherapy followed by sequenced therapy of lenzilumab, at the RP2D, and axicabtagene ciloleucel on Day 0.
干预措施: Cyclophosphamide (Drug)
Lenzilumab and Axicabtagene Ciloleucel
Phase 1: Participants will receive cyclophosphamide and fludarabine lymphodepleting chemotherapy followed by sequenced therapy of lenzilumab and axicabtagene ciloleucel on Day 0 to determine a recommended Phase 2 dose (RP2D) of lenzilumab. Phase 2: Participants will receive cyclophosphamide and fludarabine lymphodepleting chemotherapy followed by sequenced therapy of lenzilumab, at the RP2D, and axicabtagene ciloleucel on Day 0.
干预措施: Fludarabine (Drug)
Lenzilumab and Axicabtagene Ciloleucel
Phase 1: Participants will receive cyclophosphamide and fludarabine lymphodepleting chemotherapy followed by sequenced therapy of lenzilumab and axicabtagene ciloleucel on Day 0 to determine a recommended Phase 2 dose (RP2D) of lenzilumab. Phase 2: Participants will receive cyclophosphamide and fludarabine lymphodepleting chemotherapy followed by sequenced therapy of lenzilumab, at the RP2D, and axicabtagene ciloleucel on Day 0.
干预措施: Lenzilumab (Biological)
Lenzilumab and Axicabtagene Ciloleucel
Phase 1: Participants will receive cyclophosphamide and fludarabine lymphodepleting chemotherapy followed by sequenced therapy of lenzilumab and axicabtagene ciloleucel on Day 0 to determine a recommended Phase 2 dose (RP2D) of lenzilumab. Phase 2: Participants will receive cyclophosphamide and fludarabine lymphodepleting chemotherapy followed by sequenced therapy of lenzilumab, at the RP2D, and axicabtagene ciloleucel on Day 0.
干预措施: Axicabtagene Ciloleucel (Biological)
结局指标
主要结局
Phase 1: Percentage of Participants Experiencing Adverse Events (AEs) Defined as Dose Limiting Toxicities (DLTs) Related to Sequenced Therapy With Lenzilumab and Axicabtagene
时间窗: First infusion of lenzilumab and axicabtagene ciloleucel up to 28 days.
A DLT was defined as the following sequenced therapy-related events with onset within the first 28 days following lenzilumab and axicabtagene ciloleucel infusions: * Grade 4 neutropenia lasting longer than 21 days from the day of cell transfer * Grade 4 thrombocytopenia lasting longer than 28 days from the day of cell transfer * Any sequenced therapy-related AE requiring intubation, including Grade 4 encephalopathy requiring intubation for airway protection * Any sequenced therapy-related Grade 5 event
Phase 2: Percentage of Participants Experiencing Grade 2 or Higher Neurologic Events Within 28 Days of Axicabtagene Ciloleucel Administration
时间窗: Up to 28 days
次要结局
- Phase 1 and Phase 2: Percentage of Participants Experiencing Adverse Events(Enrollment through 3 months after lenzilumab and axicabtagene ciloleucel infusion.)
- Phase 1 and Phase 2: Percentage of Participants Experiencing Serious Adverse Events(Enrollment through 3 months after lenzilumab and axicabtagene ciloleucel infusion.)
- Phase 1 and Phase 2: Percentage of Participants Experiencing Cytokine Release Syndrome(Enrollment through 12 months after lenzilumab and axicabtagene ciloleucel infusion or until disease progression, whichever occurred first.)
- Phase 1 and Phase 2: Percentage of Participants Experiencing Neurologic Events(Enrollment through 12 months after lenzilumab and axicabtagene ciloleucel infusion or until disease progression, whichever occurred first.)
- Phase 1 and Phase 2: Axicabtagene Ciloleucel Pharmacokinetics: Peak Level of Anti-CD19 CAR T Cells in Blood(Baseline up to Month 3)
- Phase 1 and Phase 2: Complete Response (CR) Rate Per Internal Working Group (IWG) Lugano Classification as Determined by the Study Investigators(First infusion date axicabtagene ciloleucel to data cut off date of 09 May 2022 (maximum duration: 22.3 months).)
- Phase 1 and Phase 2: Objective Response Rate (ORR) Per IWG Lugano Classification as Determined by Study Investigators(First infusion date axicabtagene ciloleucel to data cut off date of 09 May 2022 (maximum duration: 22.3 months).)
- Phase 1 and Phase 2: Duration of Response (DOR) in Participants Who Experience an Objective Response Per IWG Lugano Classification as Determined by Study Investigators(First infusion date axicabtagene ciloleucel to data cut off date of 09 May 2022 (maximum duration: 22.3 months).)
- Phase 1 and Phase 2: Progression-Free Survival (PFS) Per IWG Lugano Classification as Determined by Study Investigators(First infusion date axicabtagene ciloleucel to data cut off date of 09 May 2022 (maximum duration: 22.3 months).)
- Phase 1 and Phase 2: Overall Survival (OS)(First infusion date axicabtagene ciloleucel to data cut off date of 09 May 2022 (maximum duration: 22.3 months).)
- Phase 1 and Phase 2: Pharmacodynamics: Peak Serum Level of CXCL10, Granzyme B, IFN-gamma, IL-1 RA, IL-2, IL-6, IL-8, TNF Alpha, GM-CSF, and MCP-1(Baseline up to Week 4)