A Phase 1-2 Multi-Center Study Evaluating the Safety and Efficacy of KTE-C19 in Combination With Atezolizumab in Subjects With Refractory Diffuse Large B-Cell Lymphoma (DLBCL)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 37
- 试验地点
- 5
- 主要终点
- Phase 1 and 2: Complete Response Rate (CRR)
研究概览
简要总结
The primary objective of phase 1 is to evaluate the safety of KTE-C19 and atezolizumab combination regimens.
The primary objective of phase 2 is to evaluate the efficacy of KTE-C19 and atezolizumab, as measured by complete response rate in participants with refractory diffuse large B-cell lymphoma (DLBCL).
Participants who received an infusion of KTE-C19 will complete the remainder of the 15 year follow-up assessments in a separate long-term follow-up study, KT-US-982-5968 (NCT05041309).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 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
- •Histologically confirmed DLBCL
- •Chemotherapy-refractory disease, defined as one or more of the following:
- •Stable disease (duration of stable disease must be less than or equal to 6 months) or progressive disease as best response to most recent chemotherapy containing regimen
- •Disease progression or recurrence less than or equal to 12 months of prior autologous stem cell transplantation (SCT)
- •Individuals must have received adequate prior therapy including at a minimum:
- •Anti-cluster of differentiate 20 (anti-CD20) monoclonal antibody unless investigator determines that tumor is CD20-negative; and
- •an anthracycline containing chemotherapy regimen
- •At least one measurable lesion per revised International Working Group (IWG) Response Criteria
- •Age 18 years or older
- •Eastern cooperative oncology group (ECOG) performance status of 0 or 1
- •Adequate organ and bone marrow function
- •All individuals or legally appointed representatives/caregivers, must personally sign and date the institutional review board (IRB)/independent ethics committee (IEC) approved consent form before initiating any study specific procedures or activities.
排除标准
- •History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (e.g., cervix, bladder, breast) or follicular lymphoma unless disease free for at least 3 years
- •History of allogeneic stem cell transplantation
- •Prior CAR therapy or other genetically modified T cell therapy
- •Clinically significant active infection
- •Known history of infection with human immunodeficiency virus (HIV) or hepatitis B (HBsAg positive) or hepatitis C virus (anti-HCV positive)
- •Individuals with detectable cerebrospinal fluid malignant cells or brain metastases or with a history of cerebrospinal fluid malignant cells or brain metastases
- •History of a seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with central nervous system (CNS) involvement
- •History of autoimmune disease. Participants with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone and participants with controlled type 1 diabetes mellitus on a stable insulin regimen may be eligible for this study.
- •History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis per chest computed tomography (CT) scan at screening. History of radiation pneumonitis in the radiation field (fibrosis) is allowed.
- •Prior treatment with Programmed Cell Death Ligand 1 (PD-L1) inhibitor, PD-1 inhibitor, anti-CTLA4, anti-CD137, anti-OX40 or other immune checkpoint blockade or activator therapy with the exception of Individuals who received atezolizumab in this study and are eligible for re-treatment
- •Prior CD19 targeted therapy
- •Note: Other protocol defined Inclusion/Exclusion criteria may apply
研究组 & 干预措施
Phase 1 Cohort 1: KTE-C19 + ATZ (After 21 Days of KTE-C19)
Participants received conditioning chemotherapy consisting of 30 mg/m^2 fludarabine and 500 mg/m^2 cyclophosphamide intravenous (IV) infusion per day for 3 days followed by KTE-C19 IV infusion at a target dose of 2 x 10^6 anti-CD19 chimeric antigen receptor (CAR) T cells/kg followed by 4 doses of atezolizumab (ATZ) (1200 mg/dose) IV infusion every 21 days, beginning 21 days following KTE-C19.
干预措施: KTE-C19 (Biological)
Phase 1 Cohort 1: KTE-C19 + ATZ (After 21 Days of KTE-C19)
Participants received conditioning chemotherapy consisting of 30 mg/m^2 fludarabine and 500 mg/m^2 cyclophosphamide intravenous (IV) infusion per day for 3 days followed by KTE-C19 IV infusion at a target dose of 2 x 10^6 anti-CD19 chimeric antigen receptor (CAR) T cells/kg followed by 4 doses of atezolizumab (ATZ) (1200 mg/dose) IV infusion every 21 days, beginning 21 days following KTE-C19.
干预措施: Atezolizumab (Biological)
Phase 1 Cohort 1: KTE-C19 + ATZ (After 21 Days of KTE-C19)
Participants received conditioning chemotherapy consisting of 30 mg/m^2 fludarabine and 500 mg/m^2 cyclophosphamide intravenous (IV) infusion per day for 3 days followed by KTE-C19 IV infusion at a target dose of 2 x 10^6 anti-CD19 chimeric antigen receptor (CAR) T cells/kg followed by 4 doses of atezolizumab (ATZ) (1200 mg/dose) IV infusion every 21 days, beginning 21 days following KTE-C19.
干预措施: Cyclophosphamide (Drug)
Phase 1 Cohort 1: KTE-C19 + ATZ (After 21 Days of KTE-C19)
Participants received conditioning chemotherapy consisting of 30 mg/m^2 fludarabine and 500 mg/m^2 cyclophosphamide intravenous (IV) infusion per day for 3 days followed by KTE-C19 IV infusion at a target dose of 2 x 10^6 anti-CD19 chimeric antigen receptor (CAR) T cells/kg followed by 4 doses of atezolizumab (ATZ) (1200 mg/dose) IV infusion every 21 days, beginning 21 days following KTE-C19.
干预措施: Fludarabine (Drug)
Phase 1 Cohort 2: KTE-C19 + ATZ (After 14 Days of KTE-C19)
Participants received conditioning chemotherapy consisting of 30 mg/m^2 fludarabine and 500 mg/m^2 cyclophosphamide IV infusion per day for 3 days followed by KTE-C19 IV infusion at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg followed by 4 doses of ATZ (1200 mg/dose) IV infusion every 21 days, beginning 14 days following KTE-C19.
干预措施: KTE-C19 (Biological)
Phase 1 Cohort 2: KTE-C19 + ATZ (After 14 Days of KTE-C19)
Participants received conditioning chemotherapy consisting of 30 mg/m^2 fludarabine and 500 mg/m^2 cyclophosphamide IV infusion per day for 3 days followed by KTE-C19 IV infusion at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg followed by 4 doses of ATZ (1200 mg/dose) IV infusion every 21 days, beginning 14 days following KTE-C19.
干预措施: Atezolizumab (Biological)
Phase 1 Cohort 2: KTE-C19 + ATZ (After 14 Days of KTE-C19)
Participants received conditioning chemotherapy consisting of 30 mg/m^2 fludarabine and 500 mg/m^2 cyclophosphamide IV infusion per day for 3 days followed by KTE-C19 IV infusion at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg followed by 4 doses of ATZ (1200 mg/dose) IV infusion every 21 days, beginning 14 days following KTE-C19.
干预措施: Cyclophosphamide (Drug)
Phase 1 Cohort 2: KTE-C19 + ATZ (After 14 Days of KTE-C19)
Participants received conditioning chemotherapy consisting of 30 mg/m^2 fludarabine and 500 mg/m^2 cyclophosphamide IV infusion per day for 3 days followed by KTE-C19 IV infusion at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg followed by 4 doses of ATZ (1200 mg/dose) IV infusion every 21 days, beginning 14 days following KTE-C19.
干预措施: Fludarabine (Drug)
Phase 1 Cohort 3: KTE-C19 + ATZ (After 1 Day of KTE-C19)
Participants received conditioning chemotherapy consisting of 30 mg/m^2 fludarabine and 500 mg/m^2 cyclophosphamide IV infusion per day for 3 days followed by KTE-C19 IV infusion at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg followed by 4 doses of ATZ (1200 mg/dose) IV infusion every 21 days, beginning 1 day following KTE-C19.
干预措施: KTE-C19 (Biological)
Phase 1 Cohort 3: KTE-C19 + ATZ (After 1 Day of KTE-C19)
Participants received conditioning chemotherapy consisting of 30 mg/m^2 fludarabine and 500 mg/m^2 cyclophosphamide IV infusion per day for 3 days followed by KTE-C19 IV infusion at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg followed by 4 doses of ATZ (1200 mg/dose) IV infusion every 21 days, beginning 1 day following KTE-C19.
干预措施: Atezolizumab (Biological)
Phase 1 Cohort 3: KTE-C19 + ATZ (After 1 Day of KTE-C19)
Participants received conditioning chemotherapy consisting of 30 mg/m^2 fludarabine and 500 mg/m^2 cyclophosphamide IV infusion per day for 3 days followed by KTE-C19 IV infusion at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg followed by 4 doses of ATZ (1200 mg/dose) IV infusion every 21 days, beginning 1 day following KTE-C19.
干预措施: Cyclophosphamide (Drug)
Phase 1 Cohort 3: KTE-C19 + ATZ (After 1 Day of KTE-C19)
Participants received conditioning chemotherapy consisting of 30 mg/m^2 fludarabine and 500 mg/m^2 cyclophosphamide IV infusion per day for 3 days followed by KTE-C19 IV infusion at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg followed by 4 doses of ATZ (1200 mg/dose) IV infusion every 21 days, beginning 1 day following KTE-C19.
干预措施: Fludarabine (Drug)
Phase 2: KTE-C19 + ATZ (After 1 Day of KTE-C19)
Participants received conditioning chemotherapy consisting of 30 mg/m^2 fludarabine and 500 mg/m^2 cyclophosphamide IV infusion per day for 3 days followed by KTE-C19 IV infusion at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg followed by 4 doses of ATZ (1200 mg/dose) IV infusion every 21 days, beginning 1 day following KTE-C19.
干预措施: KTE-C19 (Biological)
Phase 2: KTE-C19 + ATZ (After 1 Day of KTE-C19)
Participants received conditioning chemotherapy consisting of 30 mg/m^2 fludarabine and 500 mg/m^2 cyclophosphamide IV infusion per day for 3 days followed by KTE-C19 IV infusion at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg followed by 4 doses of ATZ (1200 mg/dose) IV infusion every 21 days, beginning 1 day following KTE-C19.
干预措施: Atezolizumab (Biological)
Phase 2: KTE-C19 + ATZ (After 1 Day of KTE-C19)
Participants received conditioning chemotherapy consisting of 30 mg/m^2 fludarabine and 500 mg/m^2 cyclophosphamide IV infusion per day for 3 days followed by KTE-C19 IV infusion at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg followed by 4 doses of ATZ (1200 mg/dose) IV infusion every 21 days, beginning 1 day following KTE-C19.
干预措施: Cyclophosphamide (Drug)
Phase 2: KTE-C19 + ATZ (After 1 Day of KTE-C19)
Participants received conditioning chemotherapy consisting of 30 mg/m^2 fludarabine and 500 mg/m^2 cyclophosphamide IV infusion per day for 3 days followed by KTE-C19 IV infusion at a target dose of 2 x 10^6 anti-CD19 CAR T cells/kg followed by 4 doses of ATZ (1200 mg/dose) IV infusion every 21 days, beginning 1 day following KTE-C19.
干预措施: Fludarabine (Drug)
结局指标
主要结局
Phase 1 and 2: Complete Response Rate (CRR)
时间窗: From enrollment until first occurrence of CR or PR (maximum duration: 6.2 years)
CRR was assessed based on the International Working Group Revised Response Criteria for Malignant Lymphoma (Cheson, 2007), and was defined as the percentage of participants achieving a complete response (CR) as assessed by the study investigators. CR was defined as the complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease.
Phase 1: Number of Participants Experiencing Dose-Limiting Toxicities (DLTs)
时间窗: Baseline up to 21 days
A DLT was defined as the following KTE-C19-related or ATZ-related events with an onset from immediately after the first ATZ infusion through 21 days after the first ATZ infusion: Grade 4 hematologic toxicity lasting \> 30 days (except lymphopenia or B-cell aplasia); All KTE-C19- or ATZ-related Grade 3 non-hematologic toxicities lasting for \> 7 days and all KTE-C19- or ATZ-related Grade 4 non-hematologic toxicities regardless of duration.
次要结局
- Phase 1 and 2: Duration of Response (DOR)(From the date of first confirmed objective response (CR or PR) to disease progression or death regardless of cause (maximum duration: 6.2 years))
- Phase 1 and 2: Overall Survival (OS)(From the date of first KTE-C19 infusion to the date of death regardless of cause (maximum duration: 6.2 years))
- Phase 1 and 2: Peak Anti-CD19 CAR T-Cell (KTE-C19) Level (Maximum Observed Plasma Concentration) in Blood(Pre-infusion (Baseline); Post-infusion: Days 7 (Phase 2), 14, 22 (Phase 2), 28 (Phase 2; optional), 35 (Phase 1, Cohort 3; optional), 43, 49 (optional), 64, 69 (optional), 94; long-term follow-up: every 3 months from Month 6 to Month 18, and Month 24)
- Phase 1 and 2: Percentage of Participants With Anti-KTE-C19 Antibodies(Baseline (pre-conditioning chemotherapy); Day 0 (pre-KTE-C19 infusion); Days 1, 4, 7, 14, 22 , 28, Day 35, 49, 69, and 94 post-KTE-C19 infusion)
- Phase 1 and 2: Peak Serum Levels of Ferritin in Blood(Baseline (pre-conditioning chemotherapy); Day 0 (pre-KTE-C19 infusion); Days 1, 4, 7, and 14, and 22 , optional Day 28 (Phase 2) or Day 35 (Phase 1 Cohort 3), optional Day 49, optional Day 69, and Day 94 post-KTE-C19 infusion)
- Phase 1 and 2: Peak Serum Levels of Interleukin-2 Receptor Alpha (IL-2Rα) in Blood(Baseline (pre-conditioning chemotherapy); Day 0 (pre-KTE-C19 infusion); Days 1, 4, 7, and 14, and 22 , optional Day 28 (Phase 2) or Day 35 (Phase 1 Cohort 3), optional Day 49, optional Day 69, and Day 94 post-KTE-C19 infusion)
- Phase 1 and 2: Objective Response Rate (ORR)(From enrollment until first occurrence of CR or PR (maximum duration: 6.2 years))
- Phase 1 and 2: Atezolizumab Levels in Blood(Days 1, 14, 21, 22, 35, 42, 43, 56, 63, 64, 77, 84, 154, and 174)
- Phase 1 and 2: Progression-Free Survival (PFS)(From the date of first KTE-C19 infusion to disease progression or death regardless of cause (maximum duration: 6.2 years))
- Phase 1 and 2: Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs)(Up to 1.8 years)
- Phase 1 and 2: Percentage of Participants With Serum Chemistry Toxicity Grade Shifts to Grade 3 or Higher Resulting From Increased Parameter Values(Up to 1.8 years)
- Phase 1 and 2: Percentage of Participants With Hematology Toxicity Grade Shifts to Grade 3 or Higher Resulting From Increased Parameter Values(Up to 1.8 years)
- Phase 1 and 2: Peak Serum Levels of C-X-C Motif Chemokine 10 (CXCL10), Interferon-Gamma (IFN-γ), Interleukin-1 Receptor Antagonist (IL-1RA), Interleukin (IL)-2, IL-6, IL-8, IL-15, and Tumor Necrosis Factor-Alpha (TNF-α) in Blood(Baseline (pre-conditioning chemotherapy); Day 0 (pre-KTE-C19 infusion); Days 1, 4, 7, and 14, and 22 , optional Day 28 (Phase 2) or Day 35 (Phase 1 Cohort 3), optional Day 49, optional Day 69, and Day 94 post-KTE-C19 infusion)
- Phase 1 and 2: Percentage of Participants With Serum Chemistry Toxicity Grade Shifts to Grade 3 or Higher Resulting From Decreased Parameter Values(Up to 1.8 years)
- Phase 1 and 2: Percentage of Participants With Hematology Toxicity Grade Shifts to Grade 3 or Higher Resulting From Decreased Parameter Values(Up to 1.8 years)
- Phase 1 and 2: Percentage of Participants With Anti-Atezolizumab Antibodies(Baseline (pre-conditioning chemotherapy); Day 0 (pre-KTE-C19 infusion); Days 1, 4, 7, 14, 22 , 28, Day 35, 49, 69, and 94 post-KTE-C19 infusion)
- Phase 1 and 2: Peak Serum Levels of C-Reactive Protein (CRP) in Blood(Baseline (pre-conditioning chemotherapy); Day 0 (pre-KTE-C19 infusion); Days 1, 4, 7, and 14, and 22 , optional Day 28 (Phase 2) or Day 35 (Phase 1 Cohort 3), optional Day 49, optional Day 69, and Day 94 post-KTE-C19 infusion)