A Phase 1 Open-label, Multicenter Study Evaluating the Safety of KITE-222, an Autologous Anti-CLL-1 CAR T-cell Therapy, in Subjects With Relapsed/Refractory Acute Myeloid Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 15
- 试验地点
- 9
- 主要终点
- Percentage of Participants Who Experienced Dose Limiting Toxicities (DLTs)
研究概览
简要总结
The goal of this clinical study is to learn more about the safety and dosing of the study drug, KITE-222, in participants with relapsed/refractory (r/r) acute myeloid leukemia (AML).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
- •Relapse/refractory (r/r) de novo or secondary acute myeloid leukemia (AML)
- •Morphological disease in the bone marrow and/or peripheral blood within 28 days before enrollment
- •Prior exposure to the relevant agent class for individuals with AML characterized by a mutation targeted by an approved therapy
- •Institutional criteria for allogeneic (allo) - stem cell transplant (SCT) fitness must be met: individuals must have an identified stem-cell donor readily available for potential allo-SCT after therapy with KITE-222
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- •Adequate hematologic status, defined as:
- •Absolute neutrophil count (ANC) ≥ 1000/µL unless, in the opinion of the investigator, cytopenia is due to underlying leukemia
- •Platelet count ≥ 50,000/µL unless, in the opinion of the investigator, thrombocytopenia is due to underlying leukemia
- •Absolute lymphocyte count (ALC) ≥ 100/µL
- •Adequate renal, hepatic, pulmonary and cardiac function defined as:
- •Creatinine clearance (as estimated by the Cockcroft Gault formula) ≥ 60 mL/min
- •Serum alanine aminotransferase/aspartate aminotransferase ≤ 2.5 x upper limit of normal
- •Total bilirubin ≤ 1.5 mg/dL, except in individuals with Gilbert's syndrome
- •Cardiac ejection fraction ≥ 50%, no clinically significant pericardial effusion as determined by an echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG) findings
- •Baseline oxygen saturation > 92% on room air and no clinically significant pleural effusion as determined by chest imaging
- •Contraception: males and females of childbearing potential must agree to use an effective method of contraception
- •Pregnancy testing: females of childbearing potential must have a negative serum or urine pregnancy test
排除标准
- •Diagnosis of acute promyelocytic leukemia
- •Auto-SCT within the 6 weeks before enrollment
- •Donor Lymphocyte Infusions (DLI) within 28 days prior to enrollment
- •Any drug used for graft-versus-host-disease (GVHD) within 4 weeks prior to enrollment
- •Acute GVHD grade II-IV by Mount Sinai Acute GVHD International Consortium criteria
- •Active central nervous system (CNS) disease involvement
- •Requirement for urgent therapy due to ongoing or impending oncologic emergency (eg, leukostasis or tumor lysis syndrome (TLS)) or the possible requirement for urgent therapy due to ongoing or impending oncologic emergency (eg, spinal cord compression, bowel obstruction, leukostasis, or TLS) at the time of enrollment or KITE-222 infusion
- •History of C-type lectin-like molecule-1 (CLL-1)-directed therapy or genetically modified T-cell therapy
- •History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (eg, cervix, bladder, or breast) unless disease free for at least 3 years after the last definitive therapy
- •History of severe hypersensitivity reaction to aminoglycosides
- •History of concomitant genetic syndrome associated with bone marrow failure
- •Individuals with a genetic syndrome that increases the risk of allo-SCT, including Down syndrome (trisomy 21)
- •History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, New York Heart Association Class II or greater congestive heart failure, atrial fibrillation, or other clinically significant cardiac disease within 12 months before enrollment
- •Individuals with cardiac atrial or ventricular leukemia involvement
- •History of symptomatic deep vein thrombosis (DVT) or a pulmonary embolism within 6 months of enrollment. History of upper extremity line related DVT within the 3 months of conditioning chemotherapy.
- •Primary immunodeficiency disorders
- •History of a human immunodeficiency virus (HIV) infection or acute or chronic active hepatitis B or C infection
- •History of an autoimmune disease resulting in end-organ injury or requiring systemic immunosuppression or systemic disease modifying agents within the last 2 years
- •History or presence of a CNS disorder
- •Presence or suspicion of a fungal, bacterial, viral, or other infection that is uncontrolled or requiring antimicrobials for management
- •Live vaccine received within the ≤ 4 weeks before enrollment, or anticipation of the need for a live vaccination during the course of the study
- •Inability to tolerate prophylactic antifungal and antibacterial therapy
- •Presence of any indwelling line or drain
- •Ongoing Grade 2 or higher toxicities from previous therapies, excluding hematologic toxicities
- •Females of childbearing potential who are pregnant or breastfeeding
- •Note: Other protocol defined Inclusion/Exclusion criteria may apply.
研究组 & 干预措施
Cohort 1: KITE-222 (Low Dose)
Participants with relapsed or refractory (r/r) acute myeloid leukemia (AML) will receive lymphodepleting chemotherapy (fludarabine and cyclophosphamide) followed by a single infusion of KITE-222 chimeric antigen receptor (CAR) transduced autologous T cells administered intravenously (IV) at a low dose on Day 0 based on participants body weight.
干预措施: Cyclophosphamide (Drug)
Cohort 1: KITE-222 (Low Dose)
Participants with relapsed or refractory (r/r) acute myeloid leukemia (AML) will receive lymphodepleting chemotherapy (fludarabine and cyclophosphamide) followed by a single infusion of KITE-222 chimeric antigen receptor (CAR) transduced autologous T cells administered intravenously (IV) at a low dose on Day 0 based on participants body weight.
干预措施: Fludarabine (Drug)
Cohort 1: KITE-222 (Low Dose)
Participants with relapsed or refractory (r/r) acute myeloid leukemia (AML) will receive lymphodepleting chemotherapy (fludarabine and cyclophosphamide) followed by a single infusion of KITE-222 chimeric antigen receptor (CAR) transduced autologous T cells administered intravenously (IV) at a low dose on Day 0 based on participants body weight.
干预措施: KITE-222 (Biological)
Cohort 2: KITE-222 (Higher Dose)
Participants with r/r AML will receive lymphodepleting chemotherapy (fludarabine and cyclophosphamide) followed by a single infusion of KITE-222 CAR transduced autologous T cells administered IV at a higher dose on Day 0 based on participants body weight.
干预措施: Cyclophosphamide (Drug)
Cohort 2: KITE-222 (Higher Dose)
Participants with r/r AML will receive lymphodepleting chemotherapy (fludarabine and cyclophosphamide) followed by a single infusion of KITE-222 CAR transduced autologous T cells administered IV at a higher dose on Day 0 based on participants body weight.
干预措施: Fludarabine (Drug)
Cohort 2: KITE-222 (Higher Dose)
Participants with r/r AML will receive lymphodepleting chemotherapy (fludarabine and cyclophosphamide) followed by a single infusion of KITE-222 CAR transduced autologous T cells administered IV at a higher dose on Day 0 based on participants body weight.
干预措施: KITE-222 (Biological)
Cohort 3: KITE-222 (Highest Dose)
Participants with r/r AML will receive lymphodepleting chemotherapy (fludarabine and cyclophosphamide) followed by a single infusion of KITE-222 CAR transduced autologous T cells administered IV at the highest dose on Day 0 based on participants body weight.
干预措施: Cyclophosphamide (Drug)
Cohort 3: KITE-222 (Highest Dose)
Participants with r/r AML will receive lymphodepleting chemotherapy (fludarabine and cyclophosphamide) followed by a single infusion of KITE-222 CAR transduced autologous T cells administered IV at the highest dose on Day 0 based on participants body weight.
干预措施: Fludarabine (Drug)
Cohort 3: KITE-222 (Highest Dose)
Participants with r/r AML will receive lymphodepleting chemotherapy (fludarabine and cyclophosphamide) followed by a single infusion of KITE-222 CAR transduced autologous T cells administered IV at the highest dose on Day 0 based on participants body weight.
干预措施: KITE-222 (Biological)
Dose Expansion
Participants will receive lymphodepleting chemotherapy with cyclophosphamide and fludarabine followed by a single dose [at the maximum tolerated dose (MTD) determined] of KITE-222.
干预措施: Cyclophosphamide (Drug)
Dose Expansion
Participants will receive lymphodepleting chemotherapy with cyclophosphamide and fludarabine followed by a single dose [at the maximum tolerated dose (MTD) determined] of KITE-222.
干预措施: Fludarabine (Drug)
Dose Expansion
Participants will receive lymphodepleting chemotherapy with cyclophosphamide and fludarabine followed by a single dose [at the maximum tolerated dose (MTD) determined] of KITE-222.
干预措施: KITE-222 (Biological)
结局指标
主要结局
Percentage of Participants Who Experienced Dose Limiting Toxicities (DLTs)
时间窗: Up to 28 days
DLTs defined as KITE-222-related events with an onset within the first 28 days after the KITE-222 infusion:Grade(GR) 5 event,GR 4 cytokine release syndrome(CRS) or GR 3 CRS not improving to ≤ GR 2 by 72 hours,≥GR 3 cardiac and/or pulmonary event(Exceptions:related to CRS and improve to ≤GR 2 by 72 hours, managed by noninvasive care \& resolves to baseline by Day28),GR 4 immune-effector cell-associated neurotoxicity syndrome(ICANS) or other GR 4 adverse events(AEs)associated to neurologic events,GR 3 ICANS(Exceptions: GR 3 ICANS based only on immune-effector cell-associated encephalopathy(ICE) score and/or depressed level of consciousness that improves to ≤GR 2 by 72 hours),≥GR 3 infusion or immediate hypersensitivity reaction,Ongoing GR 4 neutropenia or thrombocytopenia(not due to leukemia persistence)by Day 42 to who have not had conditioning regimen for allo-stem cell transplant,other KITE-222 related GR 3 non-hematologic AEs lasting \>7 days,KITE-222-related GR 4 non-hematologic AEs.
次要结局
- Percentage of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs)(Up to 3.2 months)
- Percentage of Participants Who Experienced Laboratory Toxicity Grade Shifts to Grade 3 or Higher Resulting From Increased Parameter Value(Up to 3.2 months)
- Percentage of Participants Who Experienced Laboratory Toxicity Grade Shifts to Grade 3 or Higher Resulting From Decreased Parameter Value(Up to 3.2 months)
- Time to Neutrophil Recovery(Up to 3.2 months)
- Time to Platelet Recovery(Up to 3.2 months)
- Composite Complete Remission (CCR) Rate(Up to 3.2 months)
- Overall Remission Rate (ORR)(Up to 3.2 months)
- Relapse-free Survival (RFS)(Up to 3.2 months)
- Allogeneic Stem Cell Transplant (Allo-SCT) Rate(Up to 3.2 months)
- Event-free Survival (EFS)(Up to 12.3 months)
- Overall Survival (OS)(Up to 12.3 months)
- All-cause Mortality Within 30 Days of KITE-222 Infusion(Up to 30 days)
- All-cause Mortality Within 60 Days of KITE-222 Infusion(Up to 60 days)
- Pharmacokinetics (PK) Parameter: Peak Level of KITE-222 CAR T Cells in Blood(Baseline (Day 0), post dose on Days 3, 7,10, Weeks 2, 3, 4, and 6)
- PK Parameter: Area Under the Curve for the Blood Level of KITE-222 CAR T Cells From Day 0 to Day 28 (AUC0-28)(Baseline (Day 0), post dose on Days 3, 7, 10, Weeks 2, 3, and 4)
- Pharmacodynamics (PD) Parameter: Peak Serum Levels of Interferon-gamma (IFNg), Interleukin (IL)-12 P40, IL-10, and IL-15(Baseline (Day 0), post dose on Days 1, 3, 5, 7, 9, 11, 13, Weeks 2, 3, 4)
- PD Parameter: Peak Serum Levels of IL-2 R Alpha and Ferritin(Baseline (Day 0), post dose on Days 1, 3, 5, 7, 9, 11, 13, Weeks 2, 3, 4)
- PD Parameter: AUC0-28 for the Serum Levels IFNg, IL-12 P40, IL-10, and IL-15 in Serum(Baseline (Day 0), post dose on Days 1, 3, 5, 7, 9, 11, 13, Weeks 2, 3, 4)
- PD Parameter: AUC0-28 for the Serum Levels of IL-2 R Alpha and Ferritin(Baseline (Day 0), post dose on Days 1, 3, 5, 7, 9, 11, 13, Weeks 2, 3, 4)
- Percentage of Participants Who Develop Anti-KITE-222 CAR Antibodies(Up to 3.2 months)