Study of KITE-222 in Participants With Relapsed/Refractory Acute Myeloid Leukemia

Phase 1

Terminated

Conditions: Acute Myeloid Leukemia

Interventions: Drug: Cyclophosphamide
Drug: Fludarabine
Biological: KITE-222

Registration Number: NCT04789408

Lead Sponsor: Kite, A Gilead Company

Brief Summary: 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).

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 15

Inclusion Criteria

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

Key

Exclusion Criteria

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Cohort 1: KITE-222 (Low Dose)	Cyclophosphamide	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.
Cohort 1: KITE-222 (Low Dose)	Fludarabine	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.
Cohort 1: KITE-222 (Low Dose)	KITE-222	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.
Cohort 2: KITE-222 (Higher Dose)	Cyclophosphamide	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.
Cohort 2: KITE-222 (Higher Dose)	Fludarabine	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.
Cohort 2: KITE-222 (Higher Dose)	KITE-222	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.
Cohort 3: KITE-222 (Highest Dose)	Cyclophosphamide	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.
Cohort 3: KITE-222 (Highest Dose)	Fludarabine	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.
Cohort 3: KITE-222 (Highest Dose)	KITE-222	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.
Dose Expansion	Cyclophosphamide	Participants will receive lymphodepleting chemotherapy with cyclophosphamide and fludarabine followed by a single dose \[at the maximum tolerated dose (MTD) determined\] of KITE-222.
Dose Expansion	Fludarabine	Participants will receive lymphodepleting chemotherapy with cyclophosphamide and fludarabine followed by a single dose \[at the maximum tolerated dose (MTD) determined\] of KITE-222.
Dose Expansion	KITE-222	Participants will receive lymphodepleting chemotherapy with cyclophosphamide and fludarabine followed by a single dose \[at the maximum tolerated dose (MTD) determined\] of KITE-222.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants Who Experienced Dose Limiting Toxicities (DLTs)	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.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs)	Up to 3.2 months	An AE was defined as any untoward medical occurrence in a clinical trial participant. The event does not necessarily have a relationship with the study treatment. The definition of an AE includes a worsening of a pre-existing medical condition. Worsening indicates that the pre-existing medical condition has increased in severity, frequency, and/or duration or has an association with a worse outcome. TEAEs were defined as any AEs with onset on or after the date of KITE-222 infusion.
Percentage of Participants Who Experienced Laboratory Toxicity Grade Shifts to Grade 3 or Higher Resulting From Increased Parameter Value	Up to 3.2 months	Grading categories are determined by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Grade 1: mild, Grade 2: moderate, Grade 3: severe or medically significant, Grade 4: life-threatening; Grade 5: Death related to AE.
Percentage of Participants Who Experienced Laboratory Toxicity Grade Shifts to Grade 3 or Higher Resulting From Decreased Parameter Value	Up to 3.2 months	Grading categories are determined by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Grade 1: mild, Grade 2: moderate, Grade 3: severe or medically significant, Grade 4: life-threatening; Grade 5: Death related to AE.
Time to Neutrophil Recovery	Up to 3.2 months	Time to neutrophil recovery after KITE-222 infusion \& before the start of the conditioning therapy for allo-SCT was calculated as the time from the date of KITE-222 infusion to the first day when neutrophils are 0.5 × 10\^9/liter (L), and as the time from the date of KITE-222 infusion to the first day when neutrophils are 1.0 × 10\^9/L. Per European Leukemia Net (ELN) 2017 classification, determined by study investigators, CR was defined as bone marrow (BM) blasts \<5%; absence of circulating blasts and blasts with Auer rods;absence of extramedullary disease;absolute neutrophil count (ANC) ≥1.0 × 10\^9/L (1000/microliter (μL));platelet count ≥100 × 10\^9/L (100000/μL). CRi was defined as all CR criteria except for residual neutropenia (\<1.0 × 10\^9/L \[1000/μL\]) or thrombocytopenia (\<100 × 10\^9/L \[100000/μL\]).
Time to Platelet Recovery	Up to 3.2 months	Time to platelet recovery after KITE-222 infusion and before the start of the conditioning therapy for subsequent allo-SCT was calculated as the time from the date of KITE-222 infusion to the first day when platelets are 50 × 10\^9/L, and the time from the date of KITE-222 infusion to the first day platelets are 100 × 10\^9/L. Per European Leukemia Net (ELN) 2017 classification, determined by study investigators, CR was defined as bone marrow (BM) blasts \<5%; absence of circulating blasts and blasts with Auer rods;absence of extramedullary disease;absolute neutrophil count (ANC) ≥1.0 × 10\^9/L (1000/microliter (μL));platelet count ≥100 × 10\^9/L (100000/μL). CRi was defined as all CR criteria except for residual neutropenia (\<1.0 × 10\^9/L \[1000/μL\]) or thrombocytopenia (\<100 × 10\^9/L \[100000/μL\]).
Composite Complete Remission (CCR) Rate	Up to 3.2 months	CCR rate=Percentage of participants who achieve complete remission (CR) + CR without measurable residual disease (CRMRD-) + CR with incomplete hematologic recovery (CRi) per European Leukemia Net (ELN) 2017 classification, determined by study investigators.CR was defined as bone marrow (BM) blasts \<5%; absence of circulating blasts and blasts with Auer rods;absence of extramedullary disease;absolute neutrophil count (ANC) ≥1.0 × 10\^9/L (1000/microliter (μL));platelet count ≥100 × 10\^9/L (100000/μL). CRMRD- if studied pretreatment was defined as CR with negativity for genetic marker by real-time quantitative polymerase chain reaction (RT-qPCR) or CR with negativity by multi-color flow cytometry (MFC).CRi was defined as all CR criteria except for residual neutropenia (\<1.0 × 10\^9/L \[1000/μL\]) or thrombocytopenia (\<100 × 10\^9/L \[100000/μL\]).
Overall Remission Rate (ORR)	Up to 3.2 months	ORR=percentage of participants who achieved CR+CRMRD- +CRi +morphologic leukemia-free state (MLFS) +partial remission (PR) per the ELN 2017 classification.CR was defined as BM blasts \<5%;absence of circulating blasts and blasts with Auer rods;absence of extramedullary disease;ANC ≥1.0 × 10\^9/L (1000/ (μL));platelet count ≥100 × 10\^9/L (100000/μL).CRMRD- if studied pretreatment = CR with negativity for genetic marker by RT-qPCR or CR with negativity by MFC.CRi was defined as all CR criteria except for residual neutropenia (\<1.0 × 10\^9/L \[1000/μL\]) or thrombocytopenia (\<100 × 10\^9/L \[100000/μL\]). MLFS=BM blasts \<5%;absence of blasts with Auer rods;absence of extramedullary disease;no hematologic recovery required.PR=hematologic criteria of CR decrease of BM blast percentage to 5% to 25%;and decrease of pretreatment BM blast percentage by at least 50%.
Relapse-free Survival (RFS)	Up to 3.2 months	For participants who experience CR, CRMRD-, or CRi, RFS was defined as the time between their first CR/CRMRD-/CRi to relapse or death due to any cause. CR was defined as BM blasts \<5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count (ANC) ≥1.0 × 10\^9/L (1000/μL); platelet count ≥100 × 10\^9/L (100000/μL). CRMRD- if studied pretreatment was defined as CR with negativity for a genetic marker by RT-qPCR or CR with negativity by MFC. CR with incomplete hematologic recovery was defined as all CR criteria except for residual neutropenia (\<1.0 × 10\^9/L \[1000/μL\]) or thrombocytopenia (\<100 × 10\^9/L \[100000/μL\]).
Allogeneic Stem Cell Transplant (Allo-SCT) Rate	Up to 3.2 months	The allo-SCT rate was defined as the number of participants who received allo-SCT after being treated with KITE-222 divided by the total number of subjects included in the safety analysis set.
Event-free Survival (EFS)	Up to 12.3 months	EFS was defined as the time from the KITE-222 infusion date to earliest date of disease relapse,progressive disease (PD),refractory disease, or death due to any cause.Relapse: Hematologic : BM blasts ≥ 5%,reappearance of blasts, or development of extramedullary disease;Molecular:If studied before treatment, re-occurrence of MRD assessed by RT-qPCR or MFC, PD:Evidence for increase in BM blast percentage and/or increase of absolute blast counts in blood:\> 50% increase in marrow blasts over baseline(minimum 15% point increase required with \< 30% blasts at baseline or persistent marrow blast \> 70%over 3 months without ≥ 100% improvement in ANC to absolute level (\> 0.5 × 10\^9/L \[500/μL\], and/or platelet count to \> 50 × 10\^9/L \[50,000/μL\] nontransfused); \> 50% increase in peripheral blasts(white blood cells (WBC) x % blasts) to \> 25 × 10\^9/L (\>25,000/μL) (absence of differentiation syndrome);New extramedullary disease.Refractory disease:No CR, CRMRD-, or CRi by Week 6 disease assessment.
Overall Survival (OS)	Up to 12.3 months	OS was defined as the time from KITE-222 infusion to the date of death from any cause.
All-cause Mortality Within 30 Days of KITE-222 Infusion	Up to 30 days	The mortality was calculated by number of deaths, regardless of cause, within 30 days from the KITE-222 infusion date.
All-cause Mortality Within 60 Days of KITE-222 Infusion	Up to 60 days	The mortality was calculated by number of deaths, regardless of cause, within 60 days from the KITE-222 infusion date.
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	Peak was defined as the maximum number of CAR T cells in blood measured after infusion.
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	AUC0-28 was defined as the area under curve in a plot of number of CAR T cells against scheduled visit from Day 0 to Day 28.
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	Peak was defined as the maximum levels of Interferon-gamma (IFNg), Interleukin (IL)-12 P40, IL-10, and IL-15 in serum from baseline to Week 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	Peak was defined as the maximum levels of IL-2 R Alpha and Ferritin in serum from baseline to Week 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	AUC0-28 was defined as the area under curve in a plot of IFNg, IL-12 P40, IL-10, and IL-15 scheduled visit from Day 0 to Day 28.
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	AUC0-28 was defined as the area under curve in a plot of IL-2 R Alpha and Ferritin scheduled visit from Day 0 to Day 28.
Percentage of Participants Who Develop Anti-KITE-222 CAR Antibodies	Up to 3.2 months

Trial Locations

Locations (9): Stanford Cancer Center
🇺🇸
Stanford, California, United States
Moffitt Cancer Center
🇺🇸
Tampa, Florida, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
Cleveland Clinic
🇺🇸
Cleveland, Ohio, United States
The Ohio State University Wexner Medical Center/James Cancer Hospital
🇺🇸
Columbus, Ohio, United States
The University of Texas MD Anderson Cancer Center
🇺🇸
Houston, Texas, United States
Fred Hutchinson Cancer Center
🇺🇸
Seattle, Washington, United States
Institut Paoli-Calmettes
🇫🇷
Marseille, France
CHU de Toulouse Institut Universitaire du Cancer Toulouse Oncopole
🇫🇷
Toulouse, France
Stanford Cancer Center
🇺🇸Stanford, California, United States