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

Study Overview
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Brief Summary
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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).

Official Title
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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

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Fludarabine
* Biological: KITE-222


Participation Criteria
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Eligibility Criteria
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Key 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 allo-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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: KITE-222<br>Dose Escalation: Participants will receive lymphodepleting chemotherapy with cyclophosphamide and fludarabine followed by a single target starting dose of KITE-222 chimeric antigen receptor (CAR) transduced autologous T cells. Based on dose limiting toxicities (DLTs) observed in the first cohort, additional participants will be enrolled and administered escalating dose of KITE-222 to determine the maximum tolerated dose (MTD) of KITE-222. Dose Expansion: Participants will receive lymphodepleting chemotherapy with cyclophosphamide and fludarabine followed by a single dose (at the MTD determined) of KITE-222. | Drug: Cyclophosphamide<br>* Administered intravenously<br>Drug: Fludarabine<br>* Administered intravenously<br>Biological: KITE-222<br>* A single infusion of chimeric antigen receptor (CAR)-transduced autologous T cells administered intravenously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs) | DLTs are defined as KITE-222-related events with an onset within the first 28 days after the KITE-222 infusion | First infusion date of KITE-222 up to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Experiencing Adverse Events |  | Up to 15 years | 
| Percentage of Participants Experiencing Clinically Significant Changes in Laboratory Parameters |  | Up to 15 years | 
| Time to Neutrophil Recovery |  | First infusion date of KITE-222 up to 24 months | 
| Time to Platelet Recovery |  | First infusion date of KITE-222 up to 24 months | 
| Composite Complete Remission (CCR) Rate | CCR rate is defined as the proportion of participants who achieve a complete remission (CR) plus the proportion of participants who achieve a CR without measurable residual disease (CRMRD-) plus the proportion of participants who achieve a CR with incomplete hematologic recovery (CRi) per the European Leukemia Net (ELN) 2017 classification, as determined by the study investigators. | Up to 24 months | 
| Overall Remission Rate (ORR) | ORR is defined as CR + CRMRD- + CRi + morphologic leukemia-free state (MLFS) + partial remission (PR) per the ELN 2017 classification, as determined by the study investigators. | Up to 24 months | 
| Relapse-free Survival (RFS) | For participants who experience CR, CRMRD-, or CRi, RFS is defined as the time between their first CR/CRMRD-/CRi to relapse or death due to any cause. | Up to 24 months | 
| Allogeneic Stem Cell Transplant (allo-SCT) Rate |  | Up to 24 months | 
| Event-free Survival (EFS) | EFS is defined as the time from the KITE-222 infusion date to the earliest date of disease relapse, progressive disease, refractory disease, or death due to any cause. | First infusion date of KITE-222 up to 24 months | 
| Overall Survival (OS) | OS is defined as the time from KITE-222 infusion to the date of death from any cause. | First infusion date of KITE-222 up to 15 years | 
| 30 Day All-cause Mortality Rate | The mortality rate is calculated by number of deaths, regardless of cause, within 30 days from the KITE-222 infusion date divided by the total number of participants included in the safety analysis set. The safety analysis set consists of all participants treated with any dose of KITE-222. | First infusion date of KITE-222 up to 30 days | 
| 60 Day All-cause Mortality Rate | The mortality rate is calculated by number of deaths, regardless of cause, within 60 days from the KITE-222 infusion date divided by the total number of participants included in the safety analysis set. The safety analysis set consists of all participants treated with any dose of KITE-222. | First infusion date of KITE-222 up to 60 days | 
| Pharmacokinetics (PK): Peak Plasma Concentration of KITE-222 CAR T Cells in Participants With Relapsed/Refractory (r/r) Acute Myeloid Leukemia (AML) Treated with KITE-222 | PK will be assessed at enrollment (before start of leukapheresis) and Day 0 (predose) and on Days 3, 7, 10, 14 & 21, Week 4, post-treatment follow-up (Week 6, Months 2, 3, 6, 9, 12, 15, 18, & 24 and at relapse for participants without allo-SCT or within 1 week before conditioning chemotherapy and Day -1 of allo-SCT, Months 1, 3, 6,12 & 24 and at relapse for participants with allo-SCT). CC=conditioning chemotherapy D=Day(s) M=Month PTFU= post-treatment follow-up W=Week | Enrollment (before leukapheresis) and D0 (predose), D3,7,10,14 &21, W4, PTFU (W6, M2,3,6,9,12,15,18 &24 and at relapse for participants without allo-SCT or within 1 W before CC, D-1 of allo-SCT, M1,3,6,12 &24 and at relapse for participants with allo-SCT | 
| PK Parameter: AUC of KITE-222 CAR T Cells in Participants With r/r AML Treated with KITE-222 | AUC is defined as the area under the concentration versus time curve. PK will be assessed at enrollment (before start of leukapheresis) and Day 0 (predose) and on Days 3, 7, 10, 14 & 21, Week 4, post-treatment follow-up (Week 6, Months 2, 3, 6, 9, 12, 15, 18, & 24 and at relapse for participants without allo-SCT or within 1 week before conditioning chemotherapy and Day -1 of allo-SCT, Months 1, 3, 6,12 & 24 and at relapse for participants with allo-SCT). CC=conditioning chemotherapy D=Day(s) M=Month PTFU= post-treatment follow-up W=Week | Enrollment (before leukapheresis) and D0 (predose), D3,7,10,14 &21, W4, PTFU (W6, M2,3,6,9,12,15,18 &24 and at relapse for participants without allo-SCT or within 1 W before CC, D-1 of allo-SCT, M1,3,6,12 &24 and at relapse for participants with allo-SCT | 
| Pharmacodynamics (PD): Peak Plasma of Key Analytes (Pro-inflammatory and Immune-modulating Cytokines, Chemokines, and Effector Molecules) in Participants With r/r AML Treated with KITE-222 |  | Enrollment (before leukapheresis) and Days -5 & 0 (predose) and Days 1-13 every other day,14,21, Week 4, post-treatment follow-up (Month 2 and at relapse for participants without allo-SCT or at relapse for participants with allo-SCT) | 
| PD Parameter: AUC of Key Analytes (Pro-inflammatory and Immune-modulating Cytokines, Chemokines, and Effector Molecules) in Participants With r/r AML Treated with KITE-222 | AUC is defined as the area under the concentration versus time curve. | Enrollment (before leukapheresis) and Days -5 & 0 (predose) and Days 1-13 every other day,14,21, Week 4, post-treatment follow-up (Month 2 and at relapse for participants without allo-SCT or at relapse for participants with allo-SCT) | 
| Percentage of Participants who Develop Anti-KITE-222 CAR Antibodies |  | Enrollment (before leukapheresis),Week 4, post-treatment follow-up (Month 3 and at relapse for participants without allo-SCT or within 1 week before conditioning chemotherapy and at relapse for participants with allo-SCT) |