Study Evaluating the Safety, Tolerability, and Efficacy of FLT3 CAR-T AMG 553 in FLT3-positive Relapsed/Refractory AML

A Phase 1 Study Evaluating the Safety, Tolerability, and Efficacy of FLT3 Chimeric Antigen Receptor T-cell (CAR-T) AMG 553 in Subjects With FLT3-positive Relapsed/Refractory Acute Myeloid Leukemia.

Evaluate the safety and tolerability of AMG 553 in adult and adolescent subjects with FLT3-positive R/R AML.

Determine the maximum tolerated cell dose (MTCD) or recommended phase 2 cell dose (RP2CD) of AMG 553.

Inclusion Criteria:

• Subject has provided informed consent/assent prior to initiation of any study-specific activities/procedures.
• Age greater than or equal to 12 years old at the time of signing the informed consent
• Relapsed/Refractory Acute Myeloid Leukemia (AML) as defined by the World Health Organization (WHO) Classification as persisting or recurring following 1 or more treatment courses (exceptions noted in exclusion criteria). Subjects must be intolerant to or ineligible for available therapies (eg, patients with FLT3 ITD/TKD mutations must have failed FLT3 inhibitors like midostaurin).
• FLT3 positivity: FLT3 expression on myeloblasts must be confirmed by local lab flow cytometry using an antibody targeting CD135 (FLT3)
• Myeloblasts greater than 5% in bone marrow and/or peripheral blood, as confirmed by immunophenotype by flow cytometry.
• Subject must have a donor or stem cell source identified for allogeneic transplantation, either related (7/8 or 8/8 allele matched or haploidentical), unrelated (7/8 or 8/8 allele matched donor), or cord blood stem cell source (at least 4/6 matched).
• Karnofsky performance score greater than or equal to 50 (for subjects aged greater than or equal to 16 years) or Lansky (for subjects aged less than 16 years) performance score greater than or equal to 50.
• Adequate organ function, defined as follows: Coagulation function: prothrombin timeprothrombin time/international normalization ratio (PT/INR) and partial thromboplastin time (PTT) less than or equal to 1.5 x Institutional Upper Limit of Normal Renal function as follows: Estimated Glomerular filtration rate by institutional formula greater than 60 mL/min/1.73 m2 or serum creatinine less than 2 times upper limit of normal (ULN) for the subject's age. Hepatic function: aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase less than 3 X upper limit of normal ULN. Total bilirubin less than 1.5 X upper limit of normal ULN. Cardiac function: Cardiac ejection fraction greater than or equal to 50%, no evidence of pericardial effusion as determined by an echocardiogram or Multigated Acquisition (MUGA) scan, and no clinically significant ECG findings.

Exclusion Criteria:

• Subjects with acute promyelocytic leukemia (APML).
• Active extramedullary AML in the central nervous system (CNS).
• Subjects with a prior or concurrent malignancy whose natural history or treatment is not anticipated to interfere with the safety or efficacy assessment of the investigational regimen may be included only after discussion with the Amgen Medical Monitor.
• History of Down syndrome or any DNA fragility syndromes such as Bloom's syndrome.
• Autologous hematopoietic stem cell transplant (HSCT) within 6 weeks prior to enrollment
• Allogeneic hematopoietic stem cell transplant (HSCT) within 3 months prior to enrollment
• Any graft-versus-host disease requiring systemic therapy with immunomodulators
• Subjects with history or presence of clinically relevant non-malignant CNS disease requiring treatment (eg, uncontrolled seizures)
• Subjects with clinically relevant or uncontrolled active infections
• History or evidence of significant cardiovascular risk including any of the following: symptomatic congestive heart failure, unstable angina, clinically significant arrhythmias (eg, ventricular fibrillation, ventricular tachycardia etc.), coronary angioplasty within 6 months before dosing, intra-cardiac defibrillators or any clinically relevant concurrent disorder that may pose a risk to subject safety or interfere with study evaluation, procedures, or completion.
• History of arterial thrombosis (eg, stroke or transient ischemic attack) within 3 months prior to enrollment.
• History of symptomatic deep vein thrombosis or pulmonary embolism within 6 months before enrollment.
• Positive test for human immunodeficiency virus (HIV)
• Positive for hepatitis B surface antigen (HepBsAg)
• Positive for acute or chronic hepatitis C. Exceptions: Acute hepatitis C and completely cleared of the virus (demonstrated by negative viral load). Chronic hepatitis C with undetectable viral load defined by sustained virologic response 24 weeks (SVR24) after completion of anti-hepatitis C treatment.
• Received live vaccine(s) within 4 weeks of enrollment.
• Unresolved toxicities from prior antitumor therapy not having resolved to Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 grade 1 with the exception of myelosuppression (eg, neutropenia, anemia, thrombocytopenia) or are stable and well controlled AND there is agreement to allow by both the investigator and sponsor.
• Treatment with systemic immune modulators including, but not limited to, non-topical systemic corticosteroids, cyclosporine, and tacrolimus within 2 weeks before enrollment (exception: low dose systemic corticosteroids if used for blood transfusion reactions or similar).
• Major surgery within 28 days of enrollment with the exception of biopsy and insertion of central venous catheter.
• Subject has known sensitivity and immediate hypersensitivity to any components of AMG 553 or lymphodepleting regimen (cyclophosphamide and fludarabine).
• Other anti-cancer therapy (eg, investigational therapy, chemotherapy, antibody therapy, molecular targeted therapy) within 14 days (or 5 half-lives, whichever is shorter) prior to leukapheresis. Use of immune checkpoint inhibitors is excluded 3 months prior to leukapheresis.
• Prior treatment with any CAR-T or other genetically modified cell therapy.
• Presence of any clinically relevant indwelling line or drain (eg, percutaneous nephrostomy tube, biliary drain, or pleural/peritoneal/pericardial catheter).
• History of autoimmune disease (eg, Crohn's, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years prior to enrollment.
• Females of child-bearing potential who are not willing to practice a highly effective method(s) of birth control from the time of consent through 6 months after AMG 553 infusion day.
• Females who are pregnant or planning to become pregnant or breastfeeding or who plan to breastfeed from the time of consent through 6 months after AMG 553 infusion day.
• Males who are unwilling to abstain from sperm donation while on study through 6 months after AMG 553 infusion day.
• Male subjects with a female partner of childbearing potential who are unwilling to practice sexual abstinence (refrain from heterosexual intercourse) or use contraception from the time of consent through 6 months after AMG 553 infusion day.
• Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the subject and investigator's knowledge.
• History or evidence of any other clinically significant disorder, condition or disease that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.
• Subjects with clinically significant pre-existing liver disease, such as cirrhosis