A Study of CD371-specific/YSNVz/IL-18 CAR T Cells in People with Relapsed or Refractory Acute Myeloid Leukemia, CLEAR-AML Trial

Inclusion Criteria

• COLLECTION of T-CELLS (PART A): History of CD371+ AML * Any disease status is eligible for collection * Expression of CD371 at any level on AML blasts (any method of detection including immunohistochemistry [IHC] and/or flow cytometry)
• COLLECTION of T-CELLS (PART A): Pediatrics: ≥ 1 year and ≥ 10kg for collection
• COLLECTION of T-CELLS (PART A): Adults: no limit on age/weight for collection
• COLLECTION of T-CELLS (PART A): Patients with history of allogeneic hematopoietic cell transplantation (allo-HCT) are eligible for collection if: * ≥ 100 days post-transplant * No evidence of active graft versus dose disease (GVHD) * Off any immunosuppressive agents for 30 days prior to collection (physiologic dose of corticosteroids is acceptable)
• TREATMENT WITH CD371-SPECIFIC/YSNVz/IL-18 CAR T-CELLS (PART B): Relapsed/Refractory CD371+ AML (meeting criteria defined below): * Primary refractory AML: Patients are eligible from disease perspective in the event of failure to achieve a complete remission (CR), complete remission with partial hematologic recovery (CRh) or complete remission with incomplete hematologic recovery (CRi) after one or more of the following regimens: ** Two or more courses of standard intensive induction chemotherapy (e.g., cytarabine and daunorubicin given as “7+3,” mitoxantrone, etoposide and cytarabine [MEC], high-dose cytarabine [HiDAC], fludarabine, cytarabine, idarubicin and granulocyte-colony stimulating factor [FLAG+idarubicin], etc.) ** Two or more cycles of venetoclax in combination with one of the following (azacitidine OR decitabine OR low-dose cytarabine), with or without other agents ** Six or more cycles of azacitidine monotherapy OR 4 or more courses of decitabine monotherapy * Early first relapse: Patients are eligible from disease perspective in the event of first morphologic relapse or new extramedullary disease less than 12 months after previously having achieved CR, CRh, or CRi following AML-directed therapy * Late first relapse: Patients with first morphologic relapse or new extramedullary disease ≥ 12 months after previously having achieved CR, CRh, or CRi following AML-directed therapy may respond to intensive re-induction using the initial induction regimen and not eligible from a disease perspective unless the treating investigator feels the patient is unlikely to benefit from repeating the initial induction regimen (for example, relapse occurring 12 months into CR on continuous azacitidine/venetoclax therapy), in which case the rationale for considering enrollment must be clearly documented and risks, benefits, and alternatives discussed with the patient * Advanced disease: Patients are eligible from disease perspective in the event of relapsed AML refractory to re-induction therapy, relapse following allogeneic hematopoietic cell transplantation, or second or later relapse * Disease eligibility considerations for all patients: Patients with relapsed or refractory AML with susceptible mutations for which there is an Food and Drug Administration (FDA) approved therapy (for example, IDH1 mutation, ivosidenib; IDH2 mutation, enasidenib; FLT3-ITD/TKD, gilteritinib) are not eligible from a disease perspective unless they meet one or more of the below criteria: ** Failure to achieve CR, CRh, or CRi following therapy with one or more targeted therapies for relapsed or refractory AML directed to the actionable mutation(s) ** Intolerance of one or more targeted therapies for relapsed or refractory AML directed to the actionable mutation(s) ** Treating investigator feels the patient would be unlikely to benefit from FDA-approved targeted therapy based on disease characteristics, in which case the rationale for considering enrollment must be clearly documented and risks, benefits, and alternatives discussed with the patient
• TREATMENT WITH CD371-SPECIFIC/YSNVz/IL-18 CAR T-CELLS (PART B): Any age is eligible for treatment if eligible for collection * The first 3 patients in the first dose cohort must be ≥ 16 years of age, while the first 2 patients in subsequent cohorts must be ≥ 16 years of age
• TREATMENT WITH CD371-SPECIFIC/YSNVz/IL-18 CAR T-CELLS (PART B): Age ≥ 16 years: Eastern Cooperative Oncology Group (ECOG) ≤ 1 or Karnosfsky ≥ 60
• TREATMENT WITH CD371-SPECIFIC/YSNVz/IL-18 CAR T-CELLS (PART B): Age < 16 years: Lansky ≥ 60
• TREATMENT WITH CD371-SPECIFIC/YSNVz/IL-18 CAR T-CELLS (PART B): Patients with history of allo-HCT are eligible for treatment if: * ≥ 100 days post-transplant * No evidence of active GVHD * Off any systemic immunosuppressive agents for 30 days prior to treatment (physiologic dose of corticosteroids is acceptable) * Treating physician considers the patient to be a candidate for second allogeneic hematopoietic stem cell transplantation (HSCT)
• TREATMENT WITH CD371-SPECIFIC/YSNVz/IL-18 CAR T-CELLS (PART B): Identification of a suitable donor/source for allogeneic HSCT as determined by the treating physician
• TREATMENT WITH CD371-SPECIFIC/YSNVz/IL-18 CAR T-CELLS (PART B): Serum total bilirubin ≤ 1.5 mg/dL, unless benign congenital hyperbilirubinemia or unless thought to be disease related
• TREATMENT WITH CD371-SPECIFIC/YSNVz/IL-18 CAR T-CELLS (PART B): Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3 times the upper limit of normal unless thought to be disease-related
• TREATMENT WITH CD371-SPECIFIC/YSNVz/IL-18 CAR T-CELLS (PART B): Serum creatinine < 2.0 mg/100 ml (> 18 years) or ≤ 2.5 x institutional upper limit of normal (ULN) for age * If serum creatinine is outside the normal range, then creatinine clearance (CrCl) > 40 mL/min/1.73m2 (calculated or estimated) or glomerular filtration rate (GFR) (mL/min/1.73m2) > 40% of predicted normal for age * Normal GFR by age: Mean GFR +/- standard deviation (SD) (mL/min/1.73 m2) ** 1 week: 40.6 +/- 14.8 ** 2-8 weeks: 65.8 +/- 24.8 ** > 8 weeks: 95.7 +/- 21.7 ** 2-12 years: 133 +/- 27 ** 13-21 years (males): 140 +/- 30 ** 13-21 years (females): 126.0 +/- 22.0 * Greater than 2 years old: Normal GFR is 100 mL/min/1.73m^2. * Infants: GFR must be corrected for body surface area
• TREATMENT WITH CD371-SPECIFIC/YSNVz/IL-18 CAR T-CELLS (PART B): Left ventricular ejection fraction (LVEF) ≥ 50% by MUGA or resting echocardiogram
• TREATMENT WITH CD371-SPECIFIC/YSNVz/IL-18 CAR T-CELLS (PART B): Adequate pulmonary function as assessed by ≥ 92% oxygen saturation on room air by pulse oximetry

Exclusion Criteria

• COLLECTION OF T-CELLS (PART A): Pregnant or lactating women; women of childbearing age, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception while receiving study treatment and for at least 12 months after all treatment is finished
• COLLECTION OF T-CELLS: Sexually active males, unless they are willing to use a condom during intercourse while receiving study treatment and for at least 12 months after all treatment is finished
• COLLECTION OF T-CELLS (PART A): Radiographically-detected or symptomatic central nervous system [CNS] disease or CNS 3 disease (i.e., presence of ≥ 5/ul white blood cell [WBC] in cerebrospinal fluid [CSF]). Subjects with adequately treated CNS leukemia are eligible
• COLLECTION OF T-CELLS (PART A): Uncontrolled, symptomatic, intercurrent illness including but not limited to infection, psychiatric illness, or social situations that would limit compliance with study requirements or in the opinion of the principal investigator (PI) would pose an unacceptable risk to the subject
• COLLECTION OF T-CELLS (PART A): Impaired cardiac function (LVEF < 50%) as assessed by ECHO or MUGA scan
• COLLECTION OF T-CELLS (PART A): Patients with following cardiac conditions will be excluded: * New York Heart Association (NYHA) stage III or IV congestive heart failure * Myocardial infarction ≤ 6 months prior to enrollment * History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration
• COLLECTION OF T-CELLS (PART A): Positive serologic test results for human immunodeficiency virus (HIV)
• COLLECTION OF T-CELLS (PART A): Acute or chronic hepatitis B virus (HBV) infection as assessed by serologic (HBV surface antigen [HBVsAg]) or polymerace chain reaction (PCR) results, defined as HBVsAg+, HBV core antibody (HBVcAb)+, HBV PCR+
• COLLECTION OF T-CELLS (PART A): Acute or chronic hepatitis C virus (HCV) infection as assessed by serologic (HCV antibody [ab]) or PCR results, defined as HCV Ab+ with reflex to positive HCV PCR
• COLLECTION OF T-CELLS (PART A): Patient/parent/legally authorized representative (LAR) unable to give informed consent
• TREATMENT WITH CD371-SPECIFIC/YSNVz/IL-18 CAR T-CELLS (PART B): Bridging chemotherapy occurring < 1 week prior to administration of lymphodepleting chemotherapy (LDC) * Exception: hydroxyurea can be continued up to 72 hours prior to leukapheresis or 24 hours prior to LDC
• TREATMENT WITH CD371-SPECIFIC/YSNVz/IL-18 CAR T-CELLS (PART B): Pregnant or lactating women
• TREATMENT WITH CD371-SPECIFIC/YSNVz/IL-18 CAR T-CELLS (PART B): Radiographically-detected or symptomatic CNS disease or CNS 3 disease (i.e., presence of ≥ 5/ul WBC in CSF). Subjects with adequately treated CNS leukemia are eligible
• TREATMENT WITH CD371-SPECIFIC/YSNVz/IL-18 CAR T-CELLS (PART B): Isolated extramedullary disease
• TREATMENT WITH CD371-SPECIFIC/YSNVz/IL-18 CAR T-CELLS (PART B): Lack of a suitable donor/source for allogeneic HSCT as determined by the treating physician
• TREATMENT WITH CD371-SPECIFIC/YSNVz/IL-18 CAR T-CELLS (PART B): Patients with prior allogeneic HSCT are allowed as long as HSCT occurred > 3 months prior to signing the informed consent form (ICF) and without ongoing requirement for systemic graft-versus-host therapy
• TREATMENT WITH CD371-SPECIFIC/YSNVz/IL-18 CAR T-CELLS (PART B): Uncontrolled, symptomatic, intercurrent illness including but not limited to infection, psychiatric illness, or social situations that would limit compliance with study requirements or in the opinion of the PI would pose an unacceptable risk to the subject
• TREATMENT WITH CD371-SPECIFIC/YSNVz/IL-18 CAR T-CELLS (PART B): Impaired cardiac function (LVEF < 50%) as assessed by ECHO or MUGA scan
• TREATMENT WITH CD371-SPECIFIC/YSNVz/IL-18 CAR T-CELLS (PART B): Patients with following cardiac conditions will be excluded: * New York Heart Association (NYHA) stage III or IV congestive heart failure * Myocardial infarction =< 6 months prior to enrollment * History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration
• TREATMENT WITH CD371-SPECIFIC/YSNVz/IL-18 CAR T-CELLS (PART B): Positive serologic test results for HIV
• TREATMENT WITH CD371-SPECIFIC/YSNVz/IL-18 CAR T-CELLS (PART B): Acute or chronic HBV infection as assessed by serologic (HBVsAg) or PCR results, defined as HBVsAg+, HBVcAb+, HBV PCR+
• TREATMENT WITH CD371-SPECIFIC/YSNVz/IL-18 CAR T-CELLS (PART B): Acute or chronic HCV infection as assessed by serologic (HCV ab) or PCR results, defined as HCV Ab+ with reflex to positive HCV PCR
• TREATMENT WITH CD371-SPECIFIC/YSNVz/IL-18 CAR T-CELLS (PART B): Active second malignancy that requires systemic treatments, with the exception of malignancy treated with curative intent and without evidence of disease for > 2 years before screening
• TREATMENT WITH CD371-SPECIFIC/YSNVz/IL-18 CAR T-CELLS (PART B): Patient/parent/LAR unable to give informed consent
• TREATMENT WITH CD371-SPECIFIC/YSNVz/IL-18 CAR T-CELLS (PART B): Any other condition/issue which, in the opinion of the treating physician, would make the patient ineligible for the study; conditions that in the Principal Investigator’s opinion might confound the results of the study, interfere with the patient’s participation for the full duration of the study, or is not in the best interest of the patient to participate