Modified Immune Cells (CLL-1 CAR T Cells) for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia Expressing Cll-1 Antigen, CARMEN Study

Inclusion Criteria

• PROCUREMENT INCLUSION CRITERIA FOR GENERATION OF CLL-1 CAR T-CELLS
• Diagnosis of primary refractory or relapsed acute myeloid leukemia (AML). Patients with targetable mutations should have failed or be ineligible for targeted therapies (e.g. FLT3 inhibitors, IDH inhibitors, or anti-CD33 drug conjugate) AND Suitable for consideration of allogeneic hematopoietic stem cell transplant with confirmation of an identified eligible donor by a Foundation for the Accreditation of Cellular Therapy (FACT) accredited transplant center and with confirmation that the center plans to proceed with transplant if CLL-1.CAR treatment induces response they consider adequate to proceed to allogeneic HSCT
• Primary refractory or resistant disease, defined as not achieving complete remission (CR) (e.g., a remaining blast count of 5% or more) after 1 to 2 cycles of intense induction therapy
• Relapse is defined as (1) hematologic relapse after complete remission based on bone marrow blasts >= 5%, or reappearance of blasts in the blood, or development of extramedullary disease; (2) molecular relapse after minimal residual disease (MRD) negative, complete remission based on reoccurrence of MRD as assessed by real time-quantitative polymerase chain reaction (RT-qPCR) or by multi-parametric flow cytometry (MFC)
• CLL-1 positive tumor with at least 30% CLL-1 blasts by flow cytometry or immunohistochemistry (tissue) assessed by a Clinical Laboratory Improvement Act (CLIA) certified flow cytometry/pathology laboratory
• Age =< 75 years NOTE: The first six (6) patients treated on the study will be adults (>= 18 yrs of age). Thereafter, a thorough review of the safety data will be performed and submitted to the Food and Drugs Administration (FDA) for approval prior to enrolling pediatric patients
• Hemoglobiln (Hgb) >= 7.0 g/dL (can be transfused)
• Life expectancy greater than 12 weeks
• If apheresis required to collect blood: Prothrombin time (PT) and activated partial thromboplastin time (APTT) < 1.5 x upper limit of normal (ULN)
• If apheresis required to collect blood: Serum creatinine < 1.5 x ULN
• If apheresis required to collect blood: Aspartate aminotransferase (AST) < 1.5 x ULN
• Informed consent
• TREATMENT INCLUSION CRITERIA
• Diagnosis of primary refractory or relapsed acute myeloid leukemia (AML). Patients with targetable mutations should have failed or be ineligible for targeted therapies (e.g. FLT3 inhibitors, IDH inhibitors, or anti-CD33 drug conjugate). AND Suitable for consideration of allogeneic hematopoietic stem cell transplant with confirmation of an identified eligible donor by a FACT accredited transplant center and with confirmation that the center plans to proceed with transplant if CLL-1.CAR treatment induces a response they consider adequate to proceed to allogeneic HSCT
• Primary refractory or resistant disease as defined by not achieving complete remission (CR) (e.g., a remaining blast count of 5% or more) after 1 to 2 cycles of intense induction therapy
• Relapse is defined as (1) hematologic relapse after complete remission based on bone marrow blasts >= 5%, or reappearance of blasts in the blood, or development of extramedullary disease; (2) molecular relapse after minimal residual disease (MRD) negative, complete remission based on reoccurrence of MRD as assessed by RT-qPCR or by multi-parametric flow cytometry (MFC)
• CLL-1 positive tumor with at least 30% CLL-1+ blasts by flow cytometry or immunohistochemistry (tissue) assessed by a CLIA certified flow cytometry/pathology laboratory
• Age =< 75 years. NOTE: The first six (6) patients treated on the study should be adults (>= 18 yrs of age). Thereafter, a thorough review of the safety data will be performed and submitted to the FDA for approval prior to enrolling pediatric patients.
• AST/alanine aminotransferase (ALT) less than 5 times the upper limit of normal
• Bilirubin less than 3 times the upper limit of normal
• Estimated glomerular filtration rate (GFR) ≥ 60ml/min
• Pulse oximetry of > 92% on room air
• Karnofsky/Lansky >= 60
• No systemic chemotherapy at least 2 weeks prior to treatment on study and must be recovered from all acute toxic effects of prior chemotherapy at time of treatment
• Available autologous transduced activated peripheral blood T-cell product with >= 20% expression of CLL-1.CAR.28z by flow cytometry
• Life expectancy > 12 weeks
• Sexually active patients must be willing to utilize one of the more effective birth control methods during the study and for 6 months after the study is concluded. The male partner should use a condom
• Informed consent explained to, understood by, and signed by patient/guardian. Patient/guardian given copy of informed consent

Exclusion Criteria

• PROCUREMENT EXCLUSION CRITERIA FOR GENERATION OF CLL-1 CAR T-CELLS
• Diagnosis of acute promyelocytic leukemia (APL)
• Active infection (bacterial, fungal, or viral) requiring ongoing treatment without improvement
• Active infection with human immunodeficiency virus (HIV) or human T-lymphotropic virus (HTLV)
• Active second cancer (except non-melanoma skin cancer or in situ breast cancer or cervical cancer) or other cancer treated =< 2 years prior to enrollment
• Ongoing treatment with immune suppression for prophylaxis/treatment of graft versus host disease (GVHD) including high dose steroids (e.g. prednisone equivalent > 0.25mg/kg/day)
• Bridging chemotherapy and disease reassessment prior to treatment: * Patients will be allowed to receive bridging therapy while awaiting manufacture of the CAR-T product. Treatment regimen will be at the discretion of the primary treating physician, but will be discussed with the study team in advance. Patients should discontinue systemic chemotherapy at least 2 weeks prior to start of lymphodepleting chemotherapy. Bone marrow aspiration and/or biopsy to confirm persistent/residual disease of > 5% blasts will be required within 2 weeks prior to consent/enrollment on the treatment phase of the study. However, if the patient has evidence of persistent peripheral blasts then bone marrow biopsy done within 4 weeks prior to start of lymphodepleting chemotherapy will be acceptable. Patients with history of central nervous system (CNS) involvement will require repeat lumbar puncture and/or imaging (if prior chloroma) to document absence of CNS disease (defined as detectable cerebrospinal blast cells in a sample of cerebrospinal fluid [CSF] with >= 5 white blood cells [WBCs] per mm^3). In addition to the above disease restaging, patients must also meet inclusion/exclusion criteria
• TREATMENT EXCLUSION CRITERIA
• Treatment with any investigational agents or having received any tumor vaccines within the previous 6 weeks
• History of hypersensitivity reactions to murine protein-containing products
• Pregnant or lactating
• Active infection with HIV or HTLV
• Clinically significant bacterial, fungal, or viral infection requiring ongoing therapy without improvement
• Cardiac criteria: Prolonged corrected QT (QTc) with maximum interval as defined by age; Uncontrolled atrial fibrillation/flutter; myocardial infarction; cardiac echocardiography with left ventricular systolic function (LVSF) < 30% or left ventricular ejection fraction (LVEF) < 50%; cardiac dysfunction New York Heart Association (NYHA) III or IV; clinically significant pericardial effusion. Confirmation of absence of these conditions within 6 months of treatment
• CNS abnormalities: Presence of CNS disease defined as detectable cerebrospinal blast cells in a sample of CSF with >= 5 WBCs per mm3 or chloroma on imaging, History or presence of an underlying CNS disorder such as a seizure disorder requiring current use of antiepileptic medications, cerebrovascular ischemia/hemorrhage within the prior 6 months, dementia, cerebellar disease, or any autoimmune disease with active CNS involvement
• Use of serotherapy with Campath or anti-thymocyte globulin (ATG) within the last 28 days
• Use of donor lymphocyte infusion (DLI) or other cellular therapy product within 30 days
• Acute GVHD >= grade 2 or moderate to severe (formerly extensive) chronic GVHD
• High dose steroids > 1 mg/kg within preceding 5 days or currently receiving > 0.25 mg/kg/day prednisone equivalent
• Hyperleukocytosis (WBC >= 50K) or rapidly progressive disease that in the estimation of the investigator would compromise the ability of the patient to complete the study