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Cytokine Induced Memory-Like Natural Killer Cells Combined with Atezolizumab for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia
Trial Status: active
This phase I trial studies the side effects and best dose of cytokine induced memory-like natural killer cells (CIML-NK cells) in combination with atezolizumab in treating patients with acute myeloid leukemia (AML) that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). CIML-NK cells are made in a laboratory from human healthy blood from a haploidentical “half-matched” donor. (Haploidentical means the donor’s cells are half-matched to the patient's cells.) The healthy donor blood cells will be collected for the separation (isolation) of natural killer (NK) cells, white blood cells that play an important role in the body’s immune system. The NK cells will then be activated into a memory-like state using proteins called cytokines. Cytokines can make the NK cells more effective at killing cancer cells. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of cancer cells to grow and spread. Patients also receive a conditioning chemotherapy with fludarabine and cyclophosphamide that briefly suppresses the immune system and prepares to body to receive the CIML-NK cell therapy. Fludarabine injection is in a class of medications called purine analogs. It works by slowing or stopping the growth of cancer cells in the body. Cyclophosphamide is in a class of medications called alkylating agents. It works by damaging the cell’s DNA and may kill cancer cells. It may also lower the body’s immune response. In addition, patients receive aldesleukin, a drug that increases the activity of white blood cells called T cells and B cells, which may help the immune system kill cancer cells. Giving the combination of conditioning chemotherapy, aldesleukin, atezolizumab, and CIML-NK cells may be a safe treatment for patients with relapsed or refractory AML.
Inclusion Criteria
Subjects must have histologically confirmed acute myeloid leukemia that meets any of the following criteria:
* Refractory to at least two attempts at prior induction therapy. An attempt is defined as either a single cycle of combination chemotherapy such as daunorubicin/anthracycline OR a single monthly cycle of a hypomethylating agent with venetoclax
* Patients with FLT3-ITD or -TKD mutations must have received at least one commercially available inhibitor of FLT3
* Patients with NPM1 mutation or rearrangements of MLL must be refractory to revumenib
* Patients with mutations in IDH1 or IDH2 must be refractory to at least one commercially available inhibitor of IDH1 or IDH2, respectively
* Relapsed AML when relapse occurred within 6 months of achieving an initial complete remission
* Patients must have either failed prior Food and Drug Administration (FDA) approved agents or, in the opinion of the treating physician, have a sufficiently low probability of response to existing FDA approved agents to warrant treatment on an investigational protocol
Patients aged 18 through 70 years old are eligible
Must have an available, haplotype mismatched related individual that meets criteria for cell donation according to the Functional Assessment of Cancer Therapy (FACT) guidelines
Patients must have Karnofsky performance status ≥ 70%
Adequate cardiac function as defined as a systolic left ventricular (LV) ejection fraction ≥ 50% at rest and absence of New York Heart Association stage III or IV congestive heart failure
Adequate pulmonary function as defined as a resting blood oxygen saturation (SpO2) ≥ 92% on room air at rest
Serum bilirubin ≤ 5 mg/dL
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5x upper limit of normal (ULN) unless thought to be disease related
Estimated or measured creatinine clearance > 50 mL/min
Subjects must be free from all systemic immune suppression for at least 4 weeks prior to the start of intended therapy
For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception and agreement to refrain from donating eggs, as defined below: Women must remain abstinent or use contraceptive methods with a failure rate < 1% per year during the treatment period and for 5 months after the final dose of atezolizumab. Women must refrain from donating eggs during this same period
Negative HIV test at screening
Negative hepatitis B surface antigen (HBsAg) test at screening OR positive HBsAg is allowed if a negative hepatitis B core antibody (HBcAb) or a negative quantitative hepatitis B virus (HBV) (deoxyribonucleic acid [DNA] < 500 IU/mL) assay are documented
Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV ribonucleic acid (RNA) test at screening The HCV RNA test must be performed for patients who have a positive HCV antibody test
For patients receiving therapeutic anticoagulation: Stable anticoagulant regimen for 2 weeks prior to enrollment
Timing of treatment relative to prior therapies:
* Bridging therapy with hydrea is allowed but is required to be tapered off prior to NK infusion
* Any experimental biological treatments must be discontinued for at least 5 half-lives prior to initiation of study therapy
* Patients must be > 5 half-lives from receipt of other cytotoxic or targeted therapy
DONOR INCLUSION CRITERIA:
Donors must be eligible for apheresis according to standard Foundation for the Accreditation of Cellular Therapy (FACT) guidelines
Donors must not have a human leukocyte antigen (HLA) genotype reactive against anti-HLA antibodies in the recipient
Subjects with active/uncontrolled central nervous system (CNS) leukemia. Subjects with prior CNS disease must have no detectable evidence of cerebrospinal fluid (CSF) disease for at least 4 weeks prior to enrollment
Subjects requiring systemic immunosuppression for any indication are excluded
Significant cardiovascular disease, as defined by:
* New York Heart Association Class II or greater congestive heart failure
* Myocardial infarction, cerebrovascular accident, or other arterial vascular disease within 6 months prior to initiation of study treatment
* Unstable arrhythmia
* Unstable angina
Subjects with isolated extramedullary disease without evidence of bone marrow involvement by immunohistochemistry
Female patients who are pregnant or breast-feeding or intend to become pregnant during study treatment or within 5 months after the final dose of atezolizumab. Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment with atezolizumab
Severe or uncontrolled infection prior to initiation of study treatment
Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment, excluding prophylactic antimicrobial agents
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan
Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL, or corrected calcium greater than ULN)
Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, anti-phospholipid antibody syndrome, Wegener granulomatosis, Sjogren syndrome, Guillain-Barre syndrome, or multiple sclerosis, with the following exceptions:
* Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study
* Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study
* Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all following conditions are met:
** Rash must cover < 10% of body surface area
** Disease is well controlled at baseline and requires only low-potency topical corticosteroids
** There has been no occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
Persons who do not meet the age and organ function criteria specified above
History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation
Additional locations may be listed on ClinicalTrials.gov for NCT07011004.
I. To estimate the maximum tolerated dose (MTD) of the combination of donor-derived cytokine-induced memory-like natural killer cells (CIML-NK) cells with atezolizumab in subjects with relapsed or refractory (r/r)-AML.
SECONDARY/EXPLORATORY OBJECTIVES:
I. To further characterize adverse events including non-dose-limiting toxicity (DLT) events following CIML-NK cells with atezolizumab at the MTD.
II. To estimate the response rate (complete response [CR]/complete response with incomplete bone marrow recovery [CRi]).
III. To estimate overall survival and event-free survival.
IV. To estimate the duration of CIML-NK in vivo persistence.
V. To explore transcriptomic changes in CIML-NK cells after infusion with PD-L1 blockade.
OUTLINE: This is a dose-escalation study of CIML-NK cells followed by a dose-expansion study.
Patients receive fludarabine intravenously (IV) over 30 minutes on days -6 to -2 and cyclophosphamide IV over 30-45 minutes on days -5 and -4 in the absence of disease progression or unacceptable toxicity. Patients then receive atezolizumab IV over 60 minutes and CIML-NK cells IV over 5-30 minutes on day 0, as well as aldesleukin subcutaneously (SC) on day 0 prior to CIML-NK cells and on days 2, 4, 6, 8, and 10 in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow biopsy and aspiration during screening, echocardiography (ECHO) on study, and computed tomography (CT) or positron emission tomography (PET)/CT scans and blood sample collection throughout the study.
After completion of study treatment, patients are followed up on days 14, 21, 28, between days 29-45, on day 60, monthly for 6 months, and then every 2 months until 1 year after CIML-NK cells infusion.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationMemorial Sloan Kettering Cancer Center