This phase I/II trial tests the safety, side effects and best dose of universal donor CD33 chimeric antigen receptor (CAR)-natural killer (NK) cells in combination with fludarabine, cytarabine and venetoclax and how well the combination works in treating patients with acute myeloid leukemia that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). CAR therapy is a type of treatment in which a patient's T cells or B cells (immune cells) are changed in the laboratory so they will attack cancer cells. NK cells are immune cells that can recognize and kill cancer cells. CD33 CAR-NK cells are genetically changed to have a CAR that recognizes and binds to the protein, CD33, on cancer cells and signals the NK cell to attack. Fludarabine blocks cells from making deoxyribonucleic acid (DNA) and may kill cancer cells. It is a type of purine antagonist and a type of ribonucleotide reductase inhibitor. Cytarabine blocks cancer growth by stopping DNA synthesis. It is a type of antimetabolite. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving universal donor CD33 CAR-NK cells in combination with fludarabine, cytarabine and venetoclax may be safe, tolerable and/or effective in treating patients with relapsed or refractory acute myeloid leukemia.
Additional locations may be listed on ClinicalTrials.gov for NCT07026942.
Locations matching your search criteria
United States
Ohio
Columbus
Nationwide Children's HospitalStatus: Approved
Contact: Margaret Lamb
Phone: 614-722-3610
PRIMARY OBJECTIVES:
I. To determine the safety and recommended phase II dose (RP2D) of allogeneic anti-CD33 CAR NK cells (CD33 CAR-NK cells) in patients with relapsed/refractory acute myeloid leukemia (AML). (Phase I)
II. To estimate the efficacy of CD33 CAR-NK cells delivered at the RP2D with fludarabine, cytarabine and venetoclax (FLA-VEN) chemotherapy in patients with relapsed/refractory AML. (Phase II)
SECONDARY OBJECTIVES:
I. To estimate the overall survival, event free survival and duration of remission.
II. To determine the depth of remission by flow minimal residual disease (MRD) or molecular remission (for those with an identified molecular marker) by day +35.
III. To determine the percentage of patients receiving this regimen who are rendered transplant-eligible.
IV. To evaluate the median time to neutrophil and platelet count recovery.
V. To determine the incidence and severity of adverse events of special interest including infection, cytokine release syndrome (CRS), hepatic veno-occlusive disease (VOD), immune effector cell related neurologic toxicity (ICANS), hemophagocytic lymphohistiocytosis (HLH).
EXPLORATORY OBJECTIVES:
I. To determine the immunophenotype and function of the CD33 CAR-NK cell product compared to post infusion, against standard AML targets and patient samples where feasible.
II. To characterize in vivo expansion and persistence of CD33 CAR-NK cells.
III. To determine the rate of alloimmunization against the CD33 CAR-NK cell product.
IV. To evaluate mechanisms of relapse by comparing relapse AML with baseline pre-treatment AML.
V. To measure changes in serum concentration of cytokines, and immune phenotype at baseline and after CD33 CAR-NK cell infusion.
VI. To quantify CD33 expression and site density on AML blasts and normal myeloid cells and correlate with NK cell expansion, persistence, and clinical response.
OUTLINE: This is a phase I dose-escalation study of CD33 CAR-NK cells followed by a phase II dose-expansion study.
Patients receive fludarabine intravenously (IV) over 30 minutes on days 1-5, cytarabine IV over 4 hours on days 1-5, venetoclax orally (PO) once daily (QD) on days 1-21 and CD33 CAR NK cell IV on day 7 or on days 7 and 14. Patients also undergo echocardiography at screening and blood sample collection and bone marrow aspiration and biopsy throughout the study. Additionally, patients may also undergo lumbar puncture and positron emission tomography (PET)/computed tomography (CT) throughout the study.
After completion of study treatment, patients are followed up at days 28, 35, 42, and 56 then at 3, 6, and 12 months. Patients are followed long term for up to 15 years for monitoring for potential gene therapy-related delayed adverse events.
Lead OrganizationNationwide Children's Hospital
Principal InvestigatorMargaret Lamb