Phase 1, Open Label, Dose Escalation Study to Evaluate the Safety, Expansion, Persistence, and Preliminary Clinical Activity of Autologous CD64 CAR T Cells in Patients With Relapsed and/or Refractory Acute Myeloid Leukemia (AML)
This is a Phase 1, open label, dose-escalation study to evaluate the safety, expansion, persistence, and preliminary clinical activity of lentivirally transduced autologous T cells expressing anti-CD64 chimeric antigen receptors (CAR) expressing tandem CD3ζ and 4-1BB (CD3ζ/4-1BB) costimulatory domains in subjects with refractory or relapsed (R/R) acute myeloid leukemia (AML). This CAR T cell product will be referred to as CD64 CAR T which is CD64 directed, autologous, genetically modified CAR T cells. The primary objective of the study is to identify the safety profile and maximum tolerated dose (MTD) of CD64 CAR T in subjects with R/R AML as determined by the defined DLTs using a standard Bayesian Optimal Interval (BOIN) design.
• ≥ 18 years of age.
• Subjects must have one of the following diagnoses per the International Consensus Classification (ICC) 2022 criteria:
• a. Acute Myeloid Leukemia (AML).
• Refractory OR relapsed AML:
• a. Refractory disease i. ≥5% blasts in the bone marrow or peripheral blood by morphology, flow cytometry, or immunohistochemistry after a minimum of 1 cycle of a hypomethylating agent (HMA) and venetoclax (Ven) combination (Ven/HMA) b. Relapsed disease i. Recurrence of ≥ 5% blasts in the bone marrow or peripheral blood by morphology, flow cytometry or immunohistochemistry.
• Subjects must have received at least one prior line of therapy, including at least one line of therapy containing Ven.
• Documentation of CD64 expression on ≥70% of myeloid blasts by flow cytometry after the most recent relapse, as determined by standardized and validated multiparameter flow cytometry assay (Hematologics, Inc., Seattle, WA).
• Total white blood cell (WBC) count ≤ 25 x 10(to the 9th)/L prior to apheresis. Hydroxyurea is permitted to achieve this
• Absolute lymphocyte count (ALC) ≥ 200/µL prior to apheresis OR ALC \< 200 µL with concurrent lymphocyte subset analysis (CD3, CD4, and CD8 counts) confirming an absolute CD3 count ≥ 150/µL.
• Confirmed availability of cells for a rescue stem cell transplant AND subject must be deemed an appropriate candidate for such therapy per institutional standards.
• Subjects who have undergone prior allogeneic stem cell transplant must be ≥ 6 months out from transplant and be off systemic immunosuppression for at least 1 month at the time of enrollment with no evidence of active graft versus host disease.
⁃ Adequate organ function, defined as:
∙ Creatinine clearance ≥ 30 mL/min, based on the CKD-EPI Creatinine Equation (2021).
‣ AST/ALT ≤ 5x upper limit of the normal range, unless considered to be due to leukemic involvement.
‣ Bilirubin ≤ 3x upper limit of the normal range, unless the subject has Gilbert's Syndrome or considered to be due to leukemic involvement.
‣ Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygen \> 92% on room air, unless considered to be due to leukemic involvement.
‣ Left Ventricle Ejection Fraction (LVEF) ≥ 40% confirmed by ECHO/MUGA.
⁃ ECOG performance status 0, 1, or 2.
⁃ Signed informed consent form.
⁃ Subjects of reproductive potential must agree to use acceptable birth control methods, as described in the protocol main text.
⁃ Willing to participate in the long-term follow-up protocol that is required if CAR T cell therapy is administered.