This is a first-in-human dose escalation/dose expansion study to evaluate the safety and identify the best dose of modified immune cells, PRGN-3006 (autologous chimeric antigen receptor (CAR) T cells), in adult patients with relapsed or refractory acute myeloid leukemia (AML), Minimal Residual Disease (MRD) positive acute myeloid leukemia or higher risk myelodysplastic syndrome (MDS). Autologous CAR T cells are modified immune cells that have been engineered in the laboratory to specifically target a protein found on tumor cells and kill them.

This is a multi-center, nonrandomized, Phase 1/1b safety and tolerability study. The safety and tolerability of PRGN-3006 T cells will be assessed following intravenous administration of escalating doses in patients with relapsed or refractory CD33-positive AML, MRD-positive AML, or higher risk MDS.

This study has completed the dose escalation phase and is further evaluating PRGN-3006 at the identified dose in the dose expansion phase.

Inclusion Criteria:

• Participants must be diagnosed with either relapsed or refractory AML (including extramedullary disease), MRD-positive AML, or higher risk MDS.
• Absolute lymphocyte count ≥ 0.2 k/μL.
• Karnofsky performance status score ≥60%.
• Life expectancy ≥ 12 weeks from the time of enrollment.
• Pretreatment calculated or measured creatinine clearance (absolute value) of ≥ 40 mL/minute or Cr < 2x upper limit of normal (ULN).
• Bilirubin ≤ 2.0 mg/dL or total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in participants with well documented Gilbert's syndrome or hemolysis or who require regular blood transfusions
• Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) < 3.0 x ULN.
• Ejection fraction measured by echocardiogram (ECHO) or multi gated acquisition scan (MUGA) > 45%.
• Participant does not require supplemental oxygen or mechanical ventilation AND has an oxygen saturation by pulse oximetry of ≥ 92% or higher on room air.
• Negative serum pregnancy test. Note: Women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for at least 1 year following study treatment (T cell infusion); should a woman participant or female partner of a male participant become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately.
• Participant has a matched bone marrow donor and is otherwise able to receive a bone marrow transplant (dose escalation phase only and for participants with MRD-positive AML)
• Participants who have undergone allo-SCT and/or donor lymphocyte infusion (DLI) are eligible if they are at least 3 months post SCT, prior to apheresis, atleast 30 days post last DLI prior to apheresis, have not received treatment or prophylaxis for GVHD 6 weeks before administration of CAR T cells, have no active GVHD.
• All participants must have the ability to understand and willingness to sign a written informed consent.

Exclusion Criteria:

• Diagnosis of acute promyelocytic leukemia (APL M3): t(15;17)(q22;q12); (promyelocytic leukemia [PML]/retinoic acid receptor [RAR] alpha [a]) and variants excluded.
• Participants with peripheral blood blasts >35%
• Known central nervous system (CNS) leukemic involvement that is refractory to intrathecal chemotherapy and/or cranio-spinal radiation; participants with a history of CNS disease that have been effectively treated to complete remission ( i.e. no blasts in cerebrospinal fluid [CSF] by cytology and flow cytometry) will be eligible.
• Prior treatment with investigational CD33 targeting CAR T therapy for any disease.
• Prior treatment with licensed or investigational CD33 targeting monoclonal antibody or antibody drug conjugate within 6 months of apheresis.
• Participants enrolled in another investigational therapy protocol for their disease within 14 days or 5 half-lives of apheresis, whichever is shorter.
• Ongoing uncontrolled serious infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, poorly controlled pulmonary disease or psychiatric illness/social situations that would limit compliance with study requirements.
• Human immunodeficiency virus (HIV) seropositivity, or active hepatitis B or C infection based on testing performed within 28 days of enrollment.
• Participants requiring agents other than hydroxyurea to control blast counts within 14 days of study enrollment.
• Participants with presence of other active malignancy within 1 year of study entry; participants with adequately resected basal or squamous cell carcinoma of the skin, or adequately resected carcinoma in situ (e.g. cervix) may enroll irrespective of the time of diagnosis.
• Pregnant and lactating women are excluded from this study
• History of allergic reactions attributed to compounds of similar chemical or biological composition to cetuximab (anti-EGFR).
• Active autoimmune disease requiring systemic immunosuppressive therapy (i.e. >10mg of prednisone daily or equivalent).
• Participant, who in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study.