A Phase 1/1b Safety Study of PRGN-3006 Adoptive Cellular Therapy in Patients with Relapsed or Refractory CD33-Positive Acute Myeloid Leukemia and Higher Risk Myelodysplastic Syndrome
This is a first-in-human dose escalation/dose expansion study to evaluate the safety and identify the best dose (or recommended Phase 2 dose) of modified immune cells, PRGN-3006 (autologous chimeric antigen receptor (CAR) T cells), in adult patients with relapsed or recurred acute myeloid leukemia (AML), high-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.
To identify and evaluate the safety and MTD of PRGN-3006 T cells in patients with relapsed or refractory AML or higher risk MDS.
Participants must be diagnosed with either relapsed or refractory CD33+ AML or higher risk MDS;CD33 positivity must be confirmed by either flow cytometry or immunohistochemistry as per institutional guidelines.
Absolute lymphocyte count >0.2 k/ul
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> Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) > 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 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 part only)
Participants who have undergone allo-SCT are eligible if they are at least 3 months post SCT, have relapsed AML/MDS as defined above, are not on treatment or prophylaxis for GVHD for at least 6 weeks before administration of CAR T cells, and have no active GVHD.
All participants must have the ability to understand and willingness to sign a written informed consent.
Diagnosis of acute promyelocytic leukemia (APL M3): t(15;17)(q22;q12); (promyelocytic leukemia [PML]/retinoic acid receptor [RAR] alpha [a]) and variants excluded.
Patients with peripheral blood blasts >35% are excluded
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 CAR T therapy for any disease.
Participants enrolled in another investigational therapy protocol for their disease within 14 days or 5 half-lives of enrollment, 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 (positive HBsAg test) or hepatitis C (positive HCV RT-PCR 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.
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