Phase 1 Study of Lentivirally Transduced T Cells Engineered to Contain Anti-CD123 Linked to TCRζ and 4-1BB Signaling Domains in Pediatric Subjects With Refractory or Relapsed Acute Myeloid Leukemia

Description

Phase 1 open-label study to evaluate the safety of intravenously administered, lentivirally transduced T cells expressing anti-CD123 chimeric antigen receptors expressing tandem TCRζ and 4-1BB (TCRζ /4-1BB) costimulatory domains in pediatric subjects with relapsed/refractory Acute Myeloid Leukemia (AML).This is a Phase 1 study designed to evaluate the safety, feasibility, and preliminary efficacy of CART123 cells in pediatric subjects with relapsed/refractory Acute Myeloid Leukemia (AML). The study was originally designed to evaluate these primary endpoints at a single CART123 dose level (2x106 CART123 cells/kg). This dose level was selected based on experience in an adult trial using this investigational product in relapsed/refractory AML patients (NCT03766126). As of Protocol Amendment V6, the study design has been converted into a 3+3 dose escalation design in order to further explore the safety of CART123 cells in the target disease population, and determine a maximum tolerated do

Trial Eligibility

Inclusion Criteria: 1. Male and female patients ≥ 1 and ≤ 29 years of age at time of consent. 2. AML in second or greater relapse, post-transplant relapse, or chemotherapy-refractory disease. Specifically: 1. Second or greater relapse defined as flow cytometric confirmation of myeloid leukemia of at least 0.1% after second documented complete remission; OR 2. Any detectable disease post-allogeneic transplant with flow cytometric confirmation (MRD) of myeloid leukemia of at least 0.1% (as confirmed by Hematologics); OR 3. Refractory disease, defined as persistent bone marrow involvement with \>5% blasts after two courses of induction chemotherapy for patients at initial presentation or \>5% bone marrow blasts after one course of re-induction chemotherapy for patients who have relapsed after previously achieving a CR. 3. Subjects must have a suitable stem cell donor identified with projected ability to proceed to transplant within 6-8 weeks of CART123 infusion. 4. Adequate organ function defined as: 1. A serum creatinine based on age/gender 2. Adequate liver function i. ALT ≤ 5 x ULN ii. Total bilirubin ≤ 3 x ULN iii. ALT and/or bilirubin results that exceed this range are acceptable if, in the opinion of the physician-investigator (or as confirmed by liver biopsy), the abnormalities are directly related to AML infiltration of the liver. c. Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and \< Grade 3 hypoxia; DLCO ≥ 40% (corrected for anemia) if PFTs are clinically appropriate as determined by the treating investigator d. Left Ventricular Shortening Fraction (LVSF) ≥ 28% or Ejection Fraction (LVEF) ≥ 45% confirmed by ECHO, or adequate ventricular function documented by a scan or a cardiologist. In cases where quantitative assessment of LVSF/LVEF is not possible, a statement by the cardiologist that the ECHO shows qualitatively normal ventricular function will suffice. 5. Adequate performance status defined as Lansky or Karnofsky score ≥ 50 6. Signed informed consent must be obtained. 7. No contraindications for leukapheresis (unless apheresis product previously acquired). 8. Subjects of reproductive potential must agree to use acceptable birth control methods. Exclusion Criteria: 1. Pregnant or lactating (nursing) women. 2. Patients with relapsed AML with t(15:17). 3. Patients \< 6 months from alloHSCT. 4. HIV infection. 5. Active hepatitis B or hepatitis C infection. 6. Active acute or chronic graft-versus-host disease (GVHD) requiring systemic therapy 7. Patients requiring chronic treatment with systemic steroids or immunosuppressant medications. Low-dose physiologic replacement therapy with corticosteroids, topical steroids and inhaled steroids are acceptable. For additional details regarding use of steroids and immunosuppressant medications (including washout requirements prior to CAR T cell administration). 8. Any uncontrolled active medical disorder that would preclude participation as outlined. 9. Uncontrolled active infection 10. Subjects with CNS3 disease that is progressive on therapy or with CNS parenchymal lesions that may increase the risk of CNS toxicity. Subjects with adequately treated CNS leukemia are eligible. 11. Known history of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40). 12. Patients with any prior history of myeloproliferative neoplasm. 13. Patients with somatic JAK2 V617F mutation by PCR or next generation sequencing.

Study Info

Interventions

Locations Recruiting

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