CD123 Redirected T Cells for AML in Pediatric Subjects

Study Overview
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Brief Summary
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Phase 1 open-label study to estimate the safety, manufacturing feasibility, and efficacy 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).

Detailed Description
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This is a Phase 1 study to determine the safety, manufacturing feasibility, and efficacy of CART123 cells following lymphodepleting chemotherapy in pediatric subjects with relapsed/refractory AML. Subjects will receive CART123 cells via a single IV infusion at a dose of 2x10^6 CART123 cells/kg, following lymphodepleting chemotherapy. The total dose administered to each subject will be based on the subject's body weight obtained at the time of apheresis. The minimum acceptable dose for infusion is 1x10^5 CART123 cells/kg. There will be a 28-day stagger between the first 3 subject infusions, such that the next subject may not receive treatment (lymphodepleting chemotherapy plus CART123 cells) until the previous subject has completed their Day 28 safety follow-up visit and a DLT assessment has been performed. Subsequent infusions will be staggered by a minimum of 14 days. It is recommended that subjects with marrow aplasia at Day 28+/-5 undergo an allogeneic hematopoietic cell transplantation (alloHCT) as a rescue strategy. If required, this procedure will be performed as part of routine care, outside of the scope of this research study; however, subjects will continue to be followed onstudy. All subjects must, therefore, have a previously identified stem cell donor as part of their eligibility to participate in this study. All subjects will be followed monthly for up to 6 months after the CART123 cell infusion (Day 0). Thereafter, subjects will be transitioned into LTFU for up to 15 years post infusion.

Official Title
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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

Conditions
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Acute Myeloid Leukemia, in Relapse, Acute Myeloid Leukemia, Pediatric, Acute Myeloid Leukemia, Refractory

Intervention / Treatment
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* Biological: CART123 cells; cyclophosphamide; fludarabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients ≥ 1 and ≤ 29 years of age at time of consent. AML in second or greater relapse, post-transplant relapse, or chemotherapy-refractory disease. Specifically: Second or greater relapse defined as flow cytometric confirmation of myeloid leukemia of at least 0.1% after second documented complete remission; OR Any detectable disease post-allogeneic transplant with flow cytometric confirmation (MRD) of myeloid leukemia of at least 0.1%; OR 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. Subjects must have a suitable stem cell donor available who may donate cells in the event the subject needs to undergo an allogeneic HCT. Donor may be matched or mismatched and must be found to be suitable according to the institution's standard criteria; donors must be fully cleared to proceed as the donor. Adequate organ function defined as: a. A serum creatinine based on age/gender b. 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 ALL 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. Adequate performance status defined as Lansky or Karnofsky score ≥ 50 Signed informed consent must be obtained. No contraindications for leukapheresis (unless apheresis product previously acquired). Subjects of reproductive potential must agree to use acceptable birth control methods. Exclusion Criteria: Pregnant or lactating (nursing) women. Patients with relapsed AML with t(15:17). Patients must be > 6 months from alloHSCT. HIV infection. Active hepatitis B or hepatitis C infection. Active acute or chronic graft-versus-host disease (GVHD) requiring systemic therapy Concurrent use of systemic steroids at the time of cell infusion or cell collection or a condition, in the treating physician's opinion, that is likely to require steroid therapy during collection or after infusion. Steroids for disease treatment at times other than cell collection or at the time of infusion are permitted. Use of physiologic replacement hydrocortisone or inhaled steroids is permitted as well. Any uncontrolled active medical disorder that would preclude participation as outlined. Uncontrolled active infection 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. Known history of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40). Patients with any prior history of myeloproliferative neoplasm. Patients with somatic JAK2 V617F mutation by PCR or next generation sequencing.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 29 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm<br>CART123 cells; cyclophosphamide; fludarabine | Biological: CART123 cells; cyclophosphamide; fludarabine<br>* CART123 cells following lymphodepleting chemotherapy in pediatric patients with relapsed/refractory AML. Subjects will be treated with a single IV dose of CART123 cells on Day 0.<br>* Other names: T Cells Containing Anti-CD123 Signaling Domains;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of CART123 in AML subjects | Occurrence of adverse events that are possibly, probably, or definitely related to CART123 cells | 5 Years | 
| Manufacturing feasibility | Percentage of manufacturing products that meet release criteria | 5 Years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of CART123 cells in AML subjects evaluated by ORR at Day 28 using standard clinical criteria | Overall Response Rate (ORR) at 28 +/- 5 days Standard morphologic complete response criteria (malignant blasts < 5% with count recovery) Malignant blasts < 5% without count recovery, and Minimal residual disease assessment | 15 Years | 
| Efficacy of CART123 cells in AML subjects evaluated by reduction of blast count in the peripheral blood and marrow using standard clinical criteria and flow cytometry | Change of blast count in the peripheral blood and marrow using standard clinical criteria (CBC with differential count, marrow aspirate with differential count) and flow cytometry | 15 Years | 
| Overall survival (OS) | Overall survival (OS) for all subjects | 15 Years | 
| Progression-Free Survival (PFS) | Progression-free survival (PFS) for all subjects; PFS will be followed until the time of first relapse or receipt of additional therapy, excluding alloHCT for marrow aplasia. | 15 Years | 
| Duration of response (DOR) | Time between date of when the response criteria of CR/CRi was met to the date of relapse | 15 Years | 
| Need for rescue alloHCT | Percentage of subjects proceeding to alloHCT (or second allogeneic HCT) | 15 Years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, refractory, relapsed, Acute, Myeloid, leukemia