Clinical Trials /

CD123 Redirected T Cells for AML in Pediatric Subjects

NCT04678336

Description:

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).

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: CD123 Redirected T Cells for AML in Pediatric Subjects
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: 834675 (19CT011)
  • NCT ID: NCT04678336

Conditions

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

Interventions

DrugSynonymsArms
CART123 cells; cyclophosphamide; fludarabineT Cells Containing Anti-CD123 Signaling DomainsTreatment Arm

Purpose

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

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment ArmExperimentalCART123 cells; cyclophosphamide; fludarabine
  • CART123 cells; cyclophosphamide; fludarabine

Eligibility Criteria

        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%; 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 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.

          4. 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.

          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 must be > 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. 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.

          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.
      
Maximum Eligible Age:29 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety of CART123 in AML subjects
Time Frame:5 Years
Safety Issue:
Description:Occurrence of adverse events that are possibly, probably, or definitely related to CART123 cells

Secondary Outcome Measures

Measure:Efficacy of CART123 cells in AML subjects evaluated by ORR at Day 28 using standard clinical criteria
Time Frame:15 Years
Safety Issue:
Description: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
Measure: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
Time Frame:15 Years
Safety Issue:
Description:Reduction 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
Measure:Overall survival (OS) and progression-free survival (PFS)
Time Frame:15 Years
Safety Issue:
Description:Overall survival (OS) and progression-free survival (PFS) and cause(s) of death for all subjects a. PFS will be followed until the time of first relapse or receipt of additional therapy, excluding alloHCT for marrow aplasia.
Measure:Duration of response (DOR)
Time Frame:15 Years
Safety Issue:
Description:Time between date of when the response criteria of CR/CRi was met to the date of relapse
Measure:Need for rescue alloHCT
Time Frame:15 Years
Safety Issue:
Description:Percentage of subjects proceeding to alloHCT (or second allogeneic HCT)

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of Pennsylvania

Trial Keywords

  • refractory
  • relapsed
  • Acute
  • Myeloid
  • leukemia
  • AML

Last Updated

December 21, 2020