Clinical Trials /

Lentivirally Redirected CD123 Autologous T Cells in AML

NCT03766126

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 Acute Myeloid Leukemia (AML) subjects.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Lentivirally Redirected CD123 Autologous T Cells in AML
  • Official Title: Phase I Study of Lentivirally Transduced T Cells Engineered to Contain Anti-CD123 Linked to TCRζ and 4-1BB Signaling Domains in Subjects With Refractory Acute Myeloid Leukemia

Clinical Trial IDs

  • ORG STUDY ID: 831619 (UPCC 35418)
  • NCT ID: NCT03766126

Conditions

  • Acute Myeloid Leukemia, in Relapse
  • Acute Myeloid Leukemia, Adult
  • 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 Acute Myeloid Leukemia (AML) subjects.

Detailed Description

      This is a phase 1 study to determine the safety, feasibility, and efficacy of CART123 cells
      following lymphodepleting chemotherapy in patients with relapsed/refractory AML. Subjects
      will be treated with IV administration of CART123 cells using a split dosing approach (10%
      Day 0, 30% Day 1; 60% Day 2).

      The total dose administered to each subject will be based on body weight obtained at the time
      of apheresis. Thus, the target total transduced dose is 1-2x106/kg CART-123 cells, preceded
      by lymphodepleting chemotherapy. The protocol-specified minimum acceptable dose for infusion
      is 1x105 CART cells/kg.

      It is recommended per routine clinical care, that all subjects with marrow aplasia at Day
      28+/-5 undergo 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 on study. All subjects
      should therefore have a previously identified stem cell donor in order to participate in this
      study. Please see Section 6.8 for additional details.

      All subjects will be followed monthly for up to 6 months post the first 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 or female subjects 18 years of age or older

          2. Subjects with active acute myeloid leukemia (AML) with no available curative treatment
             options using currently available therapies. Specifically:

               1. AML that has not achieved a complete remission or morphologic leukemia free state
                  by ELN criteria (Döhner et al., 2017 Blood, 129(4):424-447); partial remission or
                  refractory disease (including primary refractory) are eligible. Or:

               2. AML relapsed following allogeneic stem cell transplantation (including MDS
                  evolved to AML post-allogeneic stem cell transplantation). Note: morphologic
                  relapse is not required; persistent/recurrent disease-associated molecular,
                  phenotypic or cytogenetic abnormalities (measurable residual disease, MRD) at any
                  time after allogeneic HCT is eligible

          3. Subjects with relapsed disease after prior transplant must meet one of the following:

             a. Subjects with relapsed disease after prior allogeneic HCT (myeloablative or
             non-myeloablative) will be eligible if they meet all other inclusion criteria and i.
             Have no residual donor cells (by STR analysis on 2 occasions separated by at least 1
             month), OR: ii. Donor cells are present but there is no active GVHD (>Gr II), subject
             does not require systemic immunosuppression and is more than 3 months from transplant,
             and at least 1 month off GVHD prophylaxis.

             b. Subjects with relapsed disease after prior autologous or syngeneic HCT will be
             eligible if they meet all other inclusion criteria and it has been more than 3 months
             from transplant.

          4. 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.

          5. Satisfactory organ functions:

               1. Creatinine ≤ 1.6 mg/dl

               2. ALT/AST must be ≤5 x upper limit of normal unless related to disease

               3. Direct bilirubin or total bilirubin < 2.0mg/dl, unless subject has Gilbert's
                  syndrome (≤3.0 mg/dL);

               4. Left ventricular ejection fraction > 40% as confirmed by ECHO/MUGA

          6. ECOG Performance status 0-2.

          7. Written informed consent is given.

          8. No contraindications for leukapheresis.

          9. Subjects of reproductive potential must agree to use acceptable birth control methods
             (as described in protocol Section 4.3).

        Exclusion Criteria:

          1. Pregnant or lactating (nursing women) women.

          2. Patients with relapsed AML with t(15:17).

          3. HIV infection.

          4. Active hepatitis B or hepatitis C infection.

          5. Concurrent use of systemic steroids or immunosuppressant medications. Recent or
             current use of inhaled steroids or physiologic replacement with hydrocortisone is not
             exclusionary. For additional details regarding use of steroids while on study, please
             see Section 5.5.

          6. Any uncontrolled active medical disorder that would preclude participation as
             outlined.

          7. Subjects with signs or symptoms indicative of CNS involvement. A CNS evaluation should
             be performed as clinically appropriate to rule out CNS involvement.

          8. Known history of allergy or hypersensitivity to study product excipients (human serum
             albumin, DMSO, and Dextran 40).

          9. Class III/IV cardiovascular disability according to the New York Heart Association
             Classification (see Appendix 2).

         10. Patients with a known history or prior diagnosis of optic neuritis or other
             immunologic or inflammatory disease affecting the central nervous system, and
             unrelated to leukemia or previous leukemia treatment.

         11. Subjects with clinically apparent arrhythmia, or arrhythmias that are not stable on
             medical management, within 2 weeks of the Screening/Enrollment visit.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety profile of CART123 cells by monitoring the frequency and severity of adverse events assessed by the National Cancer Institute (NCI) - Common Toxicity Criteria (v5.0)
Time Frame:5 years
Safety Issue:
Description:Assess the safety of CART123 cells in AML subjects following lymphodepletion with cyclophosphamide + fludarabine.

Secondary Outcome Measures

Measure:Estimation of CART123 efficacy by evaluation of OS and PFS of subjects at protocol defined intervals which receive at least one infusion of CART123 cells
Time Frame:15 years
Safety Issue:
Description:Estimate the efficacy of at least 1 dose of CART123 cells in AML subjects
Measure:Overall Survival (OS) as percent of subjects surviving at protocol defined time points.
Time Frame:15 years
Safety Issue:
Description:Overall survival (OS) and progression-free survival (PFS)
Measure:Progression-free survival (PFS) as percent of subjects surviving without disease progression at protocol defined time points
Time Frame:15 years
Safety Issue:
Description:
Measure:Duration of response (DOR)
Time Frame:15 years
Safety Issue:
Description:Duration of response (DOR)
Measure:Necessity of rescue bone marrow transplant
Time Frame:15 years
Safety Issue:
Description:Need for rescue allogeneic hematopoietic cell transplantation (alloHCT)

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Pennsylvania

Trial Keywords

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

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