Overview

The CD123-CAR T-cell therapy is a new treatment that is being investigated for treatment of AML/myelodysplastic syndrome (MDS), T- or B- acute lymphoblastic leukemia (ALL) or blastic plasmacytoid dendritic cell neoplasia (BPDCN). The purpose of this study is to find the maximum (highest) dose of CD123-CAR T cells that is safe to give to these patients. This would include studying the side effects of the chemotherapy, as well as the CD123-CAR T-cell product on the recipient's body, disease and overall survival.

Primary Objective:

• To determine the safety of one intravenous infusion of escalating doses of autologous, CD123-CAR T cells in patients (≤21 years) with recurrent/refractory CD123+ disease (AML/MDS, B-ALL, T-ALL or BPDCN) after lymphodepleting chemotherapy.
• To determine the safety of an intravenous infusion of escalating doses of donor derived, CD123-CAR T cells in patients (≤21 years) with recurrent/refractory CD123+ disease (AML/MDS, B-ALL, T-ALL, BPDCN or MPAL) after lymphodepleting chemotherapy.

Secondary Objectives

• To evaluate the antileukemia activity of CD123-CAR T cells.

Exploratory Objectives

• To assess the immunophenotype, clonal structure and endogenous repertoire of CD123-CAR T cells and unmodified T cells
• To characterize the cytokine profile in the peripheral blood and CSF after treatment with CD123-CAR T cells
• To characterize tumor cells post CD123-CAR T-cell therapy
• To compare in vivo properties of donor-derived versus autologous CD123- CAR T cells

Eligibility

Inclusion Criteria for Procurement and T-cell Production:

• Age ≤21 years old
• Relapsed/refractory CD123+ disease defined as follows:

AML/MDS

• Relapsed disease: Patients developing recurrent disease after a first complete remission (CR)
• Refractory disease: Patients not achieving a CR after 2 cycles of induction chemotherapy

B-cell ALL

• Relapsed disease that is CD123 positive and CD19 negative/dim or patients otherwise ineligible for CD19 directed therapies including
  • Patients in 2nd or greater relapse
  • Patients with relapse after allogeneic HSCT
• Refractory disease that is CD123 positive and CD19 negative/dim or patients

  otherwise ineligible for CD19 directed therapies

T-cell All • Relapsed refractory disease that is CD123 positive

BPDCN

• Relapsed/refractory disease that has failed front-line therapy

• Estimated life expectancy of >12 weeks
• Karnofsky or Lansky (age-dependent) performance score ≥50
• Patients with a history of prior allogeneic HCT must be clinically recovered from prior HCT therapy, have no evidence of active GVHD and have not received a donor lymphocyte infusion (DLI) within the 28 days prior to apheresis
• Patient must have an identified, suitable HCT donor
• For females of child-bearing age:
• Not lactating with intent to breastfeed
• Not pregnant with negative serum pregnancy test within 7 days prior to enrollment
• Meets eligibility criteria to undergo autologous apheresis, or have previously undergone autologous apheresis

Exclusion Criteria:

• Known primary immunodeficiency
• History of HIV infection
• Severe intercurrent uncontrolled bacterial, viral or fungal infection (e.g. active hepatitis B or C infection or adenovirus infection)
• History of hypersensitivity reactions to murine protein-containing products
• Patients with acute promyelocytic leukemia (APL, t (15;17))
• Known contraindication to the protocol defined lymphodepleting chemotherapy regimen of fludarabine/cyclophosphamide.

Inclusion Criteria for Treatment:

• Age≤21 years old
• Detectable disease that is CD123+ (at least MRD+ disease)
• Estimated life expectancy of >8 weeks
• Karnofsky or Lansky (age-dependent) performance score≥50
• Patients with a history of prior allogeneic HCT must be clinically recovered from prior HCT therapy, have no evidence of active GVHD and have not received a donor lymphocyte infusion (DLI) within the 28 days prior to planned infusion
• Patient must have an identified, suitable HCT donor
• Adequate cardiac function defined as left ventricular ejection fraction >40%, OR shortening fraction ≥25%
• EKG without evidence of clinically significant arrhythmia
• Adequate renal function defined as creatinine clearance or radioisotope GFR ≥50 ml/min/1.73m2 (GFR ≥40 ml/min/1.73m2 if < 2 years of age)
• Adequate pulmonary function defined as forced vital capacity (FVC)≥50% of predicted value; or pulse oximetry≥92% on room air if patient is unable to perform pulmonary function testing
• Total Bilirubin≤3 times the upper limit of normal for age, except in subjects with Gilbert's syndrome
• Alanine aminotransferase (ALT) OR aspartate aminotransferase (AST) ≤5 times the upper limit of normal for age
• Has recovered from all NCI CTAE grade III-IV, non-hematologic acute toxicities from prior therapy
• For females of child-bearing age
  • Not lactating with intent to breastfeed
  • Not pregnant with negative serum pregnancy test within 7 days prior to enrollment
• If sexually active, agreement to use birth control until 3 months after T- cell

  infusion. Male partners should use a condom.

• Available autologous transduced T-cell product that has met GMP release criteria

Exclusion Criteria:

• Known primary immunodeficiency
• History of HIV infection
• Severe intercurrent uncontrolled bacterial, viral or fungal infection
• History of hypersensitivity reactions to murine protein-containing products
• History of severe hypersensitivity reactions to cornstarch or hydroxyethyl starch.
• Receiving systemic steroids therapy exceeding the equivalent of 0.5 mg/kg/day of methylprednisolone, in the 7 days prior to CD123-CAR T- cell infusion
• Receiving systemic therapy in the 14 days prior to CD123-CAR T-cell infusion, which will interfere with the activity of the CD123-CAR T cells in vivo (in the opinion of the study PI(s))
• Receiving rituximab therapy in the 30 days prior to CD123-CAR T cell infusion. (This exclusion criterion is intended to prevent premature exposure of CD123-CAR T cells to rituximab, which would activate the safety switch and promote CAR T-cell apoptosis).
• Receiving intrathecal chemotherapy in the 7 days prior to CD123-CAR T cell infusion.
• Known contraindication to the protocol defined lymphodepleting chemotherapy regimen of fludarabine/cyclophosphamide.
• Active CNS disease