CD123-Directed Autologous T-Cell Therapy for Acute Myelogenous Leukemia (CATCHAML)

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.

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

This study will evaluate the safety and maximum tolerated dose of CD123-CAR T cells.

This study contains 2 phases. The first part is the called the "Collection and Manufacturing Phase" and the second is the "Treatment Phase".

The Collection and Manufacturing Phase refers to your blood cells being collected and possibly frozen, via a process called apheresis. These cells will then be changed to improve their ability to recognize and kill cancer cells.

The Treatment Phase refers to the portion of the study in which you receive an infusion of the CD123-CAR T cells that were made in the Collection and Manufacturing Phase; chemotherapy is given for several days prior to the cellular infusion. You are then monitored for any possible side effects.

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Chemotherapy is given to get your body ready to accept the CATCHAML treatment.

Treatment Schedule:

Patients will receive lymphodepleting chemotherapy followed by infusion of CD123-CAR T cells

Fludarabine on day -4, -3 and -2

Cyclophosphamide on day -3 and -2

REST DAY on day -1

CD123-CAR T cell infusion on day 0 or +1

Eligibility Criteria:
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