Acute Myeloid Leukemia Clinical Trial
CD123-Directed Autologous T-Cell Therapy for Acute Myelogenous Leukemia (CATCHAML)
Summary
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 1.1.1 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
Full Description
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
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