Pilot Study of RNA-Redirected Autologous T Cells Engineered to Contain Anti-CD123 Linked to TCR and 4-1BB Signaling Domains in Patients With Refractory or Relapsed Acute Myeloid Leukemia
Overview
- Phase
- Early Phase 1
- Intervention
- Autologous Anti-CD 123 CAR TCR/4-1BB-expressing T-lymphocytes
- Conditions
- Relapsed or Refractory Acute Myeloid Leukemia
- Sponsor
- University of Pennsylvania
- Enrollment
- 7
- Locations
- 1
- Primary Endpoint
- Number of Adverse Events
- Status
- Terminated
- Last Updated
- 8 years ago
Overview
Brief Summary
Pilot open-label study to estimate the feasibility, safety and efficacy of intravenously administered, RNA electroporated autologous T cells expressing anti-CD123 chimeric antigen receptors expressing tandem TCR and 4-1BB (TCR /4-1BB) costimulatory domains (referred to as RNA CART123) in Acute Myeloid Leukemia (AML) subjects.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Male or female subjects 18 years of age or older with AML with no available curative treatment options using currently available therapies
- •Subjects must have a suitable stem cell donor available who may donate cells if the subject needs to undergo allogeneic HCT. Donor may be matched or mismatched and must be found to be suitable according to the institution's standard criteria.
- •Subjects with second or subsequent relapse, any relapse refractory to salvage, or with persistent disease after at least two lines of therapy.
- •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 experienced graft rejection (no evidence of 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, subject does not require immunosuppression and is more than 6 months from transplant
- •Subjects must have evaluable disease defined as \>5% blasts on marrow aspirate or biopsy, extramedullary disease (CNS involvement is prohibited), or at least 20% blasts in the peripheral blood within 2 weeks prior to enrollment. Note: subjects with second or subsequent relapse are considered to have evaluable disease even without meeting the above morphologic criteria if they are found to have persistent recurrent disease-associated molecular or cytogenetic abnormalities.
- •Creatinine \< 1.6 mg/dl
- •ALT/AST must be \< 5 x upper limit of normal unless related to disease
- •Bilirubin \< 2.0 mg/dl, unless subject has Gilbert's syndrome (≤3.0 mg/dL);
- •ECOG Performance status 0-
- •Left ventricular ejection fraction \> 40% as confirmed by ECHO/MUGA
Exclusion Criteria
- Not provided
Arms & Interventions
Cohort 1
The first 3 subjects to receive RNA CART123 cells will receive up to 3 doses of RNA CART123 cells, with no lymphodepleting chemotherapy prior to infusion.
Intervention: Autologous Anti-CD 123 CAR TCR/4-1BB-expressing T-lymphocytes
Cohort 2
The remaining 12 subjects of the study will receive up to six IV doses of RNA CART123 cells. Subjects in Cohort 2 may be given lymphodepleting chemotherapy 4 days (+/- 1 day) prior to the first CART123 cell infusion (if ALC\> 500/uL). Lymphodepleting chemotherapy may be repeated before the fourth dose of RNA CART123 cells (if ALC\> 500/uL). Lymphodepleting chemotherapy includes a single dose of cyclophosphamide (1g/m2) Weight used for dosing will be the weight obtained prior to the apheresis procedure Cell numbers are based on CAR+ cells with CAR expression determined by flow cytometry Based on the product release criteria, at least 20% of the total cells will be RNA CART123 cells. Dosing will not be changed for changes in subject weight The indicated doses are +/- 20% to account for manufacturing variability.
Intervention: Autologous Anti-CD 123 CAR TCR/4-1BB-expressing T-lymphocytes
Cohort 2
The remaining 12 subjects of the study will receive up to six IV doses of RNA CART123 cells. Subjects in Cohort 2 may be given lymphodepleting chemotherapy 4 days (+/- 1 day) prior to the first CART123 cell infusion (if ALC\> 500/uL). Lymphodepleting chemotherapy may be repeated before the fourth dose of RNA CART123 cells (if ALC\> 500/uL). Lymphodepleting chemotherapy includes a single dose of cyclophosphamide (1g/m2) Weight used for dosing will be the weight obtained prior to the apheresis procedure Cell numbers are based on CAR+ cells with CAR expression determined by flow cytometry Based on the product release criteria, at least 20% of the total cells will be RNA CART123 cells. Dosing will not be changed for changes in subject weight The indicated doses are +/- 20% to account for manufacturing variability.
Intervention: Cyclophosphamide
Outcomes
Primary Outcomes
Number of Adverse Events
Time Frame: 2 years