Phase I Clinical Trial of CD19 Chimeric Antigen Receptor (CAR) T Cells in Children and Adults With Relapsed or Refractory CD19 Positive B Cell Malignancies
Overview
- Phase
- Phase 1
- Intervention
- CD19 Chimeric Antigen Receptor (CAR) T Cells
- Conditions
- Relapsed/Refractory B-Cell Malignancies
- Sponsor
- National Taiwan University Hospital
- Enrollment
- 12
- Primary Endpoint
- 80% Proportion of products successfully manufactured meeting the established release criteria with a goal of at least CAR-T cell 1 X 10^6 cells/kilogram.
- Status
- Not yet recruiting
- Last Updated
- 4 years ago
Overview
Brief Summary
This study seeks to examine the feasibility and safety of the administration of autologous T cells that have been modified through the introduction of a chimeric antigen receptor targeting the B cell surface antigen CD19 following administration of chemotherapy lymphodepletion regimen in children and adults with relapsed/refractory B cell malignancies.
Detailed Description
The overall goal of this study is to validate the safety profile of administration CD19 CAR T cells and describe the toxicities in children and adults with relapsed/ refractory B cell malignancies. The dose is escalated in standard 3 +3 design with a starting dose of 1x106 cell/kilogram and maximum treatment dose of 5 x 106 cell/kilogram. The minimum number of 9 subjects would occur if no dose-limiting toxicities are observed in the 3 dose escalation cohorts. The maximum sample size of 18 subjects would be enrolled in 3 dose escalation cohorts (six in each cohort) for meeting dose-limiting toxicities request. In addition, we hypothesize that we will be able to successfully manufacture CAR T cells to meet the established release criteria at a minimum target dose of 1 X 106 +-30% cells/kilogram in this patient population using the Miltenyi CliniMACS Prodigy® closed transduction system.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Subjects must have the ability to understand and the willingness to sign a written informed consent document
- •Stated willingness to comply with all study procedures and availability for the duration of the study
- •Male or female, between the age of 1 and 65 years
- •In good general health as evidenced by medical history and diagnosed relapsed or refractory CD19+ B cell malignancies including acute lymphocytic leukemia (ALL), non-Hodgkin's lymphoma containing Diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), or small lymphocytic lymphoma (SLL), B-cell prolymphocytic leukemia(BPLL), Lymphoplasmacytic Lymphoma, Marginal Zone Lymphoma (MZL).
- •Definition of relapse or refractory as below:
- •Ineligible hematopoietic transplantation
- •Relapse after transplantation
- •Subject with ALL was evaluated by minimal residual disease \> 0.1% after treatment with at least two lines of therapy. Subjects with Philadelphia Chromosome positive acute lymphoblastic leukemia (Ph+ALL) treated by at least two lines of therapy, including tyrosine kinase inhibitors (TKIs) are eligible.
- •Subject with lymphoma treated regimens containing both anti-CD20 antibody and anthracycline-containing chemotherapy regiment. Subjects with transformed follicular lymphoma must have received prior chemotherapy for follicular lymphoma and subsequently have the chemo refractory disease after transformation to diffuse large B-cell lymphoma
- •The patient's disease must be CD19 positive, either by immunohistochemistry or flow cytometry analysis on the last biopsy available.
Exclusion Criteria
- •Current use of systemic steroids or chronic use of immunosuppressant medications. Recent or current use of inhaled steroids is not exclusionary.
- •Pregnancy or lactation
- •Known allergic reactions to components used in the intervention protocols or medication regimens in this study
- •Active Febrile illness
- •Treatment with another investigational drug or other intervention within 30 days or 5 half-lives.
- •Autologous transplant within 6weeks of planned CAR-T cell infusion.
- •Patients who are able to obtain market approved CD19 CAR T-cell therapies.
- •Active central nervous system or meningeal involvement by tumor. Subjects with untreated brain metastases/CNS disease will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients with a history of CNS or meningeal involvement must be in a documented remission by CSF evaluation and contrast-enhanced MRI imaging for at least 90 days prior to Enrollment.
- •History of active malignancy other than non-melanoma skin cancer, carcinoma in situ (e.g. cervix, bladder, breast).
- •Active HIV infection.
Arms & Interventions
CD19 Chimeric Antigen Receptor (CAR) T Cells
The dose is escalated in standard 3 +3 design with a starting dose of 1x10\^6 cell/kilogram and maximum treatment dose of 5 x 10\^6 cell/kilogram. The minimum number of 9 subjects would occur if no dose-limiting toxicities are observed in the 3 dose escalation cohorts. The maximum sample size of 18 subjects would be enrolled in 3 dose escalation cohorts (six in each cohort) for meeting dose-limiting toxicities request. In addition, we hypothesize that we will be able to successfully manufacture CAR T cells to meet the established release criteria at a minimum target dose of 1 X 106 +-30% cells/kilogram in this patient population using the Miltenyi CliniMACS Prodigy® closed transduction system.
Intervention: CD19 Chimeric Antigen Receptor (CAR) T Cells
Outcomes
Primary Outcomes
80% Proportion of products successfully manufactured meeting the established release criteria with a goal of at least CAR-T cell 1 X 10^6 cells/kilogram.
Time Frame: 3 years
To examine the feasibility of manufacture of autologous CD19 CAR T-cells at a minimum target dose of 1 X 106 cells/kilogram using the Miltenyi CliniMACS Prodigy® automated system
Incidence and severity of adverse events
Time Frame: 3 years
To determine the safety of infusion with chimeric antigen receptor T cells targeting CD19
Incidence and severity of Dose Limited Toxicities
Time Frame: 3 years
Find the recommended phase II dose (RP2D) for recurrent/refractory B cell malignancies
Incidence and severity of Maximum Toxicity Dose
Time Frame: 3 year
Find the recommended phase II dose (RP2D) for recurrent/refractory B cell malignancies