Phase I/II study of anti-CD19 Chimeric Antigen Receptor-Expressing T cells in pediatric patients affected by relapsed/refractory CD19+ Acute Lymphoblastic Leukemia and Diffuse Large B Cell Lymphoma (DLBCL) or Primary Mediastinal B Cell Lymphoma (PML)
Overview
- Phase
- Phase 1/2
- Status
- Recruiting
- Sponsor
- Ospedale Pediatrico Bambino Gesu
- Enrollment
- 32
- Locations
- 1
- Primary Endpoint
- PHASE I The safety and tolerability of CD19-CAR_Lenti will be assessed by: - Suspected adverse events, and - Suspected serious adverse events As evidenced by clinically relevant: - Changes in clinical laboratory tests (clinical chemistry, hematology, etc). - Changes in vital signs (blood pressure, pulse, respiratory rate and body temperature). - Changes in physical examination. Signs and symptoms assessed may require additional testing as clinically indicated such as ECG, PFT, radiographic studi
Overview
Brief Summary
The primary objective of the phase I portion of the study is to evaluate the safety and to establish the recommended dose of CD19-CAR_Lenti infused in pediatric patients affected by relapsed/refractory B-ALL or aggressive B-NHL, starting from a minimum target dose of 1.0 x 106 cells/kilogram recipient total body weight, using the Miltenyi CliniMACS Prodigy® automated system. The primary objective of the phase II extension is to test the efficacy of the treatment at the optimal dose defined in the phase I, by determining BM morphological complete remission (CR) and minimal residual disease (MRD), at day 28, in patients with CD19-positive ALL. In patients with B-cell aggressive lymphoma, we will evaluate the Overall Response Rate (ORR), which includes Complete Remission (CR), CR with incomplete blood count recovery (CRi), Partial Response (PR) and Stable Disease (SD), at day 28, day 90 and 180 after CD19-CAR_Lenti infusion.
Eligibility Criteria
- Ages
- 0 years to 64 years (18-64 Years, 0-17 Years)
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •Procurement eligibility
- •Diagnosis of CD19 expressing B acute lymphoblastic leukemia (ALL) or diffuse large Bcell lymphoma (DLBCL) or primary mediastinal lymphoma (PML) and one of the following: a. Patients in 1st relapse, with High-Risk (HR) features including: MLLrearrangements, E2A/TCF3-PBX1 [t(1;19)], TCF3-HLF [t(17;19)], hypodiploidy (i.e., <44 chromosomes), TP53 alterations, early (i.e., <30 months from diagnosis)/very early (i.e., <18 months from diagnosis) isolated or combined bone marrow relapse b. MRD > 0.1% after either reinduction therapy or any course of consolidation for relapsed ALL c. Patients with DLBCL or PML in 1st or subsequent relapse, after at least one standard frontline chemotherapy
- •Age: 1 year – 25 years for BCP-ALL and 1-35 years for B-NHL.
- •Adequate venous access for apheresis or eligible for appropriate catheter placement, and no other contraindications for leukapheresis
- •Voluntary informed consent is given. For subjects < 18 year-old their legal guardian must give informed consent. Pediatric subjects will be included in age-appropriate discussion and verbal assent will be obtained for those greater than or equal to 12 years of age, when appropriate.
- •Clinical performance status: Patients > 16 years of age: Karnofsky greater than or equal to 60%; Patients < 16 years of age: Lansky scale greater than or equal to 60%. Treatment eligibility (i.e., eligibility to drug product infusion)
- •Diagnosis of CD19 expressing B-ALL or DLBCL or PML and one of the following: a. Patients in 1st relapse, with High-Risk (HR) features including: MLLrearrangements, E2A/TCF3-PBX1, TCF3-HLF [t(17;19)], hypodiploidy (i.e., <44 chromosomes), TP53 alterations, early (i.e., <30 months from diagnosis)/very early (i.e., <18 months from diagnosis) isolated or combined bone marrow relapse b. MRD > 0.1% after either reinduction therapy or any course of consolidation for relapsed c. Patients with DLBCL or PML in 1st or subsequent relapse, after at least one standard frontline chemotherapy
- •Age: 1 year – 25 years for Bcp-ALL and 1-35 years for B-NHL.
- •Voluntary informed consent is given. For subjects < 18 year-old their legal guardian must give informed consent. Pediatric subjects will be included in age-appropriate discussion and verbal assent will be obtained for those greater than or equal to 12 years of age, when appropriate.
- •Clinical performance status: Patients > 16 years of age: Karnofsky greater than or equal to 60%; Patients < 16 years of age: Lansky scale greater than or equal to 60%.
Exclusion Criteria
- •Procurement eligibility
- •Severe, uncontrolled active infections
- •HIV, or active HCV and/or HBV infection (detection of viral RNA/DNA in blood)
- •Previous allogeneic HSCT in the preceding 100 days before apheresis
- •Concurrent or recent prior therapies, before apheresis: a) Systemic steroids (at a dose equivalent to or greater 2 mg/kg prednisone) in the 2 weeks before apheresis collection. Recent or current use of inhaled/topical/nonabsorbable steroids is not exclusionary. b) Systemic chemotherapy in the 2 weeks preceding apheresis collection. c) Anti-thymocyte globulin (ATG) in the 4 weeks preceding apheresis collection. d) Immunosuppressive agents in the 2 weeks preceding apheresis collection. e) Radiation therapy must have been completed at least 1 week prior to apheresis. f) Other anti-neoplastic investigational agents currently administered or within 30 days prior to apheresis (i.e., start of protocol therapy); Treatment eligibility
- •Pregnant or lactating women
- •Severe, uncontrolled active infections
- •HIV, or active HCV and/or HBV infection (detection of viral RNA/DNA in blood)
- •Life-expectancy < 6 weeks
- •Hepatic function: Inadequate liver function defined as total bilirubin > 4x upper limit of normal (ULN) or transaminase (ALT and AST) > 6 x ULN
Outcomes
Primary Outcomes
PHASE I The safety and tolerability of CD19-CAR_Lenti will be assessed by: - Suspected adverse events, and - Suspected serious adverse events As evidenced by clinically relevant: - Changes in clinical laboratory tests (clinical chemistry, hematology, etc). - Changes in vital signs (blood pressure, pulse, respiratory rate and body temperature). - Changes in physical examination. Signs and symptoms assessed may require additional testing as clinically indicated such as ECG, PFT, radiographic studi
PHASE I The safety and tolerability of CD19-CAR_Lenti will be assessed by: - Suspected adverse events, and - Suspected serious adverse events As evidenced by clinically relevant: - Changes in clinical laboratory tests (clinical chemistry, hematology, etc). - Changes in vital signs (blood pressure, pulse, respiratory rate and body temperature). - Changes in physical examination. Signs and symptoms assessed may require additional testing as clinically indicated such as ECG, PFT, radiographic studi
Secondary Outcomes
- Secondary Endpoints phase I and II Relapse rate (RR), overall survival (OS), and disease-free survival (DFS) will be evaluated at 1 and 2 years. - The expansion and persistence of CD19-CAR_Lenti will be measured by flow cytometry and qPCR. - The T cell subpopulations of the CD19-CAR_Lenti cells before and after infusion and the exhaustion profile will be measured by flow cytometry - Disease outcome will be correlated with: a) use of either steroids and/or tocilizumab for CRS/Neurotoxicity; b) pr
Investigators
Locatelli Franco
Scientific
Ospedale Pediatrico Bambino Gesu