relapsed/refractory CD19+ Acute Lymphoblastic Leukemia and Diffuse Large B Cell Lymphoma or Primary Mediastinal B Cell Lymphoma MedDRA version: 20.0 Level: SOC Classification code 10005329 Term: Blood and lymphatic system disorders System Organ Class: 10005329 - Blood and lymphatic system disorders
Conditions
Interventions
Product Name: Ciclofosfamide monoidrata
Product Code: [N.A.]
Pharmaceutical Form: Powder and solvent for solution for infusion
INN or Proposed INN: N,N-Bis(2-chloroethyl)tetrahydro-2H-1 ,3,2-oxazaphos
Sponsors
IRCCS, OSPEDALE PEDIATRICO BAMBINO GESÙ DI ROMA
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Procurement eligibility 1. Diagnosis of CD19 expressing B acute lymphoblastic leukemia (ALL) or diffuse large B-cell lymphoma (DLBCL) or primary mediastinal lymphoma (PML) and one of the following: a. Patients in 1st relapse, with High-Risk (HR) features including: MLL-rearrangements, E2A/TCF3-PBX1 [t(1;19)], TCF3-HLF [t(17;19)], hypodiploidy (i.e., 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 2. Age: 1 year – 25 years for BCP-ALL and 1-35 years for B-NHL. 3. Adequate venous access for apheresis or eligible for appropriate catheter placement, and no other contraindications for leukapheresis 4. Voluntary informed consent is given. For subjects 16 years of age: Karnofsky greater than or equal to 60%; Patients 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 2. Age: 1 year – 25 years for Bcp-ALL and 1-35 years for B-NHL. 3. Voluntary informed consent is given. For subjects 16 years of age: Karnofsky greater than or equal to 60%; Patients =65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: Procurement eligibility 1. Severe, uncontrolled active infections 2. HIV, or active HCV and/or HBV infection (detection of viral RNA/DNA in blood) 3. Previous allogeneic HSCT in the preceding 100 days before apheresis 4. 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/non-absorbable 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 1. Pregnant or lactating women 2. Severe, uncontrolled active infections 3. HIV, or active HCV and/or HBV infection (detection of viral RNA/DNA in blood) 4. Life-expectancy 4x upper limit of normal (ULN) or transaminase (ALT and AST) > 6 x ULN 6. Renal function: serum creatinine > 3x ULN for age. 7. Blood oxygen saturation 50% pre-infusion. 11. Hyperleukocytosis (greater than or equal to 20,000 blasts/microliter) or rapidly progressive disease that in the evaluation of the investigator would compromise ability to complete study therapy 12. Presence of active, grade 2-4 acute or moderate-severe chronic GvHD 13. Recurrent or refractory ALL with testicular involvement 14. Concurrent or recent prior therapies, before infusion: a) Systemic steroids (at a dose > 2 mg/kg prednisone) in the 2 weeks before infusion. Recent or current use of inhaled/topical/non-absorbable steroids is not exclusionary. b) Systemic chemotherapy in the week preceding infusion. c) Anti-thymocyte globulin (ATG) in the 4 weeks preceding infusion. d) Immunosuppressive agents in the 1 week preceding infusion. e) Radiation therapy must have been completed at least 3 weeks prior to enrollment. f) Other anti-neoplastic investigational agents currently administered or within 30 days prior to infusion (i.e. start of protocol therapy); 15. Patient-derived CD19-CAR_Lenti production failure: vitality of the fresh product 5 EU/ml) in IPC at day 5, mycoplasma contamination in IPC at day 5, failure of the visual inspection.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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.;Secondary Objective: To assess long-term response variables, including relapse rate (RR), overall survival (OS), and disease-free survival (DFS) at 1 and 2 years. To describe the in vivo expansion and persistence of CD19-CAR_Lenti, in blood and BM, measured by flow cytometry and qPCR. To characterize the T-cell subpopulations of the CD19-CAR_Lenti cells before and after infusion, including the exhaustion profile, and to describe the changes in CD19-CAR_Lenti cells after infusion and their correlation with disease response and adverse events. To characterize the cytokine profile after infusion and its correlation with cytokine release syndrome (CRS) in order to define a possible predictive profile.;Primary end point(s): 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 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 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) previous CD19-directed antibody-mediated immunotherapy; c) incidence and duration of B-cell lymphopenia and hypogammaglobulinemia; d) presence of HAMA either pre-existing to the treatment, or detected after CD19-CAR_Lenti infusion.;Timepoint(s) of evaluation of this end point: 1. At 1 and 2 years old 2. Pre-infusion; on day 0; per day 3-4; at weeks 1, 2, 4; every 2 weeks until week 12; every 3 months up to month 12; every 6 months up to month 24; annually for 15 years. 3. Screening; on day 0; on day 3-4, at weeks 1,2,4; every 2 weeks until week 12, every 3 months up to month 12; every 6 months up to month 24; annually for 15 years. 4. Pre-infusion; daily from day 3 to day 10; every 48h until normalization in patients who develop CRS 5. at week 4 and, for long-term response, 1 and 2 years 6. at week 4 | — |
Countries
Italy
Contacts
Public ContactCO-PRINCIPAL INVESTIGATOR
IRCCS OSPEDALE PEDIATRICO BAMBINO GESU'
Outcome results
None listed