Acute Lymphoblastic Leukemia and Non Hodgkin Lymphoma MedDRA version: 20.0 Level: HLGT Classification code 10018849 Term: Haematological disorders NEC System Organ Class: 10005329 - Blood and lymphatic system disorders
Conditions
Interventions
Product Name: CD19-CART01
Product Code: n.a.
Pharmaceutical Form: Solution for infusion
Product Name: AP1903
Pharmaceutical Form: Solution for infusion
Product Name: Fludarabine
Pharmaceutical Form:
Sponsors
Bambino Gesù Children's Hospital
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Procurement eligibility Inclusion Criteria The patient must meet the following eligibility inclusion criteria at the time of procurement. 1. Diagnosis of CD19 expressing B acute lymphoblastic leukemia (ALL) or Non-Hodgkin Lymphoma (NHL) with BM involvement and one of the following: a. Patients in 2nd or subsequent relapse, after at least one standard frontline chemotherapy and one salvage regimen, with BM involvement b. Relapse after allogeneic HSCT, if at least 100 days post-transplant, if there is no evidence of active GVHD and if the patient is no longer taking immunosuppressive agents for at least 30 days prior to enrollment c. MRD > 0.1% after either reinduction therapy or any course of consolidation for relapsed ALL 2. Age: 6 months – 25 years. 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 ALL 2. Measurable or evaluable disease at the time of enrollment, which may include any evidence of disease, including MRD detected by flow cytometry, cytogenetics, or polymerase chain reaction (PCR) analysis. 3. Age: 6 months – 25 years. 4. 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 0
Exclusion criteria
Exclusion criteria: Procurement eligibility Exclusion Criteria 1. Severe, uncontrolled active intercurrent infections 2. HIV, or active HCV and/or HBV infection 3. 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 3 weeks preceding apheresis collection. c. Anti-thymocyte globulin (ATG) or Alemtuzumab (Campath®) 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 3 weeks prior to apheresis. f. Other anti-neoplastic investigational agents currently administered or within 30 days prior to apheresis (i.e. start of protocol therapy); g. Exceptions: a. There is no time restriction in regard to prior intrathecal chemotherapy, provided that there is complete recovery from any acute toxic effects of such; b. Patients who relapse while receiving standard ALL maintenance chemotherapy will not be required to have a waiting period before entry onto this study provided they meet all other eligibility criteria; h. Subjects receiving steroid therapy at physiologic replacement doses only are allowed provided there has been no increase in dose for at least 2 weeks prior to starting apheresis. Treatment eligibility Patient Exclusion criteria 1. Pregnant or lactating women 2. Severe, uncontrolled active intercurrent infections 3. HIV, or active HCV and/or HBV infection 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. Active CNS disease as documented by the presence of blasts in the CSF or by MRI. This criterion could be revised once that, after the phase I portion of the study, absence of life-threatening (i.e. grade IV) neurological toxicity will be documented. 13. Presence of active, grade 2-4 acute or extensive chronic GvHD 14. Recurrent or refractory ALL with testicular involvement 15. Concurrent or recent prior therapies, before infusion: i. 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. ii. Systemic chemotherapy in the 2 weeks preceding infusion. iii. Anti-thymocyte globulin (ATG) or Alemtuzumab (Campath®) in the 4 weeks preceding infusion. iv. Immunosuppressive agents in the 2 weeks preceding infusion. v. Radiation therapy must have been completed at least 3 weeks prior to enrollment. vi. Other anti-neoplastic investigational agents currently administered or within 30 days prior to infusion (i.e. start of proto
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: at day 28 post infusion;Main Objective: Phase I The primary objective of this phase I study is to evaluate the safety and to establish the recommended dose of CD19-CART01 infused in pediatric patients affected by relapsed/refractory B-ALL or NHL with measurable BM involvement. Phase II The phase II extension is aimed at testing the efficacy of the treatment at the optimal dose defined in the phase I.;Secondary Objective: 1To assess the Overall Response Rate 2To assess the in vivo persistence and expansion of the infused T cells 3To evaluate the exhaustion of the infused T cells 4To define the serum cytokine profile and its correlation with CRS in order to define a possible predictive profile. 5To characterize the kinetics of PTX3 and its correlation with CRS to define its role as early predictive biomarker of CRS. 6To assess the long-term antitumor effect of the infused T cells without further therapy. 7To assess relapse rate, overall survival and disease-free survival. 8To assess disease outcome in patients treated with AP1903. 9To assess the kinetics of CD19-CART01 elimination after AP1903 infusion. 10To assess the clinical response and the kinetics of cytokine levels change in patients with CRS treated with AP1903. 11To assess incidence and duration of B-cell lymphopenia and hypogammaglobulinemia and its correlation with maintenance of CR. ;Primary end point(s): Phase I primary end-points 1.To evaluate the safety of the infusion of CD19-CART01 at 3 different escalating doses (0,5 x 106, 1,5 x 106 and 3,0 x 106 cells/kg recipient total body weight of CAR+ T cells) and establish the dose-limiting toxicity (DLT) of the cellular product. DLT will be defined as any of the following that is not pre-existing, due to infection or to underlying malignancy and that may be considered possibly, probably or definitely related to the study cellular products. (1) Non-hematologic DLT is any grade 3 or 4 non-hematologic toxicity, | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. To assess the Overall Response Rate (ORR) at day 28, which includes CR, CR with incomplete blood count recovery (CRi), Partial Response (PR) and Stable Disease (SD). 2. To assess the in vivo persistence and expansion of the infused T cells in the peripheral blood (PB) and in the BM using immunoassays and transgene detection (Real Time qPCR), both for the whole population and the specific T-cell subsets. 3. To evaluate the exhaustion of the infused T cells through immunoassays evaluating the expression of the specific markers of exhaustion and their activity through functional assays (such as ELISPOT for IFN-? release using CD19-positive and CD-19 negative target cells, comparing the response with the T cells at the moment of infusion, whenever possible). 4. To define the serum cytokine profile and its correlation with cytokine release syndrome (CRS) in order to define a possible predictive profile. 5. To characterize the kinetics of pentraxin 3 (PTX3) and its correlation with CRS to define its role as early predictive biomarker of CRS. 6. To assess the long-term antitumor effect of the infused T cells (both as morphologic response and as MRD in the BM) at 1 and 3 years, without further therapy. 7. To assess relapse rate, overall survival and disease-free survival at 1 and 3 years post cell infusion. 8. To assess disease outcome in patients treated with AP1903. 9. To assess the kinetics of CD19-CART01 elimination after AP1903 infusion. 10. To assess the clinical response and the kinetics of cytokine levels change in patients with CRS treated with AP1903. 11. To assess incidence and duration of B-cell lymphopenia and hypogammaglobulinemia and its correlation with maintenance of CR. 12. To assess the outcome of patients treated in the presence of HAMA either pre-existing to the treatment, or detected after CD19-CART01 infusion. ;Timepoint(s) of evaluation of this end point: 1) at day 28 post infusion 2) Pre-infusion and at 1-3h | — |
Countries
Italy
Contacts
Public ContactSub Investigator
Bambino Gesù Children's Hospital
Outcome results
None listed