CD19-CAR_LENTI_ALLO for B-cell acute lymphoblastic leukemia (relapsed/refractory)

Inclusion criteria

• {"criterion_text":"- Patients must meet the following eligibility inclusion criteria at the time of treatment. 1. Diagnosis of CD19 expressing B Acute Lymphoblastic leukemia (B-ALL) relapse and one of the following \ta. Relapse after alloHSCT b. Relapsed/refractory disease, with failure of frontline therapy and at least 2 rescue strategies, including CD19/CD22-directed monoclonal antibody AND availability of a fully matched related donor. OR"}
• {"criterion_text":"- 2. Age: 1 year – 35 years."}
• {"criterion_text":"- 3. CD19+ count > 50 cells/mcl and/or MRD > 10-4"}
• {"criterion_text":"- 4. Patients that received previously a CD19-directed therapy are eligible provided that all the following 4 criteria are present: i) the disease is still CD19-positive; ii) the inclusion criteria #3 is fulfilled; iii) at least 1 month has elapsed between the previous therapy and CD19-CAR_Lenti_ALLO infusion; iv) the previous therapy was associated with grade <3 CRS and/or ICANS, both resolved without sequelae."}
• {"criterion_text":"- 5. Patients must be ineligible for the commercially available autologous CD19-directed CAR T cell product OR have relapsed <6 months after allogeneic HSCT OR be unable to undergo an autologous CAR T cell production [peripheral CD3+ cell count < 300/mcl; relapse after treatment with an autologous CD19-CAR T cell product; >50% of circulating blasts]."}
• {"criterion_text":"- 6. 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."}
• {"criterion_text":"- 7. 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%."}
• {"criterion_text":"- 8. Women of childbearing potential must have a negative serum or urine pregnancy test at the time of screening and within the week preceding starting lymphodepletion."}
• {"criterion_text":"- 9. Female subjects of childbearing potential must agree to use acceptable method(s) of contraception from consent through at least 12 months after the CD19-CAR_Lenti_ALLO drug product infusion and, in any case, until viable positive CAR T cells are no longer detected, whichever are longer. Male subjects of reproductive capacity must agree to use effective contraception from consent through at least 12 months after the CD19-CAR_Lenti_ALLO drug product infusion and, in any case, until viable positive CAR T cells are no longer detected, whichever are longer."}

Exclusion criteria

• {"criterion_text":"- 1. Pregnant or lactating women."}
• {"criterion_text":"- 2. Burkitt acute lymphoblastic leukemia and blast crisis of chronic myeloid leukemia"}
• {"criterion_text":"- 3. Severe, uncontrolled active intercurrent infections."}
• {"criterion_text":"- 4. HIV or active HCV (<12 weeks between achievement of a sustained virological response to the specific treatment and apheresis) and/or HBV infection (either positive for Hepatitis B core antibody [HBcAb] or positive hepatitis B surface antigen [HBsAg] AND NAT tests), defined according to the American Association for the Study of Liver Diseases guidelines."}
• {"criterion_text":"- 5. Life-expectancy < 6 weeks or rapidly progressive disease that in the evaluation of the investigator would compromise ability to complete study therapy."}
• {"criterion_text":"- 6. Hepatic function: Inadequate liver function defined as total bilirubin > 3x upper limit of normal (ULN) or transaminase (ALT and AST) > 5 x ULN."}
• {"criterion_text":"- 7. Renal function: Creatinine clearance calculated using the Schwartz formula1, or radioisotope glomerular filtration rate (GFR) <70 mL/min/1.73 m2"}
• {"criterion_text":"- 8. Blood oxygen saturation < 90%."}
• {"criterion_text":"- 9. Cardiac function: Left ventricular ejection fraction lower than 45% by ECHO."}
• {"criterion_text":"- 10. Congestive heart failure, cardiac arrhythmia, psychiatric illness, or social situations that would limit compliance with study requirements or in the opinion of the PI would pose an unacceptable risk to the subject."}
• {"criterion_text":"- 11. Presence of active, grade 2-4 acute or chronic GvHD requiring steroid therapy or other immune-suppressive treatment."}
• {"criterion_text":"- 12. Relapse occurring before 60 days after alloHSCT."}
• {"criterion_text":"- 13. Concurrent or recent prior therapies, before infusion: \ti. Systemic steroids (at a dose > 2 mg/kg prednisone) in the 2 weeks before infusion of CD19-CAR_Lenti_ALLO. Recent or current use of inhaled/topical/non-absorbable steroids is not exclusionary. \tii. Systemic chemotherapy in the 2 weeks preceding infusion of CD19-CAR_Lenti_ALLO. \tiii. Anti-thymocyte globulin (ATG) or Alemtuzumab (Campath®) in the 8 weeks preceding infusion of CD19-CAR_Lenti_ALLO. \tiv. Immunosuppressive agents in the 2 weeks preceding infusion of CD19-CAR_Lenti_ALLO. \tv. Radiation therapy must have been completed at least 2 weeks before infusion of CD19-CAR_Lenti_ALLO. \tvi. Donor lymphocytes infusion in the 4 weeks preceding infusion \tvii. Other anti-neoplastic investigational agents currently administered or within 30 days prior to infusion of CD19-CAR_Lenti_ALLO (i.e., start of protocol therapy); \tix. Exceptions: \t1. There is no time restriction in regards to prior intrathecal chemotherapy, but there must be a complete recovery from any acute toxic effects from such treatment; \t2. Subjects receiving steroid therapy at physiologic replacement doses only are allowed provided that there has been no increase in dose for at least 2 weeks prior to starting apheresis."}

Primary endpoints

• {"endpoint_text":"- To evaluate the safety of the infusion of CD19-CAR_Lenti_ALLO evaluating 2 dose levels (DLs) for each cohort of patients, depending on the donor HLA-matching (for fully matched, familial or unrelated donor, DL1: 3.0 x 106; DL2: 5.0 x 106 cells/kg recipient total body weight of CAR+ T cells; for haploidentical donor, DL1: 1.0 x 106; DL2: 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 an"}
• {"definition_or_measurement_approach":"Primary objective: evaluate safety and establish recommended dose. Dose levels specified by donor HLA-matching as stated (fully matched DL1 3.0 x10^6; DL2 5.0 x10^6 cells/kg; haploidentical DL1 1.0 x10^6; DL2 3.0 x10^6 cells/kg). DLT definition text is truncated/not fully available in source."}

Secondary endpoints

• {"endpoint_text":"- 1. To estimate the rate of occurrence and the severity of acute and/or chronic GvHD","definition_or_measurement_approach":"Estimate incidence and grade/severity of acute and/or chronic graft-versus-host disease (GvHD) as reported during follow-up (grading method not specified in source)."}
• {"endpoint_text":"- 2. To evaluate the proportion of patients achieving either CR or CR with incomplete blood count recovery (CRi) and MRD negativity by either flow-cytometry or qPCR at day 28 (defined as a value < 1x10-4 ).","definition_or_measurement_approach":"Response assessed as CR or CRi; MRD negativity measured by flow-cytometry or qPCR at day 28, MRD negativity defined as < 1 x 10^-4."}
• {"endpoint_text":"- 3. To estimate the probability of obtaining CR with MRD negativity stratified according to the disease burden at time of enrollment","definition_or_measurement_approach":"Probability of CR with MRD negativity will be estimated stratified by disease burden at enrollment (stratification approach described but specific strata thresholds not provided)."}

Italy

Earliest CTIS Part Ii Submission Date

19-03-2024

Latest Decision Or Authorization Date

23-04-2024

Processing Time Days

35

Number Of Sites

1

Number Of Participants

24

Primary sponsor

Full Name

Ospedale Pediatrico Bambino Gesù

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Italy