Pediatric and young adult patients aged 1 to 25 years with first-line NCI high-risk (HR) B-cell acute lymphoblastic leukemia (B-ALL) who are in CR1 with minimal residual disease (MRD) positive (MRD = 0.01%) at the end of consolidation (EOC) therapy by central laboratory assessment. MedDRA version: 20.0 Level: LLT Classification code 10063625 Term: Acute lymphoblastic leukemia recurrent System Organ Class: 100000004864 MedDRA version: 20.0 Level: LLT Classification code 10063621 Term: Acute ly
Conditions
Sponsors
Novartis Farmacéutica, S.A
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Patients eligible for inclusion in this study have to meet all of the following criteria: 1. CD19 expressing B-cell Acute Lymphoblastic Leukemia 2. De novo NCI HR B-ALL who received 1st line treatment and are at MRD = 0.01% at EOC. EOC bone marrow MRD will be collected prior to screening and will be assessed by multi-parameter flow cytometry using central laboratory analysis. 3. Age 1 to 25 years at the time of screening 4. Lansky (age 90% on room air • Adequate cardiac function defined as LVSF = 28% confirmed by echocardiogram or LVEF = 45% confirmed by echocardiogram or MUGA within 6 weeks of screening 6. Prior induction and consolidation chemotherapy allowed, as decribed in the protocol 7. Signed written informed consent and assent forms, if applicable, must be obtained prior to any study procedures 8. Must meet the institutional criteria to undergo leukapheresis 9. Once all other eligibility criteria are confirmed, must have a leukapheresis product of non-mobilized cells received and accepted by the manufacturing site. NOTE: Leukapheresis product will not be shipped to or assessed for acceptance by the manufacturing site until documented confirmation of all other clinical eligibility criteria is received. Other protocol-defined inclusion criteria may apply. Are the trial subjects under 18? yes Number of subjects for this age range: 125 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 15 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range 0
Exclusion criteria
Exclusion criteria: Patients eligible for this study must not meet any of the following criteria: 1. M3 marrow (= 25% blasts by morphologic criteria) at the completion of first-line induction therapy 2. M2 (i.e. = 5% blasts by morphologic criteria) or M3 marrow or persistent extramedullary disease at the completion of first-line consolidation therapy. Patients with previous CNS disease are eligible if there is no active CNS involvement of leukemia at the time of enrollment. 3. Philadelphia chromosome positive (Ph+) ALL 4. Hypodiploid: less than 44 chromosomes and/or DNA index 72 hours prior to tisagenlecleucel infusion: Therapeutic systemic doses of steroids. b. Medications to be stopped at least 1 week prior to tisagenlecleucel infusion: • 6-thioguanine, asparginase (non-pegylated), vincristine, 6-mercaptopurine, and intrathecal methotrexate c. Medications to be stopped at least 2 weeks prior to tisagenlecleucel infusion: • Anthracyclines and cytarabine • Intravenous methotrexate. • Radiotherapy: Non-CNS site of radiation d. Medications to be stopped at least 4 weeks prior to tisagenlecleucel infusion: Pegylated-asparaginase e. Medications/Therapy to be stopped at least 8 weeks prior to tisagenlecleucel infusion: • Radiotherapy: Cranial radiation (for CNS 3 patient) therapy 16. Pregnant or nursing (lactating) women NOTE: Female study participants of reproductive potential must have a negative serum pregnancy test performed within 24 hours before leukapheresis, lymphodepletion and prior to tisagenlecleucel infusion. 17. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using h
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate efficacy of tisagenlecleucel therapy as measured by the 5 years disease-free survival (DFS) rate by investigator assessment.;Secondary Objective: - Proportion of patients who are disease free without allogeneic SCT at 1 year - Overall survival (OS) - Proportion of patients achieving MRD-negative CR or CRi at month 3 post-tisagenlecleucel infusion - Proportion of patients in CR or CRi with persistent B-cell aplasia over time post tisagenlecleucel infusion - Tisagenlecleucel manufacturing success rate in patients =1 year and <3 years - Impact of tisagenlecleucel on health-related Quality of Life (QoL) measures - Impact of tisagenlecleucel on neurocognitive measures - Safety of tisagenlecleucel therapy - Prevalence and incidence of immunogenicity to tisagenlecleucel and its impact on efficacy, safety and cellular kinetics - Characterize in vivo cellular kinetic profile of tisagenlecleucel transgene and CD3+ CAR-positive viable T cells including second infusion - Evaluate the relationship between B-cell and transgene persistence - Evaluate dose-exposure-response relationship;Primary end point(s): 5-year DFS rate. DFS is defined as the time from tisagenlecleucel infusion to morphologic relapse, occurrence of secondary malignancy or death due to any cause, whichever occurs first.;Timepoint(s) of evaluation of this end point: After tisagenlecleucel infusion, efficacy will be assessed at Day 28, then every 3 months for the first year, every 6 months for the second year, then yearly until the EOS. Relapse and survival will be captured every 3 months throughout the study. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - Proportion of patients who are disease free without allogeneic SCT at 1 year - OS, i.e. the time from date of tisagenlecleucel infusion to the date of death due to any reason - Proportion of patients achieving MRD-negative CR or CRi at month 3 post-tisagenlecleucel infusion - Proportion of patients in CR or CRi with persistent B-cell aplasia over time post tisagenlecleucel infusion - Proportion of patients who have tisagenlecleucel product successfully manufactured (meet all release criteria) over the total number of patients enrolled for the age = 1 year and < 3 years at respective time points - PedsQL 4.0 and EuroQol EQ-5D in patients = age 8 years; change from baseline - Cogstate computerized cognitive battery age standardized scores (5 tests: psychomotor function (DET), attention (IDN), working memory (ONB), visual learning (OCL) and executive function (GML) (in patients = age 6 years) - Evaluation of adverse events, vital signs, laboratory and other parameters. - Prevalence and incidence of pre-existing and treatment induced immunogenicity - Pre-existing and treatment induced immunogenicity on clinical response, cellular kinetics (Cmax, AUC0-28d, Clast) and safety - Tisagenlecleucel transgene levels by qPCR in blood, bone marrow, and CSF if available - Expression of tisagenlecleucel detected by flow cytometry in blood and bone marrow - Cmax, Tmax, AUCs and other relevant cellular kinetic parameters in blood, bone-marrow, and CSF if available - B-cell recovery time and transgene levels over time - Dose-exposure-response relationship: • Response endpoints (e.g. DFS, OS, Month 3 response) and key safety events (e.g. CRS, neurological events, cytopenias) and relationships with dose • Response endpoints (e.g. DFS, OS, Month 3 response) and key safety events (e.g. CRS, neurological events, cytopenias) and relationship with relevant exposure parameters (e.g. AUC and Cmax) • Cellular kinetic parameters and relationship with dose;Timepoint(s) | — |
Countries
Belgium, Canada, Denmark, Finland, France, Germany, Italy, Netherlands, Norway, Spain, Sweden, United Kingdom, United States
Contacts
Public ContactTrial Monitoring Organization (TMO)
Novartis Farmacéutica, S.A.
Outcome results
None listed