This is a phase l multi-centric, single arm, prospective open, dose-escalation study in patients with relapsed or refractory CD19-positive B cell malignancies (ALL, NHL, CLL). The trial will include adult and pediatric patients. In total approximately 48 patients will be included in the trial. There will be three individual cohorts, defined by disease biology: pediatric ALL and aggressive pediatric NHL (Cohort 1), adult ALL (Cohort 2) and adult NHL/CLL (Cohort 3).
This trial will evaluate the safety of the MB-CART19.1 and determine the recommended dose levels for each of the three disease cohorts. Dose evaluation will start in Cohorts 1 and 2 with Dose Level 1 and in Cohort 3 with Dose Level 2, sparing Dose Level 1 (see figure 1). Each of the cohorts will evaluate the safety of MB-CART19.1. In each dose level of each of the three cohorts three 3 + 3 patients will be treated. A particular dose level will be expanded to 6 patients if one patient out of 3 patients treated at that particular dose level develops DLT. Once this occurs, further dose-escalations are halted until the dose has proven to be safe in the expanded cohort. If 2 or more in a cohort of 6 patients develop DLT no further dose escalation is allowed, and the next lower dose level will be expanded to 6 patients in total. The highest dose among the dose levels tested at which no more than one out of six patients experiences DLT will be considered the MTD. In Dose Level 3, three additional patients will be treated, if no DLT occurred. Dose Level 0 will be tested only if Dose Level 1 is not tolerable. Cohort 3 will Start with Dose Level 2. If Dose Level 2 is not tolerated, Dose Level 1 will be tested. DLT will be evaluated within 4 weeks after the infusion of MB-CART19.1. An interval of at least 28 days between the treatment of the first and the second patient in each dose level (and in each cohort) is mandatory.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
48
MB-CART19.1 consists of autologous CD19 Chimeric Antigen Receptor (CAR) transduced CD4/CD8 enriched T cells targeting CD19-positive tumor cells in b cell malignancies
Charité - University clinic, pediatric clinic with focus on oncology and hematology
Berlin, Germany
Universitätsklinikum Erlangen
Erlangen, Germany
University medicine Goettingen, Clinic of hematology and medical oncology
Göttingen, Germany
Children's Hospital of Dr. von Hauner by Ludwig-Maximilian University
Munich, Germany
Universitätsklinikum Münster - Klink für Kinderheilkunde und Jugendmedizin / Pädiatrische Hämatologie und Onkologie
Münster, Germany
Universitätsklinikum Münster - Medizinische Klinik A / KMT Zentrum
Münster, Germany
Tuebingen University clinic, medical university clinic for internal medicine
Tübingen, Germany
University clinic for children and youth medicine
Tübingen, Germany
University clinic, pediatric hematology and oncology
Würzburg, Germany
Determination of the recommended dose of MB-CART19.1
Maximum tolerated dose (MTD), defined as the highest dose level of the two to three dose levels tested at which \<33% of patients experience DLT until day 28 after infusion of MB-CART19.1, on the basis of safety and toxicity assessment of MB-CART19.1 per adverse events (AE) reporting classified according to CTCAE version 5.0.
Time frame: until day 28 after infusion of MB-CART19.1
Overall incidence and severity of adverse events
per adverse events (AE) reporting classified according to CTCAE version 5.0
Time frame: through study completion, an average of 5 years
Response to treatment for each timepoint
ORR in ALL (Rate of CR/CRh)
Time frame: day 28
Response to treatment for each timepoint
Rate MRD-negative CR in ALL
Time frame: day 28, week 12, month 6, 1 year
Response to treatment for each timepoint
ORR in NHL/CLL (Rate of CR/PR)
Time frame: day 28, patients not in CR on day 28: month 3
Occurence of B-cell depletion
Circulating B cell numbers
Time frame: through study completion, an average of 5 years
Phenotype and persistence of MB-CART19.1
Blood samples for determination of persistence/phenotyping of infused MB-CART19.1 will be analysed
Time frame: days 2, 7, 10, 14, 28, weeks 8, 12, months 6, 12, 24, 36, 48, 60
Number of patients with successful MB-CART19.1 production
Number of patients meeting the inclusion criteria and none of the exclusion criteria for who an autologous MB-CART19.1 product can be generated
Time frame: day 0
Rate of ALL patients achieving MRD negative CR
Rate MRD-negative CR in ALL
Time frame: day 28, week 12, month 6, 1 year
Duration of response
Determination of response rate
Time frame: through study completion, an average of 5 years
Disease-free survival
disease-free survival at 1 year after adoptive immunotherapy with MB-CART19.1 in patients not receiving alloSCT
Time frame: at 1 year after MB-CART19.1 infusion in patients not receiving alloSCT
Overall survival
overall survival at 1 year after adoptive immunotherapy with MB-CART19.1 in patients not receiving alloSCT
Time frame: at 1 year after MB-CART19.1 infusion in patients not receiving alloSCT
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