AUTOLOGOUS T-CELLS TRANSDUCED WITH LENTIVIRAL VECTOR EXPRESSING A CHIMERIC ANTIGEN RECEPTOR DIRECTED AGAINST CD19 for Relapsed or refractory CD19-positive B-cell malignancies | Acute lymphoblastic leukemia (B-ALL) | Non-Hodgkin lymphoma | Chronic lymphocytic leukemia

Inclusion criteria

• {"criterion_text":"- Male or female patients must have r/r CD19-expressing ALL or NHL/CLL and meet the following disease-specific criteria: All Cohorts: 1a) patients with >5% blasts in BM (M2 or M3) after at least one standard chemotherapy and one salvage regimen who are ineligible for allogeneic stem cell transplant (alloSCT) or have refractory disease activity precluding alloSCT at this time, or 1b) patients who have relapsed post alloSCT no earlier than 100 days posttransplant, with no evidence of active GVHD, and not taking immunosuppressive agents for at least 30 days prior to leukapheresis. 1c) patients with Ph+ ALL if they are intolerant to tyrosine kinase inhibitor (TKI) therapy, or if they have r/r disease after treatment with at least 2 different TKIs. 1d) ALL patients with combined bone marrow and CNS and/or testicular relapse are eligible only if the extramedullary disease has been successfully cleared by conventional therapy at the time of inclusion (e.g. intrathecal chemotherapy, orchiectomy). Pediatric aggressive NHL (1-17 years): 1e) patients after at least one salvage chemotherapy as bridge to alloSCT or 1f) patients ineligible for alloSCT or 1g) patients who have relapsed post alloSCT no earlier than 100 days posttransplant, with not evidence of active GVHD, and not taking immunosuppressive agents for at least 30 days prior to leukapheresis. 1h) patients with CNS disease (excluding isolated CNS lymphoma) are eligible only if disease has been successfully cleared by intrathecal chemotherapy at the time of inclusion. Adult NHL: 1i) patients after at least one standard chemotherapy and one salvage regimen as bridge to alloSCT or 1j) patients who are ineligible for alloSCT or 1k) patients who have relapsed post alloSCT no earlier than 100 days posttransplant, with no evidence of active GVHD, and not taking immunosuppressive agents for at least 30 days prior to leukapheresis. 1l) patients with CNS disease (excluding isolated CNS lymphoma) are eligible only if disease has been successfully cleared by intrathecal chemotherapy at the time of inclusion. CLL: 1m) patients with r/r disease after established and approved treatment options have failed. 1n) patients not eligible or appropriate for conventional alloSCT."}
• {"criterion_text":"- CD19 expression must be detected on the malignant cells by flow cytometry (leukemia, malignant effusion in NHL) or immunohistochemistry (NHL). Results of previous assessments after the last treatment with CD19 targeted therapies but preceding inclusion of the patient in this trial are acceptable, if available;"}
• {"criterion_text":"- Age ≥1 year (if deemed fit by treating investigator)"}
• {"criterion_text":"- Absolute CD3+ T cell count ≥100/μl"}
• {"criterion_text":"- ECOG performance score of 0-2 if >16 years old, or Lansky performance score of >50 if ≤16 years old at screening"}
• {"criterion_text":"- No active Hepatitis B, Hepatitis C, HIV1/2"}
• {"criterion_text":"- No childbearing potential or negative pregnancy test at screening and before chemotherapy in women with childbearing potential"}
• {"criterion_text":"- Signed and dated informed consent/assent by patients and/or parents, before conduct of any trial-specific procedure."}

Exclusion criteria

• {"criterion_text":"- Isolated CNS or testicular relapse in ALL"}
• {"criterion_text":"- Renal function: GFR ≤29 mL/min/1.73 m2 by CKD-EPI for patients ≥ 18 yrs (Levey et al. 2009) or creatinine clearance ≤29 mL/min/1.73 m2 by Schwartz formula (Schwartz et al. 1976) for patients <18 yrs of age"}
• {"criterion_text":"- Liver function: Patients with a serum bilirubin >3 times upper limit of normal or an AST or ALT > 5 times upper limit of normal, unless due to leukemic liver infiltration in the estimation of the investigator"}
• {"criterion_text":"- Rapidly progressive disease that in the estimation of the investigator would compromise ability to complete study therapy"}
• {"criterion_text":"- Pregnant or breast-feeding females"}
• {"criterion_text":"- Medications: a. Systemic chemotherapies, corticosteroids with the exception of physiologic replacement dosing, tyrosine kinase inhibitors (TKI) and other kinase inhibitors (e.g. ibrutinib) within 7 days prior to leukapheresis; b. Fludarabine/clofarabine or immunosuppressive drugs and antibodies (e.g. rituximab, calcineurin inhibitors, blinatumomab) or donor lymphocyte transfusions or radiation therapy within 14 days prior to leukapheresis, c. Previous treatment with CAR T cells (e.g. Kymriah®), d. Alemtuzumab within 3 months prior to leukapheresis, e. Exception: Intrathecal chemotherapy is allowed until 8 days prior to leukapheresis, with the exception of cytarabine. After leukapheresis, a single dose of intrathecal chemotherapy is allowed but should be discontinued 10 days prior to MB-CART19.1 infusion to limit risk of neurotoxicities"}
• {"criterion_text":"- Hypersensitivity against any drug or its ingredients/impurities that is scheduled or likely to be given during trial participation, e.g. as part of the mandatory lymphodepletion protocol, pre-medication for infusion, rescue medication/salvage therapies for treatment related toxicities"}
• {"criterion_text":"- Isolated CNS lymphomas"}
• {"criterion_text":"- Active solid brain metastases or history of solid brain metastases"}
• {"criterion_text":"- Current autoimmune disease, or history of autoimmune disease with potential CNS involvement"}
• {"criterion_text":"- Active clinically significant CNS dysfunction (including but not limited to uncontrolled seizure disorders, cerebrovascular ischemia or hemorrhage, dementia, paralysis)"}
• {"criterion_text":"- History of an additional malignancy other than non-melanoma skin cancer or carcinoma in situ unless disease free for ≥3 years"}
• {"criterion_text":"- BMI ≥ 30"}
• {"criterion_text":"- Pulmonary function: Patients with pre-existing severe lung disease or an oxygen requirement of >28% O2 supplementation or active pulmonary infiltrates on chest X-ray"}
• {"criterion_text":"- Cardiac function: Pediatric patients: fractional shortening <28% or left ventricular ejection fraction <50% by echocardiography, adult patients: left ventricular ejection fraction <50% by echocardiography"}

Primary endpoints

• {"endpoint_text":"- Recommended dose of MB-CART19.1, determined on the basis of the 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, and on the basis of the safety and efficacy data.","definition_or_measurement_approach":"MTD defined as highest dose of the 2–3 dose levels tested with <33% of patients experiencing DLT until day 28 after infusion; recommended dose determined on basis of MTD and safety and efficacy data."}
• {"endpoint_text":"- Safety and toxicity assessment of MB-CART19.1 per adverse events (AE) reporting classified according to CTCAE version 5.0. defined by <33% of patients experiencing DLT, or maximal administered dose.","definition_or_measurement_approach":"AE reporting classified according to CTCAE v5.0; DLT incidence until day 28 used to define safety/toxicity (threshold <33%)."}

Secondary endpoints

• {"endpoint_text":"- Overall incidence and severity of adverse events","definition_or_measurement_approach":""}
• {"endpoint_text":"- Response to treatment: o\tOverall response rate (ORR) in ALL patients defined as the rate of complete remission (CR, CRh) on day 28; o\tRate of ALL patients achieving MRD response (<10-4); o\tORR in NHL patients is defined as the rate of overall response (CR or PR) on day 28 and at month 3 in patients not in CR on day 28","definition_or_measurement_approach":"ORR in ALL defined as CR/CRh on day 28; MRD response defined as <10^-4; ORR in NHL defined as CR or PR on day 28 and at month 3 for those not in CR on day 28."}
• {"endpoint_text":"- Occurrence of B cell depletion","definition_or_measurement_approach":""}
• {"endpoint_text":"- Phenotype and persistence of MB-CART19.1","definition_or_measurement_approach":""}
• {"endpoint_text":"- Further safety assessments.","definition_or_measurement_approach":""}
• {"endpoint_text":"- Proportion of patients meeting the inclusion criteria and none of the exclusion criteria for who an autologous MB-CART19.1 product can be generated;","definition_or_measurement_approach":""}
• {"endpoint_text":"- Rate of ALL patients achieving MRD response (<10-4)","definition_or_measurement_approach":"MRD response defined as <10^-4"}
• {"endpoint_text":"- Duration of response, relapse rate and time to relapse;","definition_or_measurement_approach":""}
• {"endpoint_text":"- Disease-free and overall survival at 1 year after adoptive immunotherapy with MB-CART19.1 in patients not receiving alloSCT;","definition_or_measurement_approach":""}

Germany

Earliest CTIS Part Ii Submission Date

09-08-2024

Latest Decision Or Authorization Date

17-07-2025

Processing Time Days

342

Number Of Sites

8

Number Of Participants

49

Primary sponsor

Full Name

Miltenyi Biomedicine GmbH

Organisation Type

Pharmaceutical company

Country Of Registered Address

Germany

Contract research organisations

Name

Pharmalog Institut fuer klinische Forschung GmbH

Responsibilities

code: 10

Name

EvidentlQ Germany GmbH

Responsibilities

code: 7

Name

SCRATCH Pharmacovigilance GmbH & Co. KG

Responsibilities

code: 13

Third parties

• {"country":"Germany","full_name":"Medizinisches Versorgungszentrum fuer Labordiagnostik und Mikrobiologie Rhein-Main GmbH","duties_or_roles":"code: 4","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Germany","full_name":"Miltenyi Biotec B.V. & Co. KG","duties_or_roles":"code: 4","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Universitaetsklinikum Tuebingen AöR","duties_or_roles":"code: 14; code: 15 (Investigational Medicinal Product Manufacturer)","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Germany","full_name":"BioAgilytix Europe GmbH","duties_or_roles":"code: 4","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"EvidentlQ Germany GmbH","duties_or_roles":"code: 7","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Germany","full_name":"Pharmalog Institut fuer klinische Forschung GmbH","duties_or_roles":"code: 10","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Miltenyi Biotec B.V. & Co. KG","duties_or_roles":"code: 15 (QP Release)","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Charite Universitaetsmedizin Berlin KöR","duties_or_roles":"code: 4","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Germany","full_name":"Universitaetsklinikum Erlangen AöR","duties_or_roles":"code: 14; code: 15 (Investigational Medicinal Product Manufacturer)","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Germany","full_name":"Mlm Medical Labs GmbH","duties_or_roles":"code: 4","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Germany","full_name":"University Of Cologne","duties_or_roles":"code: 8","organisation_type":"Educational Institution"}
• {"country":"Germany","full_name":"SCRATCH Pharmacovigilance GmbH & Co. KG","duties_or_roles":"code: 13","organisation_type":"Pharmaceutical company"}