Pediatric and adult patients with relapsed/refractory (r/r) CD19-expressing B cell acute lymphoblastic leukemia (ALL) and Non-Hodgkin lymphoma (NHL), including chronic lymphocytic leukemia (CLL). MedDRA version: 21.0 Level: LLT Classification code 10063625 Term: Acute lymphoblastic leukemia recurrent System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.0 Level: PT Classification code 10003902 Term: B-cell lymphoma recurrent Sys
Conditions
Interventions
Product Name: MB-CART19.1
Pharmaceutical Form: Solution for infusion
Sponsors
Miltenyi Biomedicine GmbH
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male or female patients must have r/r CD19-expressing ALL or NHL and meet the following disease-specific criteria: ALL: a 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 b patients who have relapsed post alloSCT at least 100 days post-transplant, with no evidence of active GVHD, and no longer taking immunosuppressive agents for at least 30 days prior to leukapheresis. c 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. d 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): e patients after at least one salvage chemotherapy as bridge to alloSCT or f patients ineligible for alloSCT or g patients who have relapsed post alloSCT at least 100 days post-transplant, with not evidence of active GVHD, and no longer taking immunosuppressive agents for at least 30 days prior to leukapheresis. h 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: i patients after at least one standard chemotherapy and one salvage regimen as bridge to alloSCT or j patients who are ineligible for alloSCT or k patients who have relapsed post alloSCT at least 100 days post-transplant, with no evidence of active GVHD, and no longer taking immunosuppressive agents for at least 30 days prior to leukapheresis. l 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: m patients with r/r disease after established and approved treatment options have failed. n patients not eligible or appropriate for conventional alloSCT 2. 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; 3. Age =1 year (if deemed fit by treating investigator); 4. Absolute CD3+ T cell count =100/µl; 5. ECOG performance score of 0-2 if >16 years old, or Lansky performance score of >50 if =16 years old at screening; 6. No active Hepatitis B, Hepatitis C, HIV1/2; 7. No childbearing potential or negative pregnancy test at screening and before chemotherapy in women with childbearing potential; 8. Signed and dated informed consent/assent by patients and/or, in case of patients =65 years) yes F.1.3.1 Number of subjects for this age range 17
Exclusion criteria
Exclusion criteria: 1. Isolated CNS or testicular relapse in ALL; 2. Isolated CNS lymphomas; 3. Active solid brain metastases or history of solid brain metastases 4. Current autoimmune disease, or history of autoimmune disease with potential CNS involvement; 5. Active clinically significant CNS dysfunction (including but not limited to uncontrolled seizure disorders, cerebrovascular ischemia or hemorrhage, dementia, paralysis); 6. History of an additional malignancy other than non-melanoma skin cancer or carcinoma in situ unless disease free for =3 years; 7. BMI = 30 8. 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; 9. Cardiac function: Pediatric patients: Fractional shortening 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; 12. Rapidly progressive disease that in the estimation of the investigator would compromise ability to complete study therapy; 13. Pregnant or breast-feeding females; 14. 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; 15. 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; 16. Intake of concomitant medication contraindicated for other reasons than hypersensitivity within 30 days prior to leukapheresis, e.g. live vaccines and fludarabine 17. Contraindication of trial related procedures as judged by the investigator, e.g. lumbar punctures for CSF sampling; 18. Female patients of child-bearing potential not willing to practice a highly effective form of birth control from the time of leukapheresis and for 12 months after dosing the IMP; 19. Male patients of fathering potential not willing to practice a highly effective form of birth control from the time of enrollment and for 12 months after dosing the IMP; 20. Concurrent participation in another interventional trial that could interact with this trial, e.g. CAR T trials; 21. Other investigational treatment within 4 weeks before I
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Part I (Phase I): To determine the recommended dose of MB-CART19.1 Part II (Phase II): To assess the response to adoptive cell therapy using autologous MB-CART19.1 ;Secondary Objective: Part I (Phase I): - Preliminary evidence of response to MB-CART19.1 treatment - Phenotype and persistence of MB-CART19.1 Part II (Phase II): - Safety and toxicity assessment of MB-CART19.1 - Phenotype and persistence of MB-CART19.1 - To determine duration of response, relapse rate, disease-free and overall survival after treatment with MB-CART19.1 ;Primary end point(s): Part I (Phase I): Determination of the 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. Safety and toxicity assessment of MB-CART19.1 per adverse events (AE) reporting classified according to CTCAE (Common Terminology Criteria for Adverse Events) version 5.0 defined by <33% of patients experiencing DLT, or maximal administered dose. Part II (Phase II): Determination of the Overall Response Rate (ORR) - ORR in ALL patients is defined as the rate of complete remission (CR, CRh) on day 28; - ORR in NHL patients is defined as the rate of overall response (CR or PR) on day 28 and on month 3 in patients not in CR on day 28. ;Timepoint(s) of evaluation of this end point: Adverse events will be documented at least 1,2, and 4 h post start of infusion. Furthermore on days 1, 2, 7,10, 14 and 28, on weeks 8, 12 and 16 as well as on months 6,8, 10 and 12 after the treatment and yearly during the long-term follow up . Adverse events observed by the investigator or reported spontaneously by the patient will also be recorded at any time. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Part I (Phase I): - Overall incidence and severity of adverse events; - Response to treatment for each timepoint: - Overall response rate (ORR) in ALL patients defined as the rate of complete remission (CR, CRh) on day 28; - Rate of ALL patients achieving MRD response (<10-4); - ORR in NHL patients 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; - Occurrence of B cell depletion; - Phenotype and persistence of MB-CART19.1. - Further safety assessments; Part II (Phase II): - Safety and toxicity of MB-CART19.1 per adverse events (AE) reporting classified according to CTCAE version 5.0; - Proportion of patients meeting the inclusion criteria and none of the exclusion criteria for who an autologous MB-CART19.1 product can be generated; - Rate of ALL patients achieving MRD response (<10-4); - Duration of response, relapse rate and time to relapse; - Disease-free and overall survival at 1 year after adoptive immunotherapy with MB-CART19.1 in patients not receiving alloSCT; - Occurrence of B cell depletion; - Phenotype and persistence of MB-CART19.1. ;Timepoint(s) of evaluation of this end point: Clinical Response assessments: PB, BM and CSF for cytomorphology and MRD analysis: screening, day -5 or day -6 (only in patients with CNS-2 or 3 status at screening), day 28, week 12, months 6 and 12. PET-CT/PET-MRI; MRI whole Body (NHL adults): screening, week 12; MRI/CT (NHL): day 28, months 6, 12, long-term FU MRI (Children): Screening Day 28, week 12, month 6, 12, long-term FU B-cell Depletion: Pre-dose (day 0), days 7, 10, 14 and 28, weeks 8, 12 and 16, months 6, 8, 10 and 12 after infusion and annually during long-term FU Persistence / Phenotyping of infused MB-CART19.1: Day -5, pre-dose (day 0), days 2, 7, 10, 14 and 28, weeks 8 and 12, months 6 and 12 after dosing and annually during the long-term FU. | — |
Countries
Germany
Contacts
Public ContactClinical Trial Manager
Miltenyi Biomedicine GmbH
Outcome results
None listed