A study to determine how safe MB-CART2019.1 is and how well it works in children and adolescents with B cell neoplasms

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Miltenyi Biomedicine GmbH

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

22 Jul 2025 → ongoing

Decision date (initial)

2024-11-05

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Miltenyi Biomedicine GmbH

External identifiers

EU CT number

2023-506348-17-00

ClinicalTrials.gov

NCT06508951

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy

The primary objective is to assess the safety, toxicity and efficacy of MB-CART2019.1 therapy, as measured by best overall response rate (BORR), after infusion in subjects with relapsed/refractory (r/r) mature B cell neoplasms.

Secondary objectives 10

1. • To assess the efficacy of MB-CART2019.1, as measured by BORR, complete response rate (CRR), duration of response (DOR), duration of complete response (DOCR), overall response rate (ORR), time to objective response (TTR), time to complete response (TTCR), event-free survival (EFS), progression-free survival (PFS), and overall survival (OS).
2. • Circulating B cell numbers and immunoglobulin M (IgM) and immunoglobulin G (IgG) levels. "
3. • To assess the proportion of subjects who proceed to transplant after MB-CART2019.1 therapy.
4. • To measure and correlate cytokines levels with cytokine release syndrome (CRS), neurotoxicities, and efficacy.
5. • To explore the relationship between cluster of differentiation (CD)19/CD20 antigen expression by B cells and the response to MB-CART2019.1 therapy.
6. • To evaluate the humoral immunogenicity against MB-CART2019.1.
7. • To assess health-related quality of life (HRQoL).
8. • To further assess the safety and toxicity of MB-CART2019.1.
9. • To monitor replication-competent lentivirus (RCL).
10. • To assess the persistence and phenotype of autologous tandem CD20-CD19-directed CAR-T cells.

Conditions and MedDRA coding

Relapsed/refractory (r/r) mature B cell neoplasms who have relapsed after one or more prior therapies, including subjects with primary refractory disease

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-003009-PIP01-21

Plan to share IPD

No

IPD plan description

Sponsor policy for IPD sharing under development

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. 1.Subjects must meet all the following inclusion criteria to be eligible for inclusion in this study: Is able to provide age-appropriate assent/consent (as applicable, according to local legislation) and/or have a guardian able to provide consent signed and dated by the parent(s) or by subject’s legal guardian before conduct of any study-specific procedures.
2. 10. Has adequate organ function as follows: o Renal function: estimated glomerular filtration rate (eGFR) >29 mL/min by Schwartz formula (Schwartz et al 1976). o Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤5 × upper limit of normal (ULN) for age. o Bilirubin <1.5 x ULN (for Gilbert’s Syndrome, subject’s total bilirubin <4 mg/dL). o Adequate pulmonary function as follows: - Resting oxygen saturation of ≥91% on room air. - No or mild dyspnea (Grade ≤1)."
3. 11. Female subjects of childbearing potential must be willing to undergo pregnancy tests before MB-CART2019.1 infusion.
4. 12. If subjects are sexually active, they must be willing to use highly effective methods of contraception. o Female subjects must agree to use two methods of contraception; - one of the following methods (Pearl index <1%): Hormonal contraceptives associated with inhibition of ovulation (oral, intravaginal, injected, implanted, transdermal), intrauterine devices (IUDs) or systems (e.g., hormonal and non-hormonal IUD), or vasectomized sexual partner AND one barrier method. - Highly effective methods of contraception must be followed from inclusion until 12 months after MB-CART2019.1 infusion. o Male subjects must agree to use a condom during intercourse from inclusion through at least 12 months after MB-CART2019.1 infusion to prevent them from fathering a child AND to prevent delivery of MB-CART2019.1 via seminal fluid to their partner. Do not use a female condom when using a male condom, since tearing can occur. In addition, male subjects must not donate sperm for the time period specified above. o Females must agree not to breast feed or donate eggs/ova during the study and until at least 12 months after MB-CART2019.1 infusion.
5. 2. Has histologically confirmed mature CD19+ and/or CD20+ B-cell neoplasm according to the WHO 2022 classification of hematolymphoid tumors such as:o Burkitt lymphoma/Burkitt leukemia o Diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) o Primary mediastinal (thymic) large B-cell lymphoma o Burkitt-like lymphoma with 11q aberration o Aggressive mature B-cell lymphoma o Other rare aggressive B-cell non-Hodgkin lymphoma (NHL) after sponsor approval."
6. 3. Has r/r B-cell neoplasms after one or more prior therapies or primary refractory to first-line therapy.Patients must have received adequate standard combination chemotherapy containing at least one anthracycline and/or methotrexate. Local therapies (e.g. radiotherapy) will not be considered a line of therapy if they are performed during the same line of treatment. Subjects who previously failed to respond to approved anti-CD19 or anti-CD20 CAR-T cell therapies will be permitted to participate in the study.
7. 4. Is a pediatric/adolescent (aged between 6 months and <18 years).
8. 5. Has a BW of ≥ 6 kg.
9. 6. Measurable disease based on the International Pediatric NHL Response Criteria (which refers to the Lugano criteria for definitions of measurability and selecting index lesions), as identified by local radiological assessment for lymphomas. Previously irradiated lesions cannot be considered measurable unless the lesion has proven radiological evidence for progression after the radiation.
10. 7. Tissue samples archival or fresh (preferred) from recent relapse or initial diagnosis (in case of primary refractory disease) must be made available for the central pathology review to confirm diagnosis (≤2 years, preferably not older than 2 months since collection).
11. 8. Has Karnofsky (aged ≥16 years) or Lansky (aged <16 years) performance status ≥60.
12. 9. Has adequate bone marrow function as defined by the following laboratory values (as assessed by local laboratory for eligibility): o Absolute neutrophil count (ANC) >1000/µL. o Platelets ≥50000/µL. o Hemoglobin ≥8.0 g/dL. o Absolute lymphocyte count ≥100/µL.
13. 13. Is willing to undergo collection of non-mobilized leukapheresis.
14. 14. In the opinion of the investigator, the subject must be able to comply with all study related procedures, medication use, and assessments.

Exclusion criteria 24

1. 1. Is receiving active treatment for malignant disease (including participation in any additional parallel investigational drug or device studies), except for pre-enrollment therapy, including radiotherapy. Lesions that are irradiated during pre-enrollment therapy may not be considered measurable lesions. For subjects with lymphoma to be eligible, there must be at least one measurable lesion after pre-enrollment therapy.
2. 2.Had allogeneic HSCT.
3. 3.Had autologous HSCT <120 days prior to written informed consent/assent.
4. 4.Had major surgery within 2 weeks before leukapheresis, or has not fully recovered from an earlier surgery, or has major surgery planned during the time the subject is expected to participate in the study.
5. 5.Subjects with B-cell neoplasms in the context of post-transplant lymphoproliferative disorders-associated lymphomas.
6. 6.Has known hypersensitivity to the excipients of the MB-CART2019.1 or to any other drug product as advised for administration in the study protocol (e.g., lymphodepleting agents).
7. 7.Has active central nervous system (CNS) involvement at the time point of eligibility confirmation, as measured by the presence of lymphoma cells in cerebral spinal fluid (CSF) on cytospin preparation.
8. 8. Has history or presence of autoimmune CNS disease, such as multiple sclerosis, optic neuritis, or other immunologic or inflammatory diseases.
9. 9. Infection with human immunodeficiency virus (HIV).
10. 10. Presence of active or prior hepatitis B or C as indicated by serology. Treated infection with hepatitis B or C virus unless confirmed to be polymerase chain reaction (PCR) negative.
11. 11. Has infection with Treponema pallidum.
12. 12. Has active infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2).
13. 13. Has infection with human T-lymphotropic virus 1/2 (HTLV 1/2).
14. 14.Has active severe systemic fungal, viral, or bacterial infection, requiring systemic antiviral, antifungal, or antimicrobial therapy.
15. 15. Has clinically significant seizures according to the opinion of by the investigator.
16. 16. Has history of cerebral vascular accident within 12 months prior to leukapheresis.
17. 17. Has impaired cardiac function: Fractional shortening <28% or left ventricular ejection fraction <50% by echocardiography or multigated acquisition, if allowed as per local law.
18. 18. Has concomitant genetic syndromes associated with bone marrow (BM) failure status, such as Fanconi anemia, Kostmann syndrome, Shwachman syndrome, or any other known BM failure syndrome.
19. 19. Is a pregnant or breast-feeding female.
20. 20. Is sexually active and not willing to use highly effective methods of contraception as described in the inclusion criteria.
21. 21. Has history of another malignancy within the prior 3 years that required systemic therapy.
22. 22. Has other medical, psychological, or social condition that, in the opinion of the investigator, would impact subject safety or confound the study results.
23. 23. Has received vaccination with live virus within 6 weeks prior to informed consent/assent.
24. 24. Has been previously treated with approved anti-CD19 or anti-CD20 CAR-T cell therapies <100 days prior to informed consent/assent.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. • Type, frequency, and severity of adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest (AESI). Primary efficacy estimand:
2. BORR, defined as the proportion of subjects with at least one partial response (PR) or complete response (CR) based on independent review committee (IRC) assessment from MB-CART2019.1 infusion until progressive disease (PD), start of new anti lymphoma therapy, lost to follow-up or death due to any cause, whichever occurs first.

Secondary endpoints 34

1. Key secondary efficacy endpoints • BORR until Week 24, defined as the proportion of subjects with at least one PR or CR after the MB-CART2019.1 infusion, based on IRC assessment until Week 24.
2. • CRR, defined as the proportion of subjects with at least one CR assessment, based on IRC assessment. "
3. • DOR, defined as the time between the date of first objective response (CR/PR) until the date of PD, based on IRC assessment, or lost to follow-up, or death due to any cause, whichever occurs first. "
4. • DOCR, defined as the time between the date of first CR until the date of PD, based on IRC assessment, or lost to follow-up, or death due to any cause, whichever occurs first. "
5. • TTR, defined as the time between the date of MB-CART2019.1 infusion and the date of a first objective response (CR/PR), based on IRC assessment. "
6. • TTCR, defined as the time between the date of MB-CART2019.1 infusion and the date of a first objective CR, based on IRC assessment. "
7. • ORR, defined as the proportion of subjects with a PR or CR, based on IRC assessment, at the following visits: Day 28, Week 8, Week 12, Week 24, Week 52, and Week 78. "
8. • EFS, defined as the time between the date of the MB-CART2019.1 infusion and the date of an event (PD, start of a new anti-lymphoma therapy after MB-CART2019.1 infusion excluding hematopoietic stem cell transplantation [HSCT], relapse, or death due to any cause), based on IRC assessment. "
9. • PFS, defined as the time between the date of MB-CART2019.1 infusion and the date of PD based on IRC assessment, or lost to follow-up, or death due to any cause, whichever occurs first. "
10. • OS, defined as the time between the date of MB-CART2019.1 infusion and the date of death due to any cause, irrespective of new anti-lymphoma therapy. "
11. • OS rates at Week 52 and at Week 78. "
12. • BORR, based on investigator assessment. "
13. • BORR until Week 24, based on investigator assessment. "
14. • CRR, based on investigator assessment. "
15. • DOR, based on investigator assessment. "
16. • DOCR, based on investigator assessment.
17. • TTR, based on investigator assessment. "
18. • TTCR, based on investigator assessment. "
19. • ORR, based on investigator assessment, at the following visits: Day 28, Week 8, Week 12, Week 24, Week 52, and Week 78. "
20. • EFS, based on investigator assessment. "
21. • PFS, based on investigator assessment.
22. • Occurrence and persistence of B-cell aplasia. "
23. • The proportion of subjects who proceed to HSCT after MB-CART2019.1 infusion until end of study (EOS). "
24. • Types and levels of cytokines (including soluble interleukin-2 receptor [sIL-2R], IL-6, IL-10, IL-15, interferon gamma [IFN-γ], and tumor necrosis factor alpha [TNF-α])
25. • Persistence and phenotype of MB-CART2019.1, based on flow cytometry analyses and persistence based on quantitative polymerase chain reaction (qPCR). "
26. • Anti-MB-CART2019.1 antibody via anti-drug antibody assay "
27. • Change from baseline in HRQoL, using the EuroQol-5 Dimensions-Youth (EQ-5D-Y) questionnaire"
28. • Hospital days within 6 months after MB-CART2019.1 infusion. "
29. • Intensive care unit (ICU) admission days within 6 months after MB-CART2019.1 infusion. "
30. • Use of tocilizumab and/or high-dose steroids and/or anti-interleukin medication. "
31. • Need for transfusions, prophylactic antimicrobial therapy, and gamma globulin substitution within 12 months after MB-CART2019.1 infusion.
32. • Change in clinical laboratory assessments, physical and neurological examinations, and electrocardiogram (ECG) parameters within 6 months after MB-CART2019.1 infusion. "
33. • Monitoring of RCL by qPCR"
34. • CD19/CD20 antigen expression in tumor biopsies in case of relapse after MB-CART2019.1 infusion

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Miltenyi Biomedicine GmbH

Sponsor organisation

Miltenyi Biomedicine GmbH

Address

Friedrich-Ebert-Strasse 68, Moitzfeld Moitzfeld

City

Bergisch Gladbach

Postcode

51429

Country

Germany

Scientific contact point

Organisation

Miltenyi Biomedicine GmbH

Contact name

Clinical Trial Desk

Public contact point

Organisation

Miltenyi Biomedicine GmbH

Contact name

Clinical Trial Desk

Third parties 14

Locations

4 EU/EEA countries · 6 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Corrective measures 1 · Art. 77 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 55 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications