Phase II Evaluation of Safety and Efficacy of Zamtocabtagene Autoleucel in Pediatric Relapsed/Refractory Mature B-Cell Neoplasms with Fludarabine and Cyclophosphamide
- Trial ID
- 2023-506348-17-00
- Protocol
- M-2021-389
- Sponsor
- Miltenyi Biomedicine GmbH
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **safety**, toxicity, and efficacy of MB-CART2019.1 therapy in pediatric subjects with relapsed/refractory mature B cell neoplasms. This is measured by the best overall response rate (BORR) following infusion. Evaluating these parameters is clinically relevant as it provides critical insights into the therapeutic potential and risk profile of MB-CART2019.1 in a population with limited treatment options.
Secondary objectives include:
- Assessing the efficacy of MB-CART2019.1 through various metrics such as BORR, complete response rate (CRR), duration of response (DOR), and overall survival (OS).
- Evaluating circulating B cell numbers and levels of immunoglobulin M (IgM) and immunoglobulin G (IgG).
- Determining the proportion of subjects proceeding to transplant post-therapy.
- Measuring and correlating cytokine levels with cytokine release syndrome (CRS), neurotoxicities, and efficacy.
- Exploring the relationship between CD19/CD20 antigen expression by B cells and response to therapy.
- Evaluating humoral immunogenicity against MB-CART2019.1.
- Assessing health-related quality of life (HRQoL).
- Further assessing the safety and toxicity of MB-CART2019.1.
- Monitoring replication-competent lentivirus (RCL).
Participants
The clinical trial involves a study population comprising **pediatric and adolescent** subjects aged between 6 months and less than 18 years, diagnosed with **relapsed/refractory mature B cell neoplasms**. The trial includes both male and female participants, and the population is considered vulnerable due to the age range. The sponsor has not provided the total number of participants. Participants were selected based on their medical condition, having relapsed after one or more prior therapies, or having primary refractory disease. The trial does not specify any particular lifestyle considerations such as diet or physical activity. Key inclusion criteria include adequate organ function, measurable disease, and a performance status of at least 60 on the Karnofsky or Lansky scale, depending on age. The trial aims to assess the safety, toxicity, and efficacy of MB-CART2019.1 therapy in this specific population.
Plans and Procedures
The clinical trial is designed as a **single-arm**, multi-center, open-label Phase II study to evaluate the safety and efficacy of **MB-CART2019.1** in pediatric subjects with relapsed/refractory mature B-cell neoplasms. The primary objective is to assess the safety, toxicity, and efficacy of MB-CART2019.1 therapy, as measured by the best overall response rate (BORR) after infusion. The trial is expected to commence recruitment on February 1, 2025, and conclude by August 11, 2029. Participants will be involved in the study for a duration that includes the initial infusion and follow-up assessments up to 78 weeks post-infusion.
The trial involves a sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, disease status, and organ function. Following the screening, eligible participants will receive the investigational product, MB-CART2019.1, via **intravenous injection**. Subsequent follow-up visits are scheduled at Day 28, Week 8, Week 12, Week 24, Week 52, and Week 78 to monitor safety and efficacy outcomes, including adverse events and response rates. The end-of-study visit will occur at the conclusion of the 78-week follow-up period.
Participant involvement is expected to last from the initial screening through the end-of-study visit, with the possibility of early termination if criteria such as disease progression, unacceptable toxicity, or withdrawal of consent are met. The study will employ rigorous monitoring to ensure participant safety and data integrity, with adverse events being closely tracked and reported. The trial's design and procedures are structured to provide comprehensive data on the investigational therapy's impact on relapsed/refractory mature B-cell neoplasms in the pediatric population.
Treatment
The clinical trial involves the administration of **MB-CART2019.1**, an experimental medication designed for the treatment of relapsed/refractory mature B-cell neoplasms. The active substance in MB-CART2019.1 is **zamtocabtagene autoleucel**, a structurally diverse substance used in cell therapy. This medication is administered via **intravenous injection** in the form of an **infusion**. The maximum daily dose is 2,500,000 IU/kg, with a total maximum dose of 2,500,000 IU/kg over a treatment period of one day. The therapy involves the use of a lentiviral vector for ex vivo transduction of T cells, specifically targeting the (anti-) CD20-CD19 CAR. Participant compliance is monitored through regular assessments of the best overall response rate (BORR) post-infusion.
In addition to the experimental treatment, the trial includes the administration of **fludarabine**, a chemical entity used as an auxiliary treatment. Fludarabine is administered via **intravenous administration** with a pharmaceutical form denoted as PHF675. The dosing regimen allows for a maximum daily dose of 30 mg/m² and a total maximum dose of 90 mg/m² over a treatment period of three days. This medication is classified under the ATC code L01BB05.
Another auxiliary treatment used in the trial is **cyclophosphamide**, also a chemical entity. Cyclophosphamide is administered through **intravenous administration** with a pharmaceutical form identified as PHF00231MIG. The dosing schedule permits a maximum daily dose of 500 mg/m² and a total maximum dose of 1,500 mg/m² over a three-day treatment period. It is classified under the ATC code L01AA01.
Lastly, **tocilizumab** is included as an auxiliary treatment, categorized as a protein entity. Tocilizumab is administered via **intravenous injection** with the same pharmaceutical form as cyclophosphamide, PHF00231MIG. The maximum daily dose is 2,400 mg, with a total maximum dose of 3,200 mg over a two-day treatment period. It is classified under the ATC code L04AC07. Compliance with the dosing schedule is monitored to ensure adherence to the treatment protocol.
Efficacy
The efficacy of the investigational product MB-CART2019.1 in the clinical trial will be assessed primarily through the **best overall response rate (BORR)**. This will be determined based on the independent review committee (IRC) assessment in pediatric and adolescent patients with relapsed/refractory mature B-cell neoplasms. The BORR will be evaluated after the MB-CART2019.1 infusion until the occurrence of a complete response (CR), progressive disease (PD), initiation of new anti-cancer therapy, death from any cause, or loss to follow-up, whichever occurs first.
Secondary efficacy endpoints include BORR until Week 24, complete response rate (CRR), duration of response (DOR), duration of complete response (DOCR), time to response (TTR), time to complete response (TTCR), overall response rate (ORR) at specified timepoints (Day 28, Week 8, Week 12, Week 24, Week 52, and Week 78), event-free survival (EFS), progression-free survival (PFS), and overall survival (OS) rates at Week 52 and Week 78. These endpoints will also be assessed based on IRC and investigator evaluations.
Additional assessments will include the occurrence and persistence of B-cell aplasia, the proportion of subjects proceeding to hematopoietic stem cell transplantation (HSCT), cytokine levels, persistence and phenotype of MB-CART2019.1, anti-MB-CART2019.1 antibody presence, changes in health-related quality of life (HRQoL) using the EuroQol-5 Dimensions-Youth (EQ-5D-Y) questionnaire, and healthcare utilization metrics such as hospital and intensive care unit (ICU) admission days. The use of tocilizumab, high-dose steroids, and anti-interleukin medication, as well as the need for transfusions and other supportive therapies, will also be monitored.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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.
- 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)."
- Female subjects of childbearing potential must be willing to undergo pregnancy tests before MB-CART2019.1 infusion.
- 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.
- 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."
- 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.
- Is a pediatric/adolescent (aged between 6 months and <18 years).
- Has a BW of ≥ 6 kg.
- 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.
- 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).
- Has Karnofsky (aged ≥16 years) or Lansky (aged <16 years) performance status ≥60.
- 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.
- Is willing to undergo collection of non-mobilized leukapheresis.
- In the opinion of the investigator, the subject must be able to comply with all study related procedures, medication use, and assessments.
Exclusion Criteria
- 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.Had allogeneic HSCT.
- 3.Had autologous HSCT <120 days prior to written informed consent/assent.
- 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.Subjects with B-cell neoplasms in the context of post-transplant lymphoproliferative disorders-associated lymphomas.
- 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.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.
- Has history or presence of autoimmune CNS disease, such as multiple sclerosis, optic neuritis, or other immunologic or inflammatory diseases.
- Infection with human immunodeficiency virus (HIV).
- 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.
- Has infection with Treponema pallidum.
- Has active infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2).
- Has infection with human T-lymphotropic virus 1/2 (HTLV 1/2).
- 14.Has active severe systemic fungal, viral, or bacterial infection, requiring systemic antiviral, antifungal, or antimicrobial therapy.
- Has clinically significant seizures according to the opinion of by the investigator.
- Has history of cerebral vascular accident within 12 months prior to leukapheresis.
- Has impaired cardiac function: Fractional shortening <28% or left ventricular ejection fraction <50% by echocardiography or multigated acquisition, if allowed as per local law.
- 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.
- Is a pregnant or breast-feeding female.
- Is sexually active and not willing to use highly effective methods of contraception as described in the inclusion criteria.
- Has history of another malignancy within the prior 3 years that required systemic therapy.
- Has other medical, psychological, or social condition that, in the opinion of the investigator, would impact subject safety or confound the study results.
- Has received vaccination with live virus within 6 weeks prior to informed consent/assent.
- Has been previously treated with approved anti-CD19 or anti-CD20 CAR-T cell therapies <100 days prior to informed consent/assent.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 02 Jun 2025 | 4 |
 Germany | Not Yet Recruiting | 02 Jun 2025 | 2 |
 Italy | Recruiting | 02 Jun 2025 | 4 |
 The Netherlands | Not Yet Recruiting | 02 Jun 2025 | — |
| Netherlands | — | — | 2 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
MB-CART2019.1 | Test | INFUSION | INTRAVENOUS INJECTION | 2500000 | 1 | PRD6952233 |
FLUDARABINE | Other | PHF675 | INTRAVENOUS ADMINISTRATION | 30 | 3 | SCP107125968 |
CYCLOPHOSPHAMIDE | Other | PHF00231MIG | INTRAVENOUS ADMINISTRATION | 500 | 3 | SCP106382672 |
TOCILIZUMAB | Other | PHF00231MIG | INTRAVENOUS INJECTION | 2400 | 2 | SCP176238 |