ZAMTOCABTAGENE AUTOLEUCEL for Diffuse large B-cell lymphoma (DLBCL) | Relapsed/refractory diffuse large B-cell lymphoma

Inclusion criteria

• {"criterion_text":"- 1. Histologically confirmed DLBCL or associated subtype, defined by WHO 2016 classification: o DLBCL not otherwise specified (NOS) o High-grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements o High-grade B cell lymphoma, NOS o Primary mediastinal (thymic) large B cell lymphoma o Transformed lymphoma (e.g. transformed follicular or marginal zone lymphoma, follicular lymphoma Grade 3) 1.1. CNS Cohort only: B-cell primary or secondary central nervous system lymphoma (PCNSL or SCNSL) 2. Relapsed or refractory disease after 2 or more lines of chemotherapy including rituximab and anthracycline and either having failed autologous stem cell transplant (ASCT), or ineligible, not intended for or not consenting to ASCT (only 2.4 applicable to CNS cohort) 2.1. Chemotherapy-refractory disease is defined as one or more of the following: • Persistent disease after last line of therapy: o Progressive disease (PD) as best response to most recent therapy regimen o Stable disease (SD) as best response to most recent therapy o Partial response (PR) with measurable lesion(s) and Deauville score of at least 4, that in the opinion of the investigator requires change of treatment to CAR-T for improvement in treatment outcome OR • Relapsed or persistent disease after prior ASCT for lymphoma o If salvage therapy is given post-ASCT, the individual must have had persistent disease (as described above) or relapsed after the last line of therapy 2.2. Disease relapse in subjects without prior ASCT is defined as relapse of disease after the last dose of most recent therapy regimen 2.3. Not intended for ASCT is defined as meeting one of the following criteria: • Chemotherapy-refractory disease after salvage therapy • Disease progression or relapse ≤ 12 months after salvage therapy • Intolerance to salvage therapy • Age ≥ 70 2.4. CNS Cohort: Subjects with relapsed/refractory PCNSL that have failed (or unable to tolerate) first-line therapy: • First-line therapy is defined as either high dose methotrexate-based therapy, temozolomide, high dose cytarabine, pemetrexed, lenalidomide or bruton thyrosine kinase (BTK) inhibitor-based therapy. • Unable to tolerate therapy is defined as Grade 3+ acute kidney injury (AKI) and/or transaminitis preventing repeat treatment exposure • Persistent disease after last line of therapy (as in 2.1) • No contraindications for MRI evaluation 2.5. CNS Cohort: Subjects with SCNSL must have relapsed or refractory disease after having received at least 1 prior line of systemic therapy • Prior lines of systemic therapy should include an anti- CD20 monoclonal antibody and anthracycline containing chemotherapy regimen and/or an autologous stem cell transplant • No contraindications for MRI evaluation In addition, all subjects must have: 3. Age ≥18 years 4. Eastern Cooperative Oncology Group (ECOG) performance status that is either 0 or 1 at screening. ECOG performance status of 2 at screen is allowed if the decrease in performance status is due to DLBCL 5. Measurable disease according to Lugano 2014 criteria for assessing FDG-PET/CT in lymphoma (Cheson et al, 2014) for DLBCL and SCNSL while IPCG criteria for the primary PCNSL."}
• {"criterion_text":"- Continued translation (1-5)"}
• {"criterion_text":"- 6. CD19 or CD20 antigen expression on tumor is not required after the most recent chemoimmunotherapy; however, 6.1 Subject must have a tumor biopsy sample (at least 16 unstained slides of tissue or tissue block) from the most recent relapse available prior to MB-CART2019.1 infusion. If medically not feasible to obtain a biopsy from the most recent relapse and for cases when the amount of tissue is limited, the sponsor should be consulted, to confirm adequacy of the sample for study required analyses 6.2 If archival tissue is not available, subject must be willing to undergo attempted repeat biopsy. 7. No clinical suspicion of central nervous system (CNS) lymphoma (not applicable to CNS cohort) 8. If the subject has history of CNS disease (not applicable to CNS cohort), then he/she must 8.1. Have no signs or symptoms of CNS disease 8.2. Have no active disease on magnetic resonance imaging (MRI) 8.3. Have no large cell lymphoma present in cerebral spinal fluid (CSF) on cytospin preparation and flow cytometry, regardless of the number of white blood cells (WBCs) 9. If has history of cerebral vascular accident (CVA) 9.1. The CVA event must be greater than 12 months prior to leukapheresis 9.2. Any neurological deficits must be stable 10. A creatinine clearance (as estimated by direct urine collection or Cockcroft-Gault Equation) > 60mL/min 11. Cardiac ejection fraction (EF) ≥ 45% as determined by an echocardiogram (ECHO) or Multigated Radionuclide Angiography (MUGA) 12. Resting O2 saturation >90% on room air 13. Serum alanine aminotransferase (ALT) / aspartate aminotransferase (AST) <5 times the Upper Limit of Normal (ULN) for age 14. Total bilirubin <1.5 mg/dl, except in individuals with Gilbert’s syndrome 15. Absolute neutrophil count (ANC) > 1000/μL 16. Absolute lymphocyte count > 100/μL 17. Platelet count > 50,000/μL 18. Estimated life expectancy of more than 3 months other than primary disease 19. Subjects of childbearing or childfathering potential must be willing to practice birth control from the time of enrollment on this study until the follow-up period of the study"}

Exclusion criteria

• {"criterion_text":"- 1. Primary CNS lymphoma (not applicable to CNS cohort) 2. Richter’s transformed DLBCL arising from chronic lymphocytic leukemia (CLL) 3. Unable to give informed consent 4. Known history of infection with human immunodeficiency virus (HIV) or active hepatitis B (HBsAg positive). If there is a history of treated hepatitis B or hepatitis C, the viral load must be polymerase chain reaction (PCR) negative; antiviral prophylaxis is required if HBsAg negative and anti-HBc positive 5. Known history of infection with hepatitis C virus (anti-HCV positive) unless viral load is undetectable per quantitative PCR and/or nucleic acid testing 6. Known history of active seizure or presence of seizure activities except CNS lymphoma related, pharmacologically controlled seizure 7. Known history of CVA within prior 12 months 8. Known history or presence of autoimmune CNS disease, such as multiple sclerosis, optic neuritis or other immunologic or inflammatory disease 9. Presence of active CNS disorder that, in the judgment of the investigator, may impair the ability to evaluate neurotoxicity 9.1. For CNS Cohort: • Bulky leptomeningeal disease and or CSF protein >100 mg/Dl • Recent (within 2 months) whole brain radiotherapy (WBRT) 10. Active systemic fungal, viral or bacterial infection 11. Pregnant or breast-feeding woman 12. Previous or concurrent malignancy with the following exceptions: • Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is required prior to study entry) • In situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 2 years prior to the study • Adequately treated breast or prostate carcinoma on hormonal therapies such as Lupron or tamoxifen and in clinical remission of ≥ 2 years • A primary malignancy which has been completely resected / treated with curative intent and in complete remission of ≥ 2 years 13. History of non-neurologic autoimmune disease (e.g. Crohn’s disease, rheumatoid arthritis, systemic lupus erythematosus) requiring systemic immunosuppressive or systemic disease modifying agents within the last 2 years 14. Medical condition requiring prolonged use of systemic corticosteroids equivalent to Prednisone >10 mg/day 15. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 6 months of enrollment 16. Concurrent radiotherapy (normal tissue sparing palliative radiotherapy allowed up to time of lymphodepletion). For systemic therapy, at least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed at the time of scheduled leukapheresis 17. Baseline dementia that would interfere with therapy or monitoring, determined using Immune Effector Cell-Associated Encephalopathy (ICE) Assessment at baseline. (Appendix 6, Section 13.6) 18. History of severe immediate hypersensitivity reaction to any of the agents used in this study 19. Refusal to participate in additional lentiviral gene therapy long-term follow-up (LTFU) protocol 20. Prior CAR-T therapy for any indication or systemic gene-modifying therapy for DLBCL 21. Prior allogeneic stem cell transplant for any indication. 22. Prior Bispecific T cell engaging (BITE) antibodies for cancer therapy 23. Prior T cell receptor-engineered T cell therapy"}

Primary endpoints

• {"endpoint_text":"- Objective Response Rate (ORR) defined as the proportion of subjects with partial response (PR) or complete response (CR) as their best overall response as assessed using Lugano Criteria (Cheson et al., 2014) as determined by an IRC","definition_or_measurement_approach":"Defined as the proportion of subjects with PR or CR as their best overall response assessed using Lugano Criteria (Cheson et al., 2014) as determined by an Independent Review Committee (IRC)."}

Secondary endpoints

• {"endpoint_text":"- • Complete response rate (CRR) using Lugano 2014 Criteria (Cheson et al, 2014)* at 1 and 6 months • Duration of Response (DOR) • ORR using Lugano 2014 criteria (Cheson et al, 2014)* at 1 and 6 month • Best Overall Response (BOR) • Progression-Free Survival (PFS) • Overall Survival (OS) • Type, frequency and severity of adverse events (AEs), serious adverse events (SAEs) and adverse events of special interest (AESI)","definition_or_measurement_approach":"CRR and ORR assessed using Lugano 2014 Criteria at 1 and 6 months; DOR, BOR, PFS, OS per standard definitions; safety assessed by type, frequency and severity of AEs/SAEs/AESIs."}
• {"endpoint_text":"- Continued translation","definition_or_measurement_approach":""}
• {"endpoint_text":"- • Incidence of anti-MB-CART2019.1 antibodies • Phenotype and persistence of MB-CART2019.1 • Measure and correlate the types and level of cytokines in subjects following MB-CART2019.1 infusion with severity of CRS, ICANS, and efficacy • Correlate the changes in tumor CD19 and CD20 antigen expression with disease progression and relapse • Quality of Life (QoL)/Patient-Reported Outcome (PRO) assessments (EQ-5D-5L and FACT-Lym)","definition_or_measurement_approach":"Immunogenicity: incidence of anti-MB-CART2019.1 antibodies; cellular phenotype and persistence measured (e.g. flow cytometry/qPCR as per sponsor lab arrangements); cytokine levels measured and correlated with CRS/ICANS and efficacy; antigen expression correlation analyses; QoL assessed using EQ-5D-5L and FACT-Lym."}

Hungary

Earliest CTIS Part Ii Submission Date

24-05-2024

Latest Decision Or Authorization Date

06-05-2026

Processing Time Days

712

Number Of Sites

1

Number Of Participants

2

Croatia

Earliest CTIS Part Ii Submission Date

31-05-2024

Latest Decision Or Authorization Date

24-04-2026

Processing Time Days

693

Number Of Sites

1

Number Of Participants

2

Primary sponsor

Full Name

Miltenyi Biomedicine GmbH

Organisation Type

Pharmaceutical company

Country Of Registered Address

Germany

Contract research organisations

Name

PPD Global Limited

Responsibilities

Clinical CRO vendor

Name

Icon Clinical Research Limited

Responsibilities

DSMB

Name

Parexel International (IRL) Limited

Responsibilities

DM, Safety, eTMF

Third parties

• {"country":"United Kingdom","full_name":"PPD Global Limited","duties_or_roles":"Clinical CRO vendor","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"EvidentlQ Germany GmbH","duties_or_roles":"EDC, SDTM, supportive statistics (Marvin tool used for building of eCRF)","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Perceptive Informatics Inc.","duties_or_roles":"IRC of disease assessment - Lymphoma","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Miltenyi Biotec B.V. & Co. KG","duties_or_roles":"IMP Manufacterer","organisation_type":"Pharmaceutical company"}
• {"country":"Ireland","full_name":"Icon Clinical Research Limited","duties_or_roles":"DSMB","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Quest Diagnostics Inc.","duties_or_roles":"Central Pathology review","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Llx Solutions LLC","duties_or_roles":"SDTM, supportive statistics","organisation_type":"Pharmaceutical company"}
• {"country":"Ireland","full_name":"Parexel International (IRL) Limited","duties_or_roles":"DM, Safety, eTMF","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Indiana University","duties_or_roles":"Replication competent lentivirus (RCL) via qPCR","organisation_type":"Educational Institution"}
• {"country":"Germany","full_name":"Medizinisches Versorgungszentrum fuer Labordiagnostik und Mikrobiologie Rhein-Main GmbH","duties_or_roles":"Specility lab - Flow cytometry based persistency and phenotyping","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Eurofins Lancaster Laboratories Inc.","duties_or_roles":"Cytokine testing; central storage of secondary endpoint samples","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Germany","full_name":"Discovery Life Sciences Biomarker Services GmbH","duties_or_roles":"Speciality lab for qPCR based persistency, qPCR based Replication competent lentivirus (RCL), sample storage","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"BioAgilytix Europe GmbH","duties_or_roles":"Specility lab - Humoral immunogenicity (Anti-Drug Antibody assay), sample storage","organisation_type":"Pharmaceutical company"}