Daly Ii USAMB-CART20191 for Dlbcl

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Miltenyi Biomedicine GmbH

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2024-07-01

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Miltenyi Biomedicine GmbH, OMS Number: ORG-100022099

External identifiers

EU CT number

2023-508508-39-01

ClinicalTrials.gov

NCT04792489

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Others, Efficacy

To determine the efficacy of MB-CART2019.1 cells administered following a conditioning lymphodepletion regimen in diffuse large B cell lymphoma (DLBCL) subjects who failed at least two lines of therapy as measured by ORR based on best overall response (BOR)

Secondary objectives 1

1. • To describe the outcome of subjects up to two years after receiving MB-CART2019.1 cells as measured by complete and objective response rate (CRR and ORR) at 1 and 6 month, and duration of response (DOR), progression-free survival (PFS), and overall survival (OS) • To evaluate safety of MB-CART2019.1 • To correlate the in vivo persistence of MB-CART2019.1 with clinical efficacy, incidence of cytokine release syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) • To characterize the types and level of serum cytokines associated MB-CART2019.1 infusion • To evaluate immunogenicity against MB-CART2019.1 • To explore the relationship between antigen expression and disease progression and relapse after MB-CART2019.1 treatment • To evaluate changes in Quality of Life (QoL)/Patient-Reported Outcome (PRO) assessments (EQ-5D-5L and FACT-Lym)

Conditions and MedDRA coding

Relapsed/refractory diffuse large B cell lymphoma (R-R DLBCL)

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Food And Drug Administration

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 3

1. 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.
2. Continued translation (1-5)
3. 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 1

1. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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

Secondary endpoints 3

1. • 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)
2. Continued translation
3. • 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)

Investigational products

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

Test 1

Auxiliary 11

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 13

Locations

2 EU/EEA countries · 2 investigational sites

By country

Investigational sites

Results and documents

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

Documents 7 files

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

Application history

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