DALY II USA/ MB-CART2019.1 for DLBCL

• ClinicalTrials.gov Identifier: NCT04792489
• Recruitment Status: Recruiting
• First Posted: March 11, 2021
• Last Update Posted: April 26, 2024
• Sponsor: Miltenyi Biomedicine GmbH
• Information provided by (Responsible Party): Miltenyi Biomedicine GmbH

Tracking Information

• First Submitted Date: February 25, 2021
• First Posted Date: March 11, 2021
• Last Update Posted Date: April 26, 2024
• Actual Study Start Date: May 25, 2021
• Estimated Primary Completion Date: December 31, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 8, 2023)

Overall Response Rate [ Time Frame: through study completion, up to 2 years ]

ORR

Original Primary Outcome Measures (submitted: March 9, 2021)

Overall Response Rate [ Time Frame: 1 month ]

ORR

Current Secondary Outcome Measures (submitted: August 8, 2023)

• Complete Response Rate [ Time Frame: 1 and 6 months ]
  CRR
• Duration of Response [ Time Frame: Up to 2 years ]
  DOR
• Overall Response Rate [ Time Frame: 1 and 6 months ]
  ORR
• Best Overall Response [ Time Frame: 2 years ]
  BOR
• Progression Free Survival [ Time Frame: Up to 2 years ]
  PFS
• Overall Survival [ Time Frame: Up to 2 years ]
  OS
• Type, frequency, and severity of adverse events [ Time Frame: Up to 2 years ]
  Safety
• Incidence of anti-MD-CART2019.1 antibodies [ Time Frame: Up to 2 years ]
  Bioanalytical
• Phenotype of MB-CART2019.1 [ Time Frame: Up to 2 years ]
  Bioanalytical
• Persistence of MB-CART2019.1 [ Time Frame: Up to 2 years ]
  Bioanalytical
• Quality of Life (QoL) assessments [EQ-5D-5L] [ Time Frame: Up to 2 years ]
  Health Outcomes - Standardized 5 question measure of health status developed by the EuroQol Group
• Patient-Reported Outcome (PRO) assessment [FACT-Lym] [ Time Frame: Up to 2 years ]
  Health Outcomes - To address health-related quality-of-life (HRQL) issues for Non-Hodgkin's lymphoma (NHL) patients
• Pharmacodynamics [Levels of cytokines in blood] [ Time Frame: Up to 2 years ]
  Bioanalytical
• Correlation of tumor CD19 and CD20 antigen expression with disease progression and relapse [ Time Frame: Up to 2 years ]
  Bioanalytical

Original Secondary Outcome Measures (submitted: March 9, 2021)

• Complete Response Rate [ Time Frame: 6 months ]
  CRR
• Duration of Response [ Time Frame: Up to 2 years ]
  DOR
• Overall Response Rate [ Time Frame: 6 months ]
  ORR
• Best Overall Response [ Time Frame: 2 years ]
  BOR
• Progression Free Survival [ Time Frame: Up to 2 years ]
  PFS
• Overall Survival [ Time Frame: Up to 2 years ]
  OS
• Pharmacokinetics of MB-CART2019.1 [Maximum concentration (Cmax)] [ Time Frame: Up to 2 years ]
  Bioanalytical
• Pharmacokinetics of MB-CART2019.1 [Time to maximum concentration (Tmax)] [ Time Frame: Up to 2 years ]
  Bioanalytical
• Pharmacokinetics of MB-CART2019.1 [Area under the curve (AUC)] [ Time Frame: Up to 2 years ]
  Bioanalytical

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: March 9, 2021)

• Pharmacodynamics [Levels of cytokines in blood] [ Time Frame: Up to 2 years ]
  Bioanalytical
• Correlation of tumor CD19 and CD20 antigen expression with disease progression and relapse [ Time Frame: Up to 2 years ]
  Bioanalytical
• Quality of Life (QoL) assessments [EQ-5D-5L] [ Time Frame: Up to 2 years ]
  Health Outcomes
• Patient-Reported Outcome (PRO) assessment [FACT-Lym] [ Time Frame: Up to 2 years ]
  Health Outcomes

Descriptive Information

• Brief Title: DALY II USA/ MB-CART2019.1 for DLBCL
• Official Title: A Multi-center Single Arm Phase II Study to Evaluate the Safety and Efficacy of Genetically Engineered Autologous Cells Expressing Anti-CD20 and Anti-CD19 Specific Chimeric Antigen Receptor in Subjects With Relapsed and/or Refractory Diffuse Large B Cell Lymphoma
• Brief Summary: DALY II USA is a phase II, multi-center, single arm study to evaluate the efficacy, safety, and pharmacokinetics of zamtocabtagene autoleucel (MB-CART2019.1) in patients with relapsed and/or refractory diffuse large B cell lymphoma (DLBCL) after receiving at least two lines of therapy.
• Detailed Description: A prospective, single arm, open label, multi-center, phase II study of autologous T cells engineered against both CD19 and CD20 antigens for subjects with relapsed or refractory DLBCL after receiving at least two lines of therapy. The investigational agent is the MB-CART2019.1 cells. After successful screening, subjects will undergo leukapheresis to collect product for manufacturing. In preparation for the fresh product infusion, subjects will undergo a lymphodepleting regimen with cyclophosphamide and fludarabine, or bendamustine. Cell infusion will be administered intravenously at a dose of 2.5 x 106 CAR+ cells/kg body weight. The study will start with enrollment of 3 subjects in the lead-in safety phase, and after safety is evaluated, the study will continue with enrollment of the remaining subjects. Subjects will be followed for up to 2 years, for efficacy and safety outcomes as well as health-related quality of life (HRQol). Additional long-term follow-up will be conducted for participants under a separate long-term follow-up protocol.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Refractory Diffuse Large B Cell Lymphoma (DLBCL)
• Relapsed Diffuse Large B Cell Lymphoma
• High Grade B-cell Lymphoma (HGBCL)
• Primary Mediastinal B-cell Lymphoma (PMBCL)
• Transformed Lymphoma
• Central Nervous System Lymphoma

Intervention

• Biological: zamtocabtagene autoleucel (MB-CART2019.1)
  Chimeric antigen receptor (CAR) T cell therapy
• Drug: Cyclophosphamide
  Lymphodepleting chemotherapy
• Drug: Fludarabine
  Lymphodepleting chemotherapy
• Drug: Bendamustine
  Lymphodepleting chemotherapy

Study Arms

Experimental: Single, open label

Interventions:

• Biological: zamtocabtagene autoleucel (MB-CART2019.1)
• Drug: Cyclophosphamide
• Drug: Fludarabine
• Drug: Bendamustine

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 8, 2023): 110
• Original Estimated Enrollment (submitted: March 9, 2021): 65
• Estimated Study Completion Date: December 31, 2026
• Estimated Primary Completion Date: December 31, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Histologically confirmed DLBCL or associated subtype, defined by WHO 2016 classification:
• CNS Cohort only: B-cell primary or secondary central nervous system lymphoma (PCNSL or SCNSL)
• 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
• Chemotherapy-refractory disease is defined as persistent disease after last line of therapy or relapsed or persistent disease after prior ASCT for lymphoma
• Disease relapse in subjects without prior ASCT is defined as relapse of disease after the last dose of most recent therapy regimen
• CNS Cohort: Subjects with relapsed/refractory PCNSL that have failed (or unable to tolerate) first-line therapy.
• CNS Cohort: Subjects with SCNSL must have relapsed or refractory disease after having received at least 1 prior line of systemic therapy
• Age ≥18 years
• 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
• 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.
• 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
• No clinical suspicion of central nervous system (CNS) lymphoma (not applicable to CNS cohort)
• If the subject has history of CNS disease (not applicable to CNS cohort), then he/she must have no signs or symptoms of CNS disease, have no active disease on magnetic resonance imaging (MRI), 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)
• If has history of cerebral vascular accident (CVA), the CVA event must be greater than 12 months prior to leukapheresis. Any neurological deficits must be stable.
• A creatinine clearance (as estimated by direct urine collection or Cockcroft-Gault Equation) > 45mL/min
• Cardiac ejection fraction (EF) ≥ 45% as determined by an echocardiogram (ECHO) or Multigated Radionuclide Angiography (MUGA)
• Resting O2 saturation >90% on room air
• Serum alanine aminotransferase (ALT) / aspartate aminotransferase (AST) <5 times the Upper Limit of Normal (ULN) for age
• Total bilirubin <1.5 mg/dl, except in individuals with Gilbert's syndrome
• Absolute neutrophil count (ANC) > 1000/μL
• Absolute lymphocyte count > 100/μL
• Platelet count > 50,000/µL
• Estimated life expectancy of more than 3 months other than primary disease

Exclusion Criteria:

• Primary CNS lymphoma (not applicable to CNS cohort)
• Richter's transformed DLBCL arising from chronic lymphocytic leukemia (CLL)
• Unable to give informed consent
• 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 quantitative polymerase chain reaction (PCR) negative; antiviral prophylaxis is required if HBsAg negative and anti-HBc positive.
• Known history of infection with hepatitis C virus (anti-HCV positive) unless viral load is undetectable per quantitative PCR and/or nucleic acid testing.
• Seizure that is not effectively controlled pharmacologically.
• Known history of CVA within prior 12 months.
• Known history or presence of autoimmune CNS disease, such as multiple sclerosis, optic neuritis, or other immunologic or inflammatory disease
• Presence of CNS disorder that, in the judgment of the investigator, may impair the ability to evaluate neurotoxicity. For CNS Cohort: Bulky leptomeningeal disease and or CSF protein >100 mg/Dl. Recent (within 2 months) whole brain radiotherapy (WBRT)
• Active systemic fungal, viral, or bacterial infection
• Pregnant or breast-feeding woman
• Previous or concurrent malignancy with the following exceptions:
• Adequately treated basal cell or squamous cell carcinoma (adequate wound healing 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
• Immunocompromised subjects e.g., due to current treatment of non-neurologic autoimmune disease (e.g., Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus).
• Medical condition requiring prolonged use of systemic corticosteroids equivalent to prednisone >10 mg/day
• History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 6 months of enrollment
• 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.
• Baseline dementia that would interfere with therapy or monitoring, determined using Immune Effector Cell-Associated Encephalopathy (ICE) Assessment at baseline
• History of severe immediate hypersensitivity reaction to any of the agents used in this study
• Refusal to participate in additional lentiviral gene therapy LTFU protocol
• Prior CAR-T therapy for any indication or systemic gene modifying therapy for DLBCL
• Prior allogeneic stem cell transplant for any indication
• Prior BITE antibodies for cancer therapy
• Prior T cell receptor-engineered T cell therapy

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Bryan Dumont; 617-218-0044; clinicaltrials@miltenyi.com

Contact: Harshita Gahankari; 617-218-0044; clinicaltrials@miltenyi.com

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04792489
• Other Study ID Numbers: M-2018-344
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Miltenyi Biomedicine GmbH
• Original Responsible Party: Same as current
• Current Study Sponsor: Miltenyi Biomedicine GmbH
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Remi Kaleta; Miltenyi Biomedicine GmbH

• PRS Account: Miltenyi Biomedicine GmbH
• Verification Date: April 2024