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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

Phase
Phase 2
Sponsor
Miltenyi Biomedicine GmbH
Enrollment
248
Timeline
May 2021 → Dec 2028
About This Study

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. Additional cohorts include subjects with B-cell primary or secondary central nervous system (CNS) lymphoma (PCNSL) and (SCNSL), mantle cell lymphoma (MCL) and Richter's transformation (RT) after receiving at least one line of therapy.

Eligibility Criteria

Inclusion Criteria

  • 1Histologically confirmed B-cell non-Hodgkin's lymphoma:
  • 2DLBCL DLBCL or associated subtype, defined by WHO 2016 classification:
  • 3DLBCL not otherwise specified (NOS)
  • 4High-grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements
  • 5High-grade B cell lymphoma (NOS)
  • 6Primary mediastinal (thymic) large B cell lymphoma
  • 7Transformed lymphoma (e.g., transformed follicular, or marginal zone lymphoma, follicular lymphoma (FL Grade 3)
  • 8CNS Cohort only: B-cell primary or secondary central nervous system lymphoma (PCNSL or SCNSL)
  • 9Mantle Cell Lymphoma (MCL) Cohort: Histologically confirmed MCL determined by overexpression of cyclin D1 or presence of t(11;14) (q13; q32) translocation
  • 10Richter's Transformation (RT) Cohort: Histologically confirmed Richter's transformation (RT) to a diffuse large B-cell lymphoma (DLBCL) subtype from underlying CLL (clonally related)
  • 11Relapsed or refractory disease is defined for DLBCL (and associated subtypes) population as failure of 2 or more lines of chemotherapy including rituximab or equivalent and anthracycline and either having failed autologous stem cell transplant (ASCT), or ineligible, not intended for or not consenting to ASCT
  • 12Chemotherapy-refractory disease is defined as persistent disease after last line of therapy or relapsed or persistent disease after prior ASCT for lymphoma
  • 13Disease relapse in subjects without prior ASCT is defined as relapse of disease after the last dose of most recent therapy regimen
  • 14CNS Cohort: Subjects with relapsed/refractory PCNSL that have failed (or unable to tolerate) at least first-line therapy.
  • 15No contraindications for MRI evaluation
  • 16CNS Cohort: Subjects with SCNSL must have relapsed or refractory disease after having received at least one prior line of systemic therapy
  • 17Prior lines of systemic therapy should include an anti-CD20 monoclonal antibody and anthracycline containing chemotherapy regimen and/or with or without an autologous stem cell transplant
  • 18No contraindications for MRI evaluation
  • 19MCL Cohort: Subjects with relapsed/refractory disease after at least one prior systemic treatment, that must include:
  • 20Cytotoxic rituximab-based chemotherapy regimen (eg, rituximab bendamustine, R-CHOP, R-DHAP, R-ARA-C) AND
  • 21BTK inhibitor
  • 22RT Cohort: Subject must have relapsed/refractory disease after at least one prior systemic treatment following Richter's Transformation
  • 23Age ≥18 years
  • 24Eastern 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 lymphoma
  • 25Measurable disease according to Lugano 2014 criteria for assessing FDG-PET/CT in systemic lymphoma (Cheson et al, 2014). Measurable disease according to IPCG criteria will be assessed by brain/spine MRI for CNS disease
  • 26Subject 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
  • 27No clinical suspicion of central nervous system (CNS) lymphoma (not applicable to CNS cohort)
  • 28If 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), regardless of the number of white blood cells (WBCs)
  • 29If 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
  • 30A creatinine clearance (as estimated by direct urine collection or Cockcroft-Gault Equation) \> 45mL/min
  • 31Cardiac ejection fraction (EF) ≥ 45% as determined by an echocardiogram (ECHO) or Multigated Radionuclide Angiography (MUGA)
  • 32Resting O2 saturation \>90% on room air
  • 33Serum alanine aminotransferase (ALT) / aspartate aminotransferase (AST)\<5 times the Upper Limit of Normal (ULN) for age
  • 34Total bilirubin \<1.5 mg/dl, except in individuals with Gilbert's syndrome
  • 35Absolute neutrophil count (ANC) \> 1000/μL
  • 36Absolute lymphocyte count \> 100/μL
  • 37Platelet count \> 50,000/µL
  • 38Estimated life expectancy of more than 3 months other than primary disease

Exclusion Criteria

  • 1Primary CNS lymphoma (not applicable to CNS cohort)
  • 2Richter's transformed DLBCL arising from chronic lymphocytic leukemia (CLL) (not applicable to RT cohort)
  • 3Unable to give informed consent
  • 4Known 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
  • 5Known history of infection with hepatitis C virus (anti-HCV positive) unless viral load is undetectable per quantitative PCR and/or nucleic acid testing.
  • 6Pharmacologically uncontrolled seizures.
  • 7Known history or presence of autoimmune CNS disease, such as multiple sclerosis, optic neuritis, or other immunologic or inflammatory disease
  • 8Presence of CNS disorder that, in the judgment of the investigator, may impair the ability to evaluate neurotoxicity. For CNS Cohort:
  • 9Midline shift on MRI
  • 10Abnormal high CSF opening pressure and or CSF protein \>150 mg/dL Recent (within 3 months) whole brain radiotherapy (WBRT)
  • 11Active systemic fungal, viral, or bacterial infection
  • 12Pregnant or breast-feeding woman
  • 13Previous or concurrent malignancy with the following exceptions:
  • 14Adequately treated basal cell or squamous cell carcinoma (adequate wound healing required prior to study entry)
  • 15In situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 2 years prior to the study
  • 16Adequately treated breast or prostate carcinoma on hormonal therapies such as Lupron or tamoxifen and in clinical remission of ≥ 2 years
  • 17A primary malignancy which has been completely resected / treated with curative intent and in complete remission of ≥ 2 years
  • 18Severely immunocompromised subjects e.g., due to current treatment of non-neurologic autoimmune disease (e.g., Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus).
  • 19Medical condition requiring prolonged use of systemic corticosteroids equivalent to prednisone \>10 mg/day. For CNS cohort: Up to 2 mg/day dexamethasone (or equivalence) may be allowed at any time, higher doses allowed up to 7 days prior to apheresis or after apheresis until lymphodepletion.
  • 20History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 6 months of enrollment
  • 21Concurrent 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.
  • 22Baseline dementia that would interfere with therapy or monitoring, determined using Immune Effector Cell-Associated Encephalopathy (ICE) Assessment at baseline
  • 23History of severe immediate hypersensitivity reaction to any of the agents used in this study
  • 24Refusal to participate in additional lentiviral gene therapy LTFU protocol
  • 25Prior CAR-T therapy for any indication or systemic gene modifying therapy for B-cell lymphoma
  • 26Prior allogeneic stem cell transplant for any indication
  • 27Prior BITE antibodies for cancer therapy
  • 28Prior T cell receptor-engineered T cell therapy

Locations

25 sites participating in this study

Winship Cancer Institute of Emory University

Atlanta, Georgia 30322

Recruiting

Jason Romancik, MD

jason.t.romancik@emory.edu

Banner MD Anderson Cancer Center

Gilbert, Arizona 85234

Recruiting

Amy Tolenada

Amy.Tolenada@bannerhealth.com

Mayo Clinic

Phoenix, Arizona 85054

Recruiting

Allison Rosenthal, DO

Rosenthal.Allison@mayo.edu
Data sourced from ClinicalTrials.govView on ClinicalTrials.gov →