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

Protocol # :
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
Disease Sites
Non-Hodgkin's Lymphoma
Principal Investigator
Jacobson, Caron, A

Trial Description

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

Eligibility Requirements

Inclusion Criteria:

- Histologically confirmed DLBCL or associated subtype, defined by WHO 2016

- CNS Cohort only: B-cell primary or secondary central nervous system lymphoma (PCNSL or

- 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

- 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

- 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