DALY II USA/ MB-CART2019.1 for DLBCL

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. Additional cohorts include transplant-ineligible subjects with relapsed and/or refractory DLBCL after first-line therapy (i.e. DLBCL transplant-ineligible 2nd-line), r/r 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. 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.

Inclusion criteria

• Histologically confirmed B-cell non-Hodgkin's lymphoma:

• DLBCL cohort (both cohorts)
• DLBCL or associated subtype, defined by WHO 2016 classification
• DLBCL not otherwise specified (NOS)
• High-grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements
• High-grade B cell lymphoma (NOS)
• Primary mediastinal (thymic) large B cell lymphoma
• Transformed lymphoma (e.g., transformed follicular, or marginal zone lymphoma, follicular lymphoma (FL Grade 3)

o CNS cohort

• B-cell primary or secondary central nervous system lymphoma (PCNSL or SCNSL)

o Mantle Cell Lymphoma (MCL) cohort

• Histologically confirmed MCL determined by overexpression of cyclin D1 or presence of t(11;14) (q13; q32) translocation

o Richter's Transformation (RT) cohort

• Histologically confirmed RT to a diffuse large B-cell lymphoma (DLBCL) subtype from underlying CLL (clonally related)
• Relapsed or refractory disease is defined for DLBCL (and associated subtypes) population as:

For DLBCL cohort (after receiving at least two prior lines of therapy): persistent disease after failure of 2 or more lines of chemotherapy including rituximab or equivalent and anthracycline and either after failed ASCT, or ineligible, not intended for or not consenting to ASCT

• Chemotherapy-refractory disease (applies to all cohorts) 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

For disease specific cohorts added after the initial DLBCL cohort the definition of relapsed/refractory disease is as described below:

CNS cohort: Subjects with relapsed/refractory PCNSL that have failed (or unable to tolerate) at least first-line therapy.

• First-line therapy is defined as either high dose methotrexatebased therapy, temozolomide, high dose cytarabine, pemetrexed, lenalidomide or Bruton tyrosine kinase (BTK) inhibitor-based therapy.
• No contraindications for MRI evaluation
• CNS cohort: Subjects with SCNSL must have relapsed or refractory disease after having received at least one prior line of systemic therapy
• Prior 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

MCL cohort: Subjects with relapsed/refractory disease after at least one prior systemic treatment, that must include:

• Cytotoxic rituximab [or equivalent] based chemotherapy regimen (eg, rituximab bendamustine, R-CHOP, R-DHAP, R-ARA-C) AND
• BTK inhibitor

RT cohort: Subject must have relapsed/refractory disease after at least one prior systemic treatment following Richter's Transformation

DLBCL transplant ineligible 2nd cohort: subject must have failure of first-line chemotherapy (including rituximab or equivalent and anthracycline).

• For this cohort subjects are considered transplant ineligible if they meet one of the following criteria:
• Age ≥70 years
• ECOG status is 2 at screening
• Impaired pulmonary function: diffusing capacity of the lung for carbon monoxide [DLCO] ≤ 60% adjusted for gender-specific hemoglobin concentration (Coates formula)
• Impaired cardiac function: left ventricular ejection fraction (LVEF) < 50%; must be assessed by echocardiogram or multiple uptake gated acquisition (MUGA) scan performed within 4 weeks of determination of eligibility
• Impaired renal function: calculated creatinine clearance (Cockcroft and Gault) < 60 mL/min
• Impaired hepatic function: aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 2 x upper limit of normal (ULN)

In addition, all subjects must have:

• 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 lymphoma

• Subjects in DLBCL transplant-ineligible 2nd-line cohort with ECOG performance status of 2, regardless of attribution, will be allowed for inclusion
• Measurable disease will be assessed by FDG-PET/CT in systemic lymphoma . and by brain/spine MRI for CNS disease
• 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)

• Subjects in DLBCL transplant-ineligible 2nd-line cohort with SCNSL will be allowed for inclusion
• 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), 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)
• Subjects in DLBCL transplant-ineligible 2nd-line cohort with a lower ejection fraction of > 40% will be allowed for inclusion
• 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
• Subjects in DLBCL transplant-ineligible 2nd-line cohort with a total bilirubin of < 2.0 mg/dL will be allowed for inclusion
• 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) (not applicable to RT cohort)
• 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.
• Pharmacologically uncontrolled seizures.
• 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:

• For CNSL and DLBCL transplant-ineligible 2nd-line cohort patients that have a CNS lesion(s): Midline shift on MRI or Abnormal high CSF opening pressure and or CSF protein ≥150 mg/dL Recent (within 3 months) whole brain radiotherapy (WBRT) are exclusionary
• 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
• Severely 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. 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.
• History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 6 months of enrollment.
• Concurrent radiotherapy (allowed up to time of lymphodepletion). For prior 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 long-term follow-up (LTFU) protocol
• Prior CAR-T therapy for any indication or systemic gene modifying therapy for B-cell lymphoma
• Prior allogeneic stem cell transplant for any indication
• Prior Bispecific T cell engaging (BITE) antibodies for cancer therapy
• Prior T cell receptor-engineered T cell therapy