DALY 2.0 USA/ MB-CART2019.1 for DLBCL

Study Overview
=================
Brief Summary
-----------------
This is an open label, single arm, phase II study to determine the efficacy, safety and PK (persistence) of MBCART2019.1 cells in adults with relapsed or refractory 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.

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

Conditions
-----------------
DLBCL

Intervention / Treatment
-----------------
* Biological: MB-CART2019.1


Participation Criteria
=================
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) > 60mL/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 Known history of active seizures or presence of seizure activities except CNS lymphoma related, pharmacologically controlled seizure. 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 History of non-neurologic autoimmune disease (e.g. Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus)requiring systemic immunosuppressive or system disease modifying agents within the last 2 years 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single, open label<br> | Biological: MB-CART2019.1<br>* Chimeric antigen receptor (CAR) T cell therapy<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | ORR | through study completion, up to 2 years | 

Secondary Outcome Measures

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

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Chimeric antigen receptor, CAR T, CD19, CD20