MB-CART20.1 Lymphoma

Study Overview
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Brief Summary
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This trial is a phase I/II trial to assess safety, dose finding and feasibility of ex vivo generated MB-CART20.1 cells in patients with relapsed or refractory CD20 positive B-NHL.

Detailed Description
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MB-CART20.1 consists of autologous Anti-CD20 Chimeric Antigen Receptor (CAR) transduced CD4 /CD8 enriched T cells targeting CD20-positive tumor cells in Non-Hodgkin-Lymphoma (NHL)

Official Title
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A Phase I/II Safety, Dose Finding and Feasibility Trial of MB-CART20.1 in Patients With Relapsed or Resistant CD20 Positive B-NHL

Conditions
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Relapsed or Refractory B-cell Non-Hodgkin's Lymphoma, Non-Hodgkin's Lymphoma, B-cell Lymphoma Refractory, B-cell Lymphoma Recurrent

Intervention / Treatment
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* Biological: MB-CART20.1


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Refractory/relapsed CD20+ B-NHL (including malignant transformation like Richter's transformation) with no curative treatment option. At least 18 years of age Estimated life expectancy of more than 3 months ECOG performance status (Eastern cooperative oncology group) of 0-2 Negative serological HBV (Hepatitis B virus) test, negative testing of HCVAb (Hepatitis C virus Antibody), negative HIV1/2 (Human immunodeficiency virus 1/2 ) test within 6 weeks prior to enrollment No childbearing potential or negative pregnancy test at screening and before chemotherapy in women with childbearing potential. Signed and dated informed consent before conduct of any trial-specific procedure Exclusion Criteria: Participation in another interventional trial that could interact with this trial Any evidence 0f CNS (Central nervous system) involvement Known history or presence of clinically relevant CNS pathology Patients with history of primary immunodeficiency, Patients with any history of auto-immune induced condition such as those caused by checkpoint inhibitors, MEK inhibitors or BRAF inhibitors, for example pituitary hypophysitis must be excluded Patients with Chronic Lymphocytic Leukemia unless suffering from malignant transformation Active systemic fungal, viral or bacterial infection Serious cardiac functional incapacity (class III or IV as defined by the New York Heart Association Classification) Severe pulmonary disease (DLCO (Transfer factor of the lung for carbon monoxide) and/or FEV1 (Forced expiratory volume in 1 second) < 65%, dyspnea at rest) Liver dysfunction as indicated by a total bilirubin, AST (Aspartate Aminotransferase), and ALT (Alanine aminotransferase) ≥ 2 the institutional ULN (Upper limit of normal) value, unless directly attributable to the patient's tumor Creatinine clearance <50 ml/min calculated according to the modified formula of Cockcroft and Gault Pregnant or lactating women Active secondary malignancy requiring treatment (except basal cell carcinoma or malignant tumor curatively treated by surgery) within the last 5 years before enrollment. Medical condition requiring prolonged use of systemic corticosteroids (> 1 month) Prior therapy with genetically modified substances Use of anti-CD20 antibodies within 4 weeks before leukapheresis Chemotherapy within 4 weeks prior to leukapheresis Other treatment within 4 weeks or two half-lives, whichever is longer before MB-CART20.1 infusion. This pertains to immunomodulatory therapies such as checkpoint inhibitors because of the influence on the immune system Concurrent systemic radiotherapy Hypersensitivity against any drug or its ingredients/impurities that is scheduled or likely to be given during trial participation e.g. as part of the mandatory lymphodepletion protocol, pre-medication for infusion, rescue medication/salvage therapies for treatment of related toxicities Patients in which such medication is contraindicated for other reasons than hypersensitivity (e.g. live vaccines and fludarabine) Patients in which trial related procedures are contraindicated as judged by the investigator, e.g. lumbar punctures for CSF (Cerebrospinal fluid) sampling Patient's lack of accountability, inability to appreciate the nature, meaning and consequence of the trial and to formulate his/her own wishes correspondingly Patients who have a relationship of dependence or employer employee relationship to the sponsor or the investigator Committal to an institution on judicial or official order Cerebral dysfunction, legal incapacity Other investigational treatment within 4 weeks before IMP (Investigational Medicinal Product) infusion Clinically relevant autoimmune diseases or history of autoimmune disease

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I - Safety Dose Level<br>In phase I three (3) + 3 patients will be treated with 1x10^5 MB-CART20.1 cells per kg body weight administered intravenously as single dose in the preceding safety dose level | Biological: MB-CART20.1<br>* MB-CART20.1 consists of autologous CD20 Chimeric Antigen Receptor (CAR) transduced CD4 /CD8 enriched T cells targeting CD20-positive tumor cells in NHL<br>* Other names: Anti-CD20 CAR T cells;|
| Experimental: Phase I - Dose Level 1<br>In phase I six (6) + 3 patients will be treated with 1x10^6 MB-CART20.1 cells per kg body weight administered intravenously as single dose in the dose level 1 | Biological: MB-CART20.1<br>* MB-CART20.1 consists of autologous CD20 Chimeric Antigen Receptor (CAR) transduced CD4 /CD8 enriched T cells targeting CD20-positive tumor cells in NHL<br>* Other names: Anti-CD20 CAR T cells;|
| Experimental: Phase I - Dose Level 2<br>In phase I six (6) + 3 patients will be treated with 3x10^6 MB-CART20.1 cells per kg body weight administered intravenously as single dose in the dose level 2 | Biological: MB-CART20.1<br>* MB-CART20.1 consists of autologous CD20 Chimeric Antigen Receptor (CAR) transduced CD4 /CD8 enriched T cells targeting CD20-positive tumor cells in NHL<br>* Other names: Anti-CD20 CAR T cells;|
| Experimental: Phase II<br>The number of additional patients who will be treated with MB-CART20.1 cells in Phase II is depending on the number of evaluable patients treated with the maximum tolerated dose (MTD) level and the results in Part I | Biological: MB-CART20.1<br>* MB-CART20.1 consists of autologous CD20 Chimeric Antigen Receptor (CAR) transduced CD4 /CD8 enriched T cells targeting CD20-positive tumor cells in NHL<br>* Other names: Anti-CD20 CAR T cells;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I - Determination of the maximum tolerated dose (MTD) | MTD is defined as the highest dose level at which < 33% of patients experience Dose Limiting Toxicity (DLT). Safety and toxicity assessment of MB-CART20.1 per adverse events (AE) reporting classified according to CTCAE version 5.0. | until day 28 after infusion of MB-CART20.1 | 
| Phase II - Best overall response rate | Response (Complete response (CR), Partial response (PR), Stable disease (SD), Progressive disease (PD)) is defined according to Cheson criteria. | 3 months after infusion of MB-CART20.1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I - Related safety and toxicity of MB-CART20.1 | Per adverse events (AE) reporting classified according to CTCAE version 5.0. | months 3, 6, 9 and 12 after infusion of MB-CART20.1 | 
| Phase I - Best overall response rate over 4 weeks and 3 months | Response (CR, PR, SD and PD) is defined according to Cheson criteria. | 4 weeks and 3 months after infusion of MB-CART20.1 | 
| Phase I - Best overall response rate over 1 year | Response (CR, PR, SD and PD) is defined according to Cheson criteria. | 1 year after infusion of MB-CART20.1 | 
| Phase I - Occurrence of B-cell aplasia | Circulating B cell numbers in the peripheral blood will be assessed by Flow cytometry. | 1 year after infusion of MB-CART20.1 | 
| Phase I - Phenotype and Persistence of MB-CART20.1 | Blood samples for determination of persistence/phenotyping of infused MB-CART20.1 will be analysed. | 1 year after infusion of MB-CART20.1 | 
| Phase II - Best overall response rate over 1 year | Response (CR, PR, SD and PD) is defined according to Cheson criteria. | 1 year after infusion of MB-CART20.1 | 
| Phase II - Overall response rate over 4 weeks and 3 months | Response (CR, PR, SD and PD) is defined according to Cheson criteria. | 4 weeks and 3 months after infusion of MB-CART20.1 | 
| Phase II - Overall response rate over 1 year | Response (CR, PR, SD and PD) is defined according to Cheson criteria. | 1 year after infusion of MB-CART20.1 | 
| Phase II - Number of patients with CR, PR, SD and PD | Response (CR, PR, SD and PD) is defined according to Cheson criteria. | 1 year after infusion of MB-CART20.1 | 
| Phase II -Percentage of patients with CR, PR, SD and PD | Response (CR, PR, SD and PD) is defined according to Cheson criteria. | 1 year after infusion of MB-CART20.1 | 
| Phase II - Safety and toxicity assessment of MB-CART20.1 | Per adverse events (AE) reporting classified according to CTCAE version 5.0. | 1 year after infusion of MB-CART20.1 | 
| Phase II - Occurrence of B-cell aplasia | Circulating B cell numbers in the peripheral blood will be assessed by Flow cytometry. | 1 year after infusion of MB-CART20.1 | 
| Phase II - Phenotype and Persistence of MB-CART20.1 | Blood samples for determination of persistence/phenotyping of infused MB-CART20.1 will be analysed. | 1 year after infusion of MB-CART20.1 |