A Phase I Trial to Establish the Safety and Maximum Tolerated Dose of High-affinity Autologous BCMA-targeting Chimeric Antigen Receptor (CAR) T-cells in Patients With Relapsed and Refractory B-cell Malignancies

3. measurable disease defined by serum M-Protein ≥ 10 g/l OR urine M-Protein ≥ 200 mg/24h OR serum free light chain \> 100 mg/l of involved free light chain and abnormal serum free light chain ratio

OR

Diffuse large B-cell lymphoma (DLBCL):

4. Relapsed after or refractory to standard curative therapy (such as R-CHOP) and refractory to at least one course of standard salvage chemotherapy OR

5. Relapsed within one year after high-dose chemotherapy and autologous stem cell support OR

6. Relapsed after allogeneic stem-cell transplantation or approved anti-cluster of differentiation 19 CAR T-cell therapies.

AND (applicable to all DLBCL patients)

7. Not be eligible for treatment with other regimen available according to local standard of care and known to confer clinical benefit. This includes but is not limited to anti-cluster of differentiation 19 directed CAR T-cell therapies with approved constructs AND (applicable to all DLBCL patients)

8. Measurable disease according to Lugano criteria

Adequate organ function defined as:

1. Neutrophils ≥ 0.5 Gpt/l and Platelets ≥ 50 Gpt/l (unless due to subtotal infiltration of the bone marrow by underlying malignancy)

2. Lymphocytes ≥ 0.1 Gpt/l

3. Alaninaminotransferase and Asparataminotransferase ≤ 3.0x Upper limit of normal

4. Bilirubin ≤ 1.5x Upper limit of normal

5. Creatinine ≤ 1.5x Upper limit of normal

6. Adequate cardiac function i.e. left ventricular ejection fraction ≥ 50%, no major valve abnormalities or dyskinesias

A female of childbearing potential\* may be enrolled providing she has a negative pregnancy test at screening and is routinely using a highly effective method of birth control (pearl index of ≤ 1 required) resulting in a low failure rate (e.g. hormonal contraception, intrauterine device, total sexual abstinence or sterilization). Male patients must also prac-tice a highly effective method of birth control and should not father a child at least until 12 months after infusion of CAR T-cells

Any Central nervous system (CNS)-involvement by underlying disease

History of seizure or cerebrovascular ischemia / hemorrhage within the last 12 months

History of any autoimmune Central nervous system disease (e.g. multiple sclerosis, amyotrophic lateral sclerosis, optic neuritis)

Ongoing neurologic conditions that in the opinion of the investigator might increase the risk for neurotoxicity or impair the assessment of CAR-associated neurotoxicity

Inadequate pulmonary function (i.e. need for continuous oxygen support)

Patients on hemodialysis

Any contraindications to Fludarabine and/or Cyclophosphamide as given in the Summary of product characteristics

Any other active malignancy requiring active treatment or interfering with the assessment of primary or secondary trial endpoints, adjuvant hormonal therapy is allowed

Positivity for anti-human immunodeficiency virus (HIV) immunoglobulin

Active or chronic infectious hepatitis B (HBV) and C (HCV) virus unless serology demonstrates clearance of infection (i.e. Polymerase chain reaction undetectable viral load for hepatitis)

Active infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) or history of SARS-CoV2 infection within the past 3 months or active long coronavirus disease (COVID) syndrome

Uncontrolled bacterial, viral or fungal infections defined as infections needing in-patient and/or i.v. antimicrobial treatment\*

Active Graft versus Host Disease defined as active symptoms of graft-versus-host disease or ongoing immunosuppressive treatment or prophylaxis within the last 30 days prior to application of MDC-CAR-BCMA001

Psychologic disorders, drug abuse or any other condition which might significantly impair a patient's ability to comply with the trial protocol

Patients who are expected to deteriorate during the time needed for manufacturing MDC-CAR-BCMA001 in spite of bridging therapy in the opinion of the investigator including

Any condition requiring systemic treatment with immunosuppressive drugs (including but not limited to steroids exceeding 20 mg Prednisolone per day)

Any antineoplastic treatment within 7 days prior to leukapheresis or within 2 weeks or 5 half-lives (whatever is shorter) of the start of lymphodepleting chemotherapy (palliative radiotherapy to lesions not essential for response assessment is allowed without a minimal washout period)

Any investigational therapy within 4 weeks or 5 half-lives (whatever is shorter) prior to apheresis or the start of lymphodepleting chemotherapy

History of allergic reactions to any drug or its ingredients / impurities foreseen to be given as part of this trial according to the protocol\*

Receipt of live vaccines within 2 weeks prior to leukapheresis and start of lymphodepleting chemotherapy

Pregnant or breastfeeding women. Breastfeeding has to be discontinued before onset of and during treatment and should be discontinued for at least 3 months after end of treatment.

Women of childbearing potential, except women who meet the following criteria:

1. post-menopausal (12 months natural amenorrhoea or 6 months amenorrhoea with serum Follicle stimulating hormone \> 40 U/ml)

2. postoperative (6 weeks after bilateral ovariectomy with or without hysterectomy)

3. regular and correct use of a contraceptive method with an Pearl Index \< 1% per year

4. sexual abstinence

5. Vasectomy of the partner

Hypersensitivity known from medical history to one of the drugs used or their ingredients or to drugs with a similar chemical structure

Simultaneous participation in another interventional clinical trial (including within the last 4 weeks before inclusion)

Addictions or other illnesses that do not allow the person concerned to assess the nature and extent of the clinical trial and its possible consequences

Indications that the subject is unlikely to adhere to the protocol (e.g., lack of compliance).

What this study is about