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

Inclusion criteria

• Male or female patients aged ≥ 18 years
• Written informed consent of the subject
• Able and willing to adhere to the trial protocol
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Either Multiple Myeloma (MM):

• relapsed or refractory disease after at least 2 lines of treatment including an Immunomodulatory drug, a proteasome inhibitor and an anti-cluster of differentiation 38 antibody or anti-cluster of differentiation 319 (SLAMF7; Elotuzumab) antibody AND
• not eligible for treatment with other regimen available according to local standard of care and known to confer clinical benefit according to the investigator's discretion, prior treatment with other BCMA-targeting immunotherapies (including T-cell engaging antibodies, CAR T-cells and antibody-drug immuno-conjugates) is allowed AND
• 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):

• Relapsed after or refractory to standard curative therapy (such as R-CHOP) and refractory to at least one course of standard salvage chemotherapy OR
• Relapsed within one year after high-dose chemotherapy and autologous stem cell support OR
• Relapsed after allogeneic stem-cell transplantation or approved anti-cluster of differentiation 19 CAR T-cell therapies.

AND (applicable to all DLBCL patients)

• 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)
• Measurable disease according to Lugano criteria
• Adequate organ function defined as:

• Neutrophils ≥ 0.5 Gpt/l and Platelets ≥ 50 Gpt/l (unless due to subtotal infiltration of the bone marrow by underlying malignancy)
• Lymphocytes ≥ 0.1 Gpt/l
• Alaninaminotransferase and Asparataminotransferase ≤ 3.0x Upper limit of normal
• Bilirubin ≤ 1.5x Upper limit of normal
• Creatinine ≤ 1.5x Upper limit of normal
• 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

Exclusion criteria

• 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:

• post-menopausal (12 months natural amenorrhoea or 6 months amenorrhoea with serum Follicle stimulating hormone > 40 U/ml)
• postoperative (6 weeks after bilateral ovariectomy with or without hysterectomy)
• regular and correct use of a contraceptive method with an Pearl Index < 1% per year
• sexual abstinence
• 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).