The risk-benefit assessment was not as expected.

This is a phase l multi-centric, single arm, prospective, open, dose-escalation study in patients with unresectable stage III oder IV melanoma. The trial will include 15 adult patients. The trial is a classic 3+3 design with 1 Log dose increments and maximum 3 dose levels of the intravenously administered MB-CART20.1.

This Phase I trial will be the first trial with CD20 CAR transduced T cells in Europe targeting melanoma. The rationale for the trial is based on the finding that melanoma cancer sustaining cells express CD20 and that targeting CD20+ cells in preclinical model has a strong antitumor effect.

Inclusion Criteria:

Male or female patients with

• Histologically confirmed unresectable stage III or stage IV melanoma
• Willingness to provide a tumor biopsy between the screening visit and prior to administration of the IMP and eight weeks after treatment
• Progressive disease despite treatment with indicated standard therapies. Time window for decision about progressive disease is to be made depending on the treatment regimen chosen.
• Measurable lesions according to RECIST1.1
• ECOG (Eastern cooperative oncology group) performance status of 0-2
• Negative serological hepatitis B (HBV) test defined as negative tests for HBsAg and HBcAb, unless serology is positive due to recent IVIG therapy, HBcAb positivity will be allowed if HbsAb is present, negative testing of HCVAb, negative human immunodeficiency virus (HIV) 1/2 test within 6 weeks prior to enrollment.
• Estimated life expectancy of more than 6 months
• At least 18 years of age
• WBC ≥ 2500/µL
• ANC ≥ 1000/µL
• Platelets ≥ 75 x 103/µL
• Hemoglobin ≥ 9 g/dL
• AST ≤ 3 x upper limit of normal (ULN) for patients without liver metastasis
• AST < 5 x ULN for patients with liver metastasis
• Total Bilirubin ≤ 2 x ULN
• patients with Gilbert's Syndrome increase of indirect bilirubin < 6mg/dL
• No childbearing potential (i.e. postmenopausal, absence of menstrual bleeding for at least 1 year, hysterectomy, bilateral ovariectomy or tubal section/ligation) or negative pregnancy test at screening and before chemotherapy in women with childbearing potential. Sexually active female patients of childbearing potential should use one of the following highly effective methods of contraception (Pearl index < 1%): hormonal contraceptives (oral, injected, implanted, transdermal), intrauterine devices or systems (e.g. hormonal and non-hormonal IUD), or vasectomized sexual partner for at least 1 month before the trial start, during the course of the trial and in the 6 months following dosing. Sexual abstinence is restricted to true abstinence ( in line with the preferred and usual lifestyle of the subject).
• male patients, unless surgically sterile, must be using two acceptable methods for contraception (e.g. spermicide and condom) during the trial and refrain from fathering a child throughout the trial and for up to 12 months after dosing.
• Signed and dated informed consent before conduct of any trial-specific procedure.

Exclusion Criteria:

• Any evidence of brain metastases
• CNS (central nervous system) disorders and previous strokes, if clinically relevant
• Patients with epilepsy
• Clinically relevant autoimmune disorders or history of clinically relevant autoimmune disorders
• Patients with T-cell lymphoma
• Treatment with anti-CD20 antibodies or checkpoint blockade inhibitors within 6 weeks before leukapheresis
• Chemotherapy within 6 weeks prior to leukapheresis
• History of primary immunodeficiency
• Creatinine clearance < 50 ml/min calculated according to the modified formula of Cockcroft and Gault
• concurrent systemic radiotherapy
• Use of systemic corticosteroids and immunosuppressive medication except prednisone ≤ 10 mg QD or equivalent
• Patients with severe cardiac disease (e.g. NYHA Functional Class III or IV, myocardial infarction within 6 months before inclusion, ventricular tachyarrhythmia requiring ongoing treatment, unstable angina pectoris)
• Other investigational treatment within 4 weeks before MB-CART20.1 infusion
• 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 related toxicities
• Patients in which such medication (likely to be given during trial participation) is contraindicated for other reasons than hypersensitivity, e.g. live vaccines and fludarabine.
• Severe pulmonary disease (DLCO and/or FEV1 < 65%, dyspnoea at rest)
• Active systemic fungal, viral or bacterial infection
• Pregnant or lactating women
• 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