Safety of MB-CART2019.1 in Lymphoma Patients (MB-CART2019.1 Lymphoma / DALY 1)
Safety of MB-CART2019.1 in Lymphoma Patients (MB-CART2019.1 Lymphoma / DALY 1)
This is a prospective, multi-center, open phase I/II trial to evaluate feasibility, dosage,
 safety and toxicity as well as efficacy of ex vivo expanded autologous T cells genetically
 modified to express anti-CD20 and CD19 immunoreceptor (MBCART2019.1) in patients with
 relapsed or resistant aggressive CD20 and CD19 positive B-NHL/CLL/SLL.
This trial will be performed as a multi-center phase I/II trial with MB-CART2019.1 and
 consists of part I. In part I, 12 to 18 patients with relapsed or resistant CD20 and CD19
 positive NHL/CLL/SLL will be treated. Six plus three (6+3) patients in dose level 1 and 2
 will be treated.

 The trial will be conducted in Hematology Departments of Hospitals which meet the structural
 and personnel requirements for performing the planned regular trial-related investigations.
 Only sites will be chosen with expertise in and necessary facilities for managing cytokine
 release storm and other severe adverse events associated with this therapy such as
 neurotoxicity. A corresponding training to site personnel prior to trial start must be
 performed. The responsible intensive care unit (ICU) must be informed about the clinical
 trial before inclusion of the first patient and the respective dosing date in order to make
 sure that the medical staff of the ICU is able to react appropriately without any loss of
 time in case of emergency. The University Hospital of Cologne will provide the Coordinating
 Investigator. Additional clinical sites may be added during the trial.

 Patients will be screened between day -30 and day -15. If the patient satisfies all the
 protocol inclusion and none of the exclusion criteria, he/she will be included in the
 clinical trial. Leukapheresis will be performed at the collection center on day -14 according
 to local standard practice. The leukapheresis product of the patient will be shipped by a
 special courier to the designated manufacturing center assigned by the sponsor. The
 leukapheresis sample will be used for the individual manufacturing of MB-CART2019.1 by using
 the automated CliniMACS Prodigy® System. The manufacturing of MB-CART2019.1 will start on day
 -13 and will be finished on day -1.

 On day 5 of the manufacturing process the IPC (in-process-control) will indicate, if the
 manufacturing process is successful. Therefore, the lymphodepleting chemotherapy must only be
 started after the positive result of the IPC was confirmed by the manufacturer. Chemotherapy
 for lymphodepletion will be done on days -5 to -3.

 Administration of MB-CART2019.1 will be performed on day 0 in the Hematology Departments of
 all sites. Patients will be followed up as inpatients until week 4 with close monitoring of
 their vital functions and lab parameters for signs of adverse events. In the second follow-up
 phase (week 4 until week 12), response will be assessed, and adverse events will be
 documented. A follow-up examination will be performed at week 12 (achievement of primary
 endpoint) and at month 12 which is considered end of trial or end of active part of the
 trial. In the long-term follow-up yearly until 5 years or patient's death, safety and
 response assessment as well as persistence of MBCART2019.1 will be performed. These
 assessments will be analyzed and reported separately and are not part of the entire clinical
 trial. This is a 6+3 trial design with a 0.3 log dose increment (1x106/2.5x106 MBCART2019.1
 per kg BW in a single infusion) and maximum 2 dose levels. If none or one of the six patients
 at dose level 1 experiences a dose limiting toxicity, another six patients will be treated at
 dose level 2. If two DLTs are observed at dose level 1 another three patients will be treated
 with the same dose. If more than two DLTs are observed at dose level 1, trial will continue
 at dose level 0. Dose escalation continues until at least >2 patients among a cohort of six
 to nine patients experience dose-limiting toxicities or dose level 2 is completed. The MTD is
 defined as the dose level below the dose inducing a DLT in more than 2 patients within one
 dose level. DLT will be evaluated within 4 weeks after the infusion of MB-CART2019.1. An
 interval of at least 28 days between the treatment of the first and the second patient in
 each dose level is mandatory. An observation period for DLT of 28 days is considered to be
 safe to exclude potential toxicities prior to inclusion of the next patients into the same
 dose group or prior to dose escalation.
Inclusion Criteria:

 1. Refractory/relapsed B-NHL (including malignant transformation like Richter's
 transformation) with no available approved standard therapy. Including, but not
 restricted to:

 1. Diffuse large B cell lymphoma (DLBCL): relapsed/refractory disease after ASCT or
 ineligible for ASCT after first-line therapy; transformation from CLL, SLL or FL
 allowed

 2. Follicular lymphoma: at least 2 prior regimens and progression <2 years after
 most recent line of therapy

 3. Mantle cell lymphoma: beyond 1st CR with relapsed disease, progressive disease
 during first-line rituximab chemotherapy, or persistent disease after first-line
 rituximab-chemotherapy and not eligible or appropriate for conventional therapy,
 ASCT or relapsed after prior autologous SCT, prior therapies including ibrutinib
 if not contraindicated

 4. CLL and SLL: after at least two lines of treatment including btk inhibitor
 ibrutinib and bcl2 inhibitor venetoclax (if not contraindicated), patients must
 have been refractory to at least one of the substances

 Patients with criteria 1b-d will only be eligible for Part I, dose cohort 1.

 2. Patients in cohort 1a must have histologically confirmed DLBCL and associated subtypes
 with relapse or refractory disease after first line chemo-immunotherapy and be
 ineligible for HSCT

 3. Histologically confirmed DLBCL and associated subtypes, defined by WHO 2016
 classification:

 -  DLBCL not otherwise specified (NOS)

 -  High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with
 DLBCL histology (DHL/THL) and FL3B

 -  Aggressive B-cell lymphoma

 -  T-cell/histocyte rich B-cell lymphoma

 -  Primary mediastinal B-cell lymphoma

 -  EBV+ DLBCL

 -  Transformed lymphoma (e.g. transformed follicular or marginal zone lymphoma)

 4. First line chemo-immunotherapy is defined as therapy containing the combination of
 CD20 targeted immunotherapy and cytotoxic chemotherapy.

 5. Chemotherapy-refractory disease is defined as one or more of the following:

 -  No response to first line of therapy

 -  PD as best response to first line therapy regimen

 -  SD as best response after 4 cycles of first line therapy

 -  Disease progression or relapsed ≤12 months of first line therapy (must have
 biopsy proven recurrence in relapsed individuals)

 6. Ineligibility for HSCT is defined as having ONE of the following criteria:

 -  Age based on country-specific definition

 -  Impaired pulmonary function (DLCO or FEV1 ≤60%)

 -  Impaired cardiac function (LVEF <50%)

 -  Impaired renal function (CrCl <60 mL/min)

 -  Impaired hepatic function (AST/ALT >3 x ULN, bilirubin >1.5 x ULN or patient's
 baseline)

 In addition, all patients must fulfil the following criteria:

 7. Age ≥18 years

 8. Measurable disease according to Lugano criteria

 9. CD19 or CD20 tumor expression is not required after first line chemo-immunotherapy.

 1. Must have archival tissue available, if received CD19 targeted therapy or CD20
 antibody, archival tissue must have been obtained subsequent to that therapy

 2. Must have at least 10 unstained slides of tissue available

 3. If archival tissue is not available, must be willing to undergo attempted repeat
 biopsy and fine needle Aspiration

 10. If has history of CNS disease, then must have:

 1. No signs or symptoms of CNS disease

 2. No active disease on magnetic resonance imaging (MRI)

 3. Absence of large cell lymphoma in cerebral spinal fluid (CSF) on cytospin
 preparation and flow cytometry, regardless of the number of white blood cells

 11. If has history of cerebral vascular accident (CVA):

 1. The CVA event must be >12 months prior to leukapheresis

 2. Any neurological deficits must be stable

 12. Estimated life expectancy of >3 months other than primary disease

 13. 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 of 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 trial and in the 6 months following
 dosing. Male patients, unless surgically sterile (meaning at least two consecutive
 analyses following vasectomy demonstrate absence of sperms in the ejaculate), 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

 14. Signed and dated informed consent before conduct of any trial-specific procedure

 Exclusion Criteria:

 1. Eastern Cooperative Oncology Group (ECOG) performance status >2

 2. Absolute neutrophil count (ANC) <1,000/µL

 3. Platelet count <50,000/µL

 4. Absolute lymphocyte count <100/µL

 5. Presence of leukemia/lymphoma cells in peripheral blood

 6. Primary CNS lymphoma

 7. Unable to give informed consent

 8. Known history of infection with human immunodeficiency virus (HIV) or active infection
 with hepatitis B (HGsAg positive)

 9. Known history of infection with hepatitis C virus unless treated and confirmed to be
 polymerase chain reaction (PCR) negative

 10. Known history or presence of seizure activities or on active anti-seizure medications
 within the previous 12 months

 11. Known history of CVA within prior 12 months

 12. Known history or presence of autoimmune CNS disease, such as multiple sclerosis, optic
 neuritis or other immunologic or inflammatory disease

 13. Presence of CNS disease that, in the judgment of the investigator, may impair the
 ability to evaluate neurotoxicity

 14. Active systemic fungal, viral or bacterial infection

 15. Clinical heart failure with New York Heart Association class ≥2 or LVEF <30%

 16. Resting oxygen saturation <90% on room air

 17. Liver dysfunction as indicated by total bilirubin, AST and/or ALT >5 x institutional
 ULN, unless directly attributable to patient's tumor

 18. CrCl <30 mL/min calculated according to the modified formula of Cockcroft and Gault or
 by direct urine collection

 19. Pregnant or breast-feeding woman

 20. Active secondary malignancy requiring treatment

 21. Medical condition requiring prolonged use of systemic corticosteroids >10 mg/day

 22. Concurrent radiotherapy (allow up to time of leukapheresis)

 23. Baseline dementia that would interfere with therapy or monitoring, determined using
 mini-mental status exam at baseline

 24. History of severe immediate hypersensitivity reaction against any drug or its
 ingredients/impurities that is scheduled to be given during trial participation e.g.
 as part of the mandatory lymphodepletion protocol, premedication for infusion, or
 rescue medication/salvage therapies for treatment related toxicities

 25. Patients in which such medication (see exclusion criterion 24) is contraindicated for
 other reasons than hypersensitivity (e.g. live vaccines and fludarabine)

 26. Refusal to participate in CAR-T long-term follow-up (LTFU).

 27. Refusal to undergo core needle biopsy or fine needle aspiration of tumor on day 2-5
 after MB-CART infusion and at time of disease progression and relapse