Efficacy and Safety of MB-CART2019.1 vs. SoC in Lymphoma Patients
Efficacy and Safety of MB-CART2019.1 vs. SoC in Lymphoma Patients
This is a pivotal Phase II randomised, multi-centre, open-label study to evaluate the
 efficacy and safety of MB-CART2019.1 compared to standard of care therapy in participants
 with relapsed/refractory diffuse large B-cell lymphoma, who are not eligible for high-dose
 chemotherapy and autologous stem cell transplantation.
This study should determine superiority of MB-CART2019.1 treatment compared to SoC therapy
 with R-GemOx (rituximab, gemcitabine and oxaliplatin) with respect to progression-free
 survival in second-line therapy in participants with R-R DLBCL, who are non-eligible for
 high-dose chemotherapy and autologous stem cell transplantation.

 MB-CART2019.1 is designed to effectively target malignant B cells in patients suffering from
 late stage haematological B-cell malignancies. MB-CART2019.1 consists of autologous cluster
 of differentiation CD20/CD19 chimeric antigen receptor (CAR) transduced CD4/CD8 enriched T
 cells, derived from a leukapheresis and processed by using the CliniMACS Prodigy® device.
 Patients who are suitable for this study will be randomized 1:1 to either MB-CART2019.1 or
 SoC. Both treatment arms are unblinded.

 MB-CART2019.1 arm: Single infusion of fresh formulation of 2.5 × 10^6 CAR-transduced
 autologous T cells. IMP is only to be administered after a lymphodepleting chemotherapy with
 fludarabine and cyclophosphamide. For MB-CART2019.1 production, patients will undergo a
 leukapheresis.

 SoC arm: R-GemOx (8 cycles of 14 days each) or (10% of SoC arm) BR (Bendamustine/Rituximab) +
 polatuzumab vedotin (6 cycles of 21 days each).

 The duration of the active part of the study for each individual participant from screening
 to the end of the 1-year follow-up after infusion of MB-CART2019.1 cells (experimental arm)
 or the start of SoC therapy (comparator arm) will be approximately 55 weeks. The LTFU in Year
 2 after infusion of MB-CART2019.1 cells or the start of treatment in the comparator arm will
 not be part of the active part of the clinical study and will be reported separately.
Inclusion Criteria:

 1. Histologically proven DLBCL and associated subtypes, according to the WHO 2016
 classification including:

 -  DLBCL not otherwise specified (NOS).

 -  High-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements
 with DLBCL histology (double hit lymphoma/triple hit lymphoma).

 -  High-grade BCL, NOS.

 -  Primary (thymic) large mediastinal BCL.

 -  Disease transformed from an earlier diagnosis of low-grade lymphoma (e.g. an
 indolent pathology such as follicular lymphoma, marginal zone lymphoma) into
 DLBCL with DLBCL disease progression subsequent to DLBCL directed systemic
 treatment.

 2. Relapsed or refractory disease after first-line chemoimmunotherapy:

 -  Refractory disease is defined as no CR to first-line therapy,

 -  PD as best response after at least 4 full cycles of R-CHOP (rituximab,
 cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone) cycles as
 first-line therapy.

 -  Stable disease (SD) after 6 R-CHOP cycles as first-line therapy.

 -  PR as best response after at least 6 R-CHOP cycles and biopsy-proven disease
 progression (except where prohibited due to comorbidities) within ≤ 12
 months from the completion of the first-line therapy.

 -  Relapsed disease defined as complete remission to a first-line therapy followed
 by biopsy-proven disease progression (except where prohibited due to
 comorbidities) within ≤ 12 months from the completion of the first-line therapy.

 3. Participant must have received adequate first-line therapy containing at least the
 combination of an anthracycline-based regimen and rituximab (anti-CD20 monoclonal
 antibody). Local therapies (e.g. radiotherapies) will not be considered as line of
 therapy if performed during the same line of treatment.

 4. Archival paraffin-embedded tumour tissue acquired ≤ 3 years prior to screening for
 central pathology review to confirm DLBCL diagnosis and for analysis of CD20/CD19
 expression must be made available for participation in this study. If archival
 paraffin-embedded tumour tissue is not available, fresh tumour tissue sample
 (preferred) or core-needle biopsy for this protocol must be made available.

 5. Participants deemed ineligible to receive HDC followed by ASCT based on the treating
 physician's assessment and meeting the following criteria:

 -  Age ≥ 18 years and

 -  Prior ASCT (as first-line consolidation) or

 -  Haematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) > 3.

 -  Age ≥ 65 years and 1 of the criteria below:

 -  Prior ASCT (as first-line consolidation), or

 -  Comorbidities as assessed by an HCT-CI score > 3, or

 -  Impaired cardiac function (left ventricular ejection fraction (LVEF) < 50%),
 or

 -  Impaired renal function (creatinine clearance [CrCl] < 60 mL/min) as
 determined by MDRD (Modification of Diet in Renal Disease) formula or

 -  Impaired pulmonary function (diffusing capacity for carbon monoxide or
 forced expiratory volume in 1 second of 66% to 80%) or dyspnoea on slight
 activity, or

 -  Eastern Cooperative Oncology Group (ECOG) performance status > 1.
 Documentation of the reason for ineligibility for ASCT must be present in
 the participant's source data.

 In addition, all participants must fulfil the following criteria:

 6. Age ≥18 years.

 7. Measurable disease according to Lugano criteria. The lesion must be positive on a
 positron emission tomography scan.

 8. Estimated life expectancy of > 3 months for other reasons than the primary disease.

 9. Woman of childbearing potential (WOCBP) must agree to use highly effective
 contraceptive measures (Pearl index < 1) or practice true sexual abstinence from any
 heterosexual intercourse (True abstinence is only acceptable if it is in line with the
 preferred and usual life style of the participant.) or must have a vasectomised
 partner as the sole sexual partner (The vasectomised partner must have received
 medical assessment of the surgical success.) for at least 1 month before the study
 start, during the study and in the 12 months following the last dose of study
 treatment. A woman is considered a WOCBP, i.e. fertile, following menarche and until
 becoming post-menopausal unless permanently sterile. Highly effective methods of
 contraception include hormonal contraceptives (oral, intravaginal, transdermal,
 injectable, implantable) and intrauterine devices or systems (e.g. hormonal and
 non-hormonal) and bilateral tubal occlusion. Permanent sterilisation methods include
 hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A post-menopausal
 state is defined as no menses for 12 months without an alternative medical cause. WOBC
 must refrain from egg donation throughout the study until 12 months after the last
 dose of study treatment.

 Men must agree to use 2 acceptable methods for contraception (e.g. spermicide and
 condom) or practice true sexual abstinence from any heterosexual intercourse (True
 abstinence is only acceptable if it is in line with the preferred and usual life style
 of the participant.), unless they are surgically sterile (meaning at least 2
 consecutive analyses following vasectomy demonstrate absence of sperms in the
 ejaculate), during the study and in the 12 months following the last dose of study
 treatment. Men must furthermore refrain from sperm donation throughout the study until
 12 months after the last administration of study treatment.

 10. In the opinion of the investigator, the participant must be able to comply with all
 study-related procedures, medication use and evaluations.

 11. Mental capacity and legal ability to consent to participation in the clinical study.

 Exclusion Criteria:

 1. Contraindications for R-GemOx and BR plus polatuzumab vedotin as judged by the
 treating physician.

 2. Prior chimeric antigen receptor therapy or other genetically modified T-cell therapy.

 3. ECOG performance status > 2.

 4. Absolute neutrophil count < 1,000/μL (unless secondary to bone marrow involvement by
 DLBCL as demonstrated by bone marrow biopsy required for screening).

 5. Platelet count < 50,000/μL (unless secondary to bone marrow involvement by DLBCL as
 demonstrated by bone marrow biopsy required for screening).

 6. Absolute lymphocyte count < 100/μL.

 7. Participants who have CNS lymphoma involvement in present or past medical history.

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

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

 10. Active infection with SARS-CoV-2.

 11. Known history or evidence of severely immunocompromised state; i.e. corticosteroid
 treatment > 10 mg/day for more than 6 months.

 12. Has received vaccination with live virus vaccines within 6 weeks prior to
 randomisation.

 13. Prior CD19 targeted therapy

 14. Known history or presence of seizure activities or on active antiseizure medications
 within the previous 12 months.

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

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

 17. Known history or presence of cerebral vascular accident (CVA) within 12 months prior
 to randomisation. Note: In case of history of CVA > 12 months prior to leukapheresis,
 then the participant must not have any unstable or life-threatening neurological
 deficits.

 18. Participants with Richter's transformation or Richter's syndrome.

 19. Participants who are concurrently on any other experimental treatments or during the
 previous 4 weeks or 5-half-lives.

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

 21. Resting peripheral oxygen saturation < 90% on room air.

 22. Liver dysfunction as indicated by total bilirubin, aspartate aminotransferase and/or
 alanine aminotransferase > 5 × institutional upper limit of normal (ULN).

 23. Serum creatinine ≥ 2.0 × ULN or CrCl < 30 mL/min calculated according to the modified
 formula of MDRD.

 24. Pregnant or breast-feeding woman.

 25. Prior history of malignancies other than DLBCL, unless the participant has been free
 of the disease for ≥ 3 years prior to screening. Exceptions to the ≥ 3-year time limit
 include history of the following:

 -  Basal cell carcinoma of the skin.

 -  Squamous cell carcinoma of the skin.

 -  Carcinoma in situ of the cervix.

 -  Carcinoma in situ of the breast.

 -  Carcinoma in situ of the bladder.

 -  Incidental histological finding of untreated localized (T1a or T1b) prostate
 cancer under surveillance.

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

 27. Any medical condition likely to interfere with assessment of safety or efficacy of
 study treatment.

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