A Pivotal Phase II Randomised, Multi-centre, Open-label Study to Evaluate the Efficacy and Safety of MB-CART2019.1 Compared to SoC Therapy in Participants With r/r DLBCL, Who Are Not Eligible for HDC and ASCT
In the current protocol version, there are two parts. Part I 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. Part II is a Phase II single-arm, open-label, multi-centre study evaluating the efficacy and safety of MB-CART2019.1 in younger, fit participants with R-R DLBCL. Part II will start after completion of enrolment in Part I.
⁃ Part I:
• Histologically proven DLBCL and associated subtypes, according to the World Health Organization (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/blastoid/intermediate histology or HGBL with MYC and BCL2 and/or BCL6 rearrangements (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.
⁃ Follicular lymphoma Grade 3B.
• Relapsed or refractory disease after first-line chemoimmunotherapy:
‣ Refractory disease defined as no CR to first-line therapy (e.g. R-CHOP \[rituximab, cyclophosphamide, daunorubicin, vincristine and prednisone\]).
• Progressive disease (PD) after at least 2 full cycles of first-line therapy.
∙ Stable disease (SD) after 4 cycles of first-line therapy.
∙ PR as best response after at least 6 cycles of first-line therapy and biopsy-proven persistent disease (except where prohibited due to comorbidities) within ≤ 24 months from the start of the first-line therapy.
⁃ Relapsed disease defined as complete remission to first-line therapy followed by biopsy-proven disease progression (except where prohibited due to comorbidities) within ≤ 24 months from the start of the first-line therapy.
• Participants 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.
• Archival paraffin-embedded tumour tissue acquired ≤ 2 years (preferred: ≤ 2 months) prior to screening for the central pathology review to confirm DLBCL diagnosis 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 must be made available for the central pathology review.
• Participants deemed ineligible to receive HDC followed by ASCT based on the treating physician's assessment and meeting the following criteria:
• EITHER
⁃ Age ≥ 18 years and
• Prior ASCT (as first-line consolidation) or
∙ Haematopoietic cell transplantation-specific comorbidity index (HCT-CI) \> 3. OR
⁃ Age ≥ 65 years and ≥ 1of the criteria below:
• Impaired cardiac function (left ventricular ejection fraction \[LVEF\] \< 50%), or
∙ Impaired renal function (estimated glomerular filtration rate \[eGFR\] \< 60 mL/min) calculated according to the modified Modification of Diet in Renal Disease (MDRD) formula, or
∙ Impaired pulmonary function (diffusing capacity for carbon monoxide or forced expiratory volume in 1 second \< 80%) or dyspnoea on slight activity, or
∙ Eastern Cooperative Oncology Group (ECOG) performance status \> 1. OR
⁃ Age ≥ 70 years. 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:
• Age ≥ 18 years.
• Measurable disease according to Lugano criteria. The lesion must be measurable (nodes \> 1.5 cm in the long axis; extranodal lesions \> 1 cm in the long axis) and positive on a positron emission tomography scan.
• Estimated life expectancy of \> 3 months for other reasons than the primary disease.
• Women 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 associated with inhibition of ovulation (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. WOCBP who want to become pregnant after completing treatment should seek advice about oocyte cryoconservation prior to treatment because of possible irreversible infertility. WOCBP must refrain from egg donation throughout the study until 12 months after the last dose of study treatment.
• Men with non-pregnant WOCBP partners must agree to use highly effective contraceptive measures (Pearl index \< 1, e.g. spermicide and condom or other highly effective contraceptive measures (Pearl index \< 1) taken by their WOCBP partner) 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 should seek advice about sperm conservation prior to treatment because of possible irreversible infertility. Men must furthermore refrain from sperm donation throughout the study until 12 months after the last administration of study treatment.
⁃ In the opinion of the investigator, the participant must be able to comply with all study-related procedures, medication use and evaluations.
⁃ Mental capacity and legal ability to consent to participation in the clinical study.