| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed/refractory diffuse large B cell lymphoma (R-R DLBCL) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Diffuse large B cell lymphoma (DLBCL) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10003903 |
| E.1.2 | Term | B-cell lymphoma refractory |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10003902 |
| E.1.2 | Term | B-cell lymphoma recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective is to determine superiority of MB-CART2019.1 treatment compared to standard-of-care (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 (ASCT). |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of MB-CART2019.1 compared to SoC therapy.
• To evaluate the safety and toxicity of MB-CART2019.1 compared to SoC therapy.
• To evaluate changes in health-related quality of life (HRQoL) and lymphoma symptoms of participants receiving MB-CART2019.1 compared to SoC therapy.
•To evaluate the humoral immunogenicity against MB-CART2019.1.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologically proven DLBCL and associated subtypes, according to the World Health Organisation (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. 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.
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 the MDRD
(Modification of Diet in Renal Disease) formular, 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 of childbearing potential (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. oophorectomy. A post-menopausal state is defined as no menses for 12 months without an alternative medical cause. WOCBP must refrain from egg donation throughout the study until 12 months after the last dose of study treatment. WOCBP must refrain from egg donation throughout the study until 12 months after the last dose of study treatment.
FOR FULL LIST OF INCLUSION CRITERIA PLEASE REFER TO THE STUDY PROTOCOL
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|
| E.4 | Principal 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).
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival (PFS), defined as the time between the date of randomisation and the date of objective disease progression or death of any cause, whichever occurs first, based on Independent Review Committee (IRC) assessment. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The time between the date of randomisation and the date of objective disease progression or death of any cause, whichever occurs first, based on Independent Review Committee (IRC) assessment. |
|
| E.5.2 | Secondary end point(s) |
Key Efficacy Endpoints:
1. Event-free-survival (EFS; progression of disease, start of new anti-cancer treatment, relapse or death of any cause), defined as the time between the date of randomisation and the date of the event.
2. Best complete response rate (BCRR), defined as the proportion of participants with at least one complete response assessment, based on IRC assessment.
3. Duration of complete response, defined as the time between the date of a first complete response (CR) and the date of assessment of relapse or the date of death due to DLBCL, whichever occurs first, based on IRC assessment.
4. Overall survival (OS), defined as time between the date of randomisation and the date of death of any cause.
Other Secondary Endpoints:
• PFS rates at 6 and 12 months, based on investigator and/or IRC assessment.
• BCRR, defined as the proportion of participants with at least one CR assessment, based on investigator assessment.
• Duration of complete response, defined as the time between the date of a first CR and the date of assessment of relapse or the date of death due to
DLBCL, whichever occurs first, based on investigator assessment.
• Duration of response (DOR), defined as the time between the date of a first objective response (CR/partial response [PR]) and the date of assessment of relapse or the date of death due to DLBCL, whichever occurs first, based on investigator and/or IRC assessment.
• Time to objective response (TTR), defined as the time between the date of randomisation and the date of a first objective response (CR/PR), based on investigator and/or IRC assessment.
• Objective response rate (ORR), defined as the proportion of participants with either a CR or PR, based on investigator and/or IRC assessment.
• Complete response rate (CRR), defined as the proportion of participants with a CR, based on investigator and/or IRC assessment.
• Best objective response (BOR), defined as the best objective response in the time between the date of randomisation and the date of the occurrence of progressive disease (PD) or relapse, the start of new anticancer therapy or the date of death from any cause, whichever occurs first, based on investigator and/or IRC assessment.
• Change in B symptoms from baseline (fever [> 38°C], night sweats and/or unintentional weight loss [≥ 10% of body weight]).
• Changes in HRQoL and lymphoma symptoms.
In MB-CART2019.1 arm only:
• Persistence of MB-CART2019.1 and phenotype and immune cell compositions, based on flow cytometry analyses and qPCR.
• Types and levels of cytokines (including sIL-2R, IL-6, IL-10, IL-15, IFN-γ and TNFα).
• Anti-MB-CART2019.1 antibody.
Safety Endpoints:
• Type, frequency and severity of adverse events (AEs), serious adverse events (SAEs) and adverse events of special interest (AESIs).
• Hospital days within 7 month after randomisation.
• Intensive care unit (ICU) admission days within 7 months after randomisation.
• Use of tocilizumab and/or high-dose steroids.
• Need for transfusions, prophylactic antimicrobial therapy and gamma globulin substitution. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. The time between the date of randomisation and the date of the event.
2. The proportion of participants with at least one complete response assessment, based on IRC assessment.
3. The time between the date of a first complete response (CR) and the date of assessment of relapse or the date of death due to DLBCL, whichever occurs first, based on IRC assessment.
4. The time between the date of randomisation and the date of death of any cause.
For other Secondary Endpoints:
• PFS rates at 6 and 12 months, based on investigator and/or IRC assessment.
• The proportion of participants with at least one CR assessment, based on investigator assessment
FOR FULL LIST OF TIMEPOINTS OF EVALUATION PLEASE REFER TO THE STUDY PROTOCOL |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
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