| 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/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.
2. Relapsed or refractory disease after first-line chemoimmunotherapy:
• Refractory disease is defined as no CR to first-line therapy(e.g. R-CHOP [rituximab, cyclophosphamide, daunorubicin, vincristine and prednisone]).
- Progressive disease (PD) as best response 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 ≤ 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 ≤ 2 years (preferred: ≤ 2 months) prior to screening for 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.
5. 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 ≥ 1 of 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 of < 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:
6. Age ≥ 18 years.
7. Measurable disease according to Lugano criteria. The lesion must be measurable (nodes> 1.5 cm in the long axismeasurable (nodes > 1.5 cm in the long axis; extranodal lesions > 1 cm in the long axis) and positive on a positron emission tomography scan.
8. Estimated life expectancy of > 3 months for other reasons than the primary disease.
FOR FULL LIST OF INCLUSION CRITERIA PLEASE REFER TO THE STUDY PROTOCOL
|
|
| E.4 | Principal exclusion criteria |
1. Contraindications for R-GemOx,BR plus polatuzumab vedotin, cyclophosphamide and fludarabine as judged by the treating physician.
2. Prior chimeric antigen receptor therapy or other genetically modified T-cell therapy.
3. Participants who have received more than one line of treatment for DLBCL or associated subtypes.
4. Prior haematopoietic stem cell transplantation (HSCT; as first-line consolidation) < 3 months at the time of leukapheresis.
5. ECOG performance status > 2.
6. Absolute lymphocyte count < 100/µL (unless secondary to bone marrow involvement by DLBCL as demonstrated by bone marrow
biopsy).
7. Platelet count < 50,000/µL (unless secondary to bone marrow involvement by DLBCL as demonstrated by bone marrow biopsy).
8. Absolute lymphocyte count < 100/µL.
9. Participants who have central nervous system (CNS) lymphoma involvement in present or past medical history.
10. Participants with the requirement for urgent therapy due to tumour mass effects.
11. Infection with human immunodeficiency virus.
12. Presence of active or prior hepatitis B or C as indicated by serology (for detailed criteria see Section 10.2.7.10). Treated infection with
hepatitis B or C virus unless confirmed to be polymerase chain reaction negative.
13. Active infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
14. Active, severe systemic fungal, viral or bacterial infection.
15. Known history or evidence of severely immunocompromised state, i.e. corticosteroid treatment > 10 mg/day for more than 6 months.
16. Has received vaccination with live virus vaccines 6 weeks prior to randomisation.
17. Prior CD19-targeted therapy
18. Known history or presence of seizure activities or on active antiseizure medications within the previous 12 months.
19. History or presence of non-malignant CNS disease that, in the judgement of the investigator, may impair the ability to evaluate neurotoxicity.
20. Known history or presence of autoimmune CNS disease, such as multiple sclerosis, optic neuritis or other immunologic or inflammatory
disease.
21. 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.
22. Participants with Richter's transformation or Richter's syndrome.
23. Participants who are concurrently on any other experimental treatments or during the previous 4 weeks or 5-half-lives.
24. Clinical heart failure with New York Heart Association class ≥ 2 or LVEF < 30% or severe cardiac arrhythmias or QT prolongation (resting
QTcF ≥ 450 msec [male] or ≥ 460 msec [female] at screening) that would (according to the evaluation of the investigator) face an
uncontrollable risk by receiving the medications administered in the trial.
25. Resting peripheral oxygen saturation < 90% on room air.
26. Liver dysfunction as indicated by total bilirubin > 2.5 × institutional upper limit of normal (ULN), aspartate aminotransferase and/or alanine
aminotransferase > 5 × ULN or typical symptoms like jaundice.
27. Serum creatinine ≥ 2.0 × ULN or eGFR < 30 mL/min calculated according to the modified MDRD formula.
28. Pregnant or breast-feeding women.
29. Prior history of malignancies other than DLBCL. Exceptions include participants who have been free of the disease for ≥ 3 years prior to
screening and participants with adequately treated and removed 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 or incidental histological finding of
untreated localised (T1a, T1b and T1c) prostate cancer under surveillance.
30. History of severe immediate hypersensitivity to any investigational medicinal product (IMP), auxiliary medicinal product (AMP),
premedication or rescue medication or its excipients that is scheduled to be given during study participation.
31. Major surgery less than 30 days before start of treatment.
32. Any medical condition likely to interfere with assessment of safety or efficacy of study treatment. |
|
| 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), defined as the time between the date of randomisation and the date of the event (objective disease progression,
the start of new anti-lymphoma therapy or death of any cause) based on IRC assessment.
2. Best complete response rate (BCRR), defined as the proportion of participants with at least one complete response (CR) assessment until
Week 24 in the MB-CART2019.1 arm and Week 26 in the comparator arm based on IRC assessment.
3. Duration of complete response (DOCR), defined as the time between the date of a first CR and the date of assessment of objective disease
progression 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 at 12 months based on investigator assessment and based on IRC assessment.
• PFS based on investigator assessment.
• EFS based on investigator assessment.
• EFS rates at 6 and at 12 months based on investigator assessment and based on IRC assessment.
• Modified EFS (mEFS) defined as the time between the date of randomisation and the date of the event (start of new anti-lymphoma therapy or death of any cause).
• BCRR, defined as the proportion of participants with at least one CR assessment until Week 24 in the MB-CART2019.1 arm and Week 26 in
the comparator arm based on investigator assessment.
• BCRR until Week 48 in the MB-CART2019.1 arm and Week 50 in the comparator arm based on investigator assessment and based on IRC
assessment.
• Modified BCRR (mBCRR), defined as the proportion of participants with at least one CR assessment without symptoms (B symptoms,
symptomatic splenomegaly, symptomatic hepatomegaly, symptomatic lymphadenopathy and infections) at the time of this CR based on
investigator assessment and based on IRC assessment.
• DOCR, defined as the time between the date of a first CR and the date of assessment of objective disease progression 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 objective disease progression or the date of death due to DLBCL, whichever occurs first, based on investigator assessment and
based on 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 assessment and based on IRC assessment.
• Time to complete response (TTCR), defined as the time between the date of randomisation and the date of a first objective CR based on
investigator assessment and based on IRC assessment.
• Time to modified complete response (TTmCR), defined as the time between the date of randomisation and the date of a first objective CR
without symptoms (B symptoms, symptomatic splenomegaly, symptomatic hepatomegaly, symptomatic lymphadenopathy and
infections) at the time of this CR based on investigator assessment and based on IRC assessment.
• Objective response rate (ORR), defined as the proportion of participants with either a CR or PR based on investigator assessment
and based on IRC assessment.
• Complete response rate (CRR), defined as the proportion of participants with a CR based on investigator assessment and based on
IRC assessment.
• Best objective response (BOR), defined as the best objective response in the time between the date of randomisation and the date of objective
disease progression, the start of new anti-lymphoma therapy or the date of death from any cause, whichever occurs first, based on investigator
assessment and based on IRC assessment.
• Change in B symptoms (recurrent, unexplained fever > 38 °C without signs of infection, drenching night sweats without signs of infection
and/or unintentional weight loss ≥ 10% within the preceding 6 months), defined as the proportion of participants with B symptoms at baseline
and with changes in B symptoms from baseline at any time following randomisation.
• Changes in HRQoL.
• Changes in 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 real time
quantitative polymerase chain reaction (qPCR).
• Types and levels of cytokines (including sIL-2R, IL 6, IL-10, IL-15, IFN-γ and TFNα).
• Anti-MB-CART2019.1 antibody.
FOR FULL LIST OF SECONDARY ENDPOINTS, PLEASE REFER TO THE STUDY PROTOCOL |
|
| 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 until Week 24 in the MB-CART2019.1 arm and Week 26 in
the comparator arm based on IRC assessment.
3. The time between the date of a first complete response (CR) and the date of assessment of objective disease progression 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 FULL LIST OF TIMEPOINTS OF EVALUATION, PLEASE REFER TO THE STUDY PROTOCOL |
|
| 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 | 15 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| 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
|
| Day when the last participant completes the last assessment, is considered lost to follow-up, withdraws consent or dies. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
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