Beschreibung

Rekrutierung gestartet

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 (R-R DLBCL), who are not eligible for high-dose chemotherapy and autologous stem cell transplantation

Studientherapie

Experimental: MB-CART2019.1: Single infusion of 2.5 × 10^6 CD20/CD19 CAR-transduced autologous T cells per kg/body weight.

Active Comparator: SoC
Immunochemotherapy will be administered from the following 2 predefined regimens: R-GemOx (8 cycles of 14 days each) or BR plus polatuzumab vedotin (6 cycles of 21 days each). BR plus polatuzumab vedotin will be capped at a maximum of 10% of participants.

Studienstatus

Rekrutierung gestartet/nimmt Patienten auf

Allgemeine Infos zum Antrag

Frau Dr. Silke Holtkamp
Silke.Holtkamp@miltenyi.com

Miltenyi (Unternehmen, 11896)
Biotec GmbH
Friedrich-Ebert-Straße 68
51429 Bergisch Gladbach

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).

• 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.

Adult participants with R-R DLBCL after first-line therapy who are non-eligible for high-dose chemotherapy (HDC) and ASCT.

It is planned that a total of 168 participants will be enrolled; 84 participants will be randomised to the MB-CART2019.1 arm and 84 participants to the comparator arm (76 R-GemOx participants and 8 BR plus polatuzumab vedotin participants).

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.

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.

Spezifische Infos zum Antrag

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 d 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 d 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 d 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 e 18 years and
 Prior ASCT (as first-line consolidation) or
 Haematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) > 3.
• Age e 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) 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, further protocol-defined criteria must be fulfilled.

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 < 1,000/¼L (unless secondary to bone marrow involvement by DLBCL as demonstrated by bone marrow biopsy required for screening).
5. Platelet count < 50,000/¼L (unless secondary to bone marrow involvement by DLBCL as demonstrated by bone marrow biopsy required for screening).
6. Absolute lymphocyte count < 100/¼L.
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 e 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 e 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 e 3 years prior to screening. Exceptions to the e 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.

Enrolment is expected to be completed in approximately 12 months.
The duration of the active part of the study for each individual participant from screening to the end of the 1-year primary 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 secondary follow-up 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.
The active part of the study will be considered complete when all participants have completed the primary follow-up visit planned for Week 48 (experimental arm) or Week 50 (comparator arm), died or withdrawn early from the study, whereas the secondary follow-up will be considered complete when all participants have completed the last scheduled visit shown in the SoAs for the last participant in the study globally.
The maximum duration of the study is expected to be approximately 25 months (12 months for recruitment + 13 months for the active part of the study).

Approx. 45 in 9 EU countries, 16 of those in Germany

Miltenyi Biomedicine GmbH

45

Ja