Efficacy and Safety of MB-CART2019.1 vs. SoC in Lymphoma Patients

Diffuse Large B-cell Lymphoma Clinical Trial

— DALY 2-EU  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04844866
• Other study ID #: M-2020-371
• Status: Recruiting
• Phase: Phase 2
• Start date: August 18, 2021
• Est. completion date: July 31, 2027

Study information

• Verified date: April 2024
• Source: Miltenyi Biomedicine GmbH
• Contact: Gregor Zadoyan, Dr.
• Phone: +49 2204 8306
• Email: gregor.zadoyan[@]miltenyi.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

This study should determine superiority of MB-CART2019.1 treatment compared to SoC therapy with R-GemOx (rituximab, gemcitabine and oxaliplatin) with respect to event-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®. 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). Participants from the SoC arm are allowed to be treated with MB-CART2019.1 upon request by the investigator if at least one of the following criteria is confirmed by the IRC: - Relapse or progression occurring at any time within 1 year after randomisation. - Failure to achieve PR or CR at or beyond Week 8 after randomisation (after 4 cycles of R-GemOx or 3 cycles of BR plus polatuzumab vedotin) and the start of a new anti-lymphoma therapy is warranted. 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 168
• Est. completion date: July 31, 2027
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

1. 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.

2. 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.

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 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.

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 = 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:

6. Age = 18 years.

7. 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.

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

9. 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.

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.

Criteria for Exclusion:

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 neutrophil count < 1,000/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 anti-seizure 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 or T1c) prostate cancer under surveillance.

30. History of severe immediate hypersensitivity to any investigational medicinal product (IMP), auxiliary medicinal product (AxMP), 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.

Related Conditions & MeSH terms

• Diffuse Large B-cell Lymphoma
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Large B-Cell, Diffuse

Intervention

Genetic:
• MB-CART2019.1
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.

Drug:
• R-GemOx or BR plus polatuzumab vedotin
Immunochemotherapy will be administered as per arm description.

Locations

Country	Name	City	State
Austria	Medizinische Universitaetsklinik Graz	Graz
Austria	Universitatsklinikum Innsbruck Universitatsklinik fur Innere Medizin V	Innsbruck
Austria	Ordensklinikum Linz GmbH Elisabethinen	Linz
Austria	LKH - Universitaetsklinikum der PMU Salzburg	Salzburg
Austria	Medizinische Universitaet Wien - Allgemeines Krankenhaus der Stadt Wien (AKH)	Wien
Belgium	Jules Bordet lnstitute	Anderlecht
Belgium	Universitaire Ziekenhuizen Leuven - Campus Gasthuisberg	Leuven
Belgium	Universite Catholique de Louvain Namur, Centre Hospitalier Universitaire Dinant Godinne Site Godinne	Yvoir
Czechia	University Hospital Hradec Kralove	Hradec Králové
Czechia	FNsP Ostrava	Ostrava
France	Centre Hospitalier Universitaire (CHU) - Hopital Henri Mondor	Créteil
France	CHRU de Lille - Hopital Claude Huriez	Lille
France	Centre Hospitalier Lyon Sud, Hospices Civils de Lyon Groupement Hospitalier Sud	Lyon
France	Centre Paoli Calmettes	Marseille
France	Centre Hospitalier Universitaire de Montpellier - Hopital Saint-Eloi	Montpellier
France	Centre Hospitalier Universitaire de Nantes (CHU de Nantes) - Hopital Hotel Dieu	Nantes
France	Hospital Saint-Louis - APHP	Paris
France	Centre Hospitalier Universitaire de Bordeaux - Hopital Haut-Leveque	Pessac
France	Centre Hospitalier Universitaire de Poitiers	Poitiers
France	CHU de Rennes - Hopital de Pontchaillou	Rennes
France	Institut Universitaire du Cancer Service d´hématologie	Toulouse
France	CHU de Nancy Hopitaux de Brabois	Vandœuvre-lès-Nancy
Germany	Universitatsklinikum Augsburg	Augsburg
Germany	Helios Klinikum Berlin - Buch	Berlin
Germany	Universitaetsklinikum Knappschaftskrankenhaus Bochum der Ruhr-Universitat Bochum	Bochum
Germany	Universitaetsklinikum Koeln	Cologne
Germany	Klinikum Erlangen der Friedrich-Alexander-Universitaet Erlangen-Nuernberg	Erlangen
Germany	Universitaetsklinikum Essen	Essen
Germany	Asklepios Klinik St. Georg	Hamburg
Germany	University Medical Center Hamburg-Eppendorf	Hamburg
Germany	Universitaetsklinikum Heidelberg	Heidelberg
Germany	Universitätsklinikum Leipzig	Leipzig
Germany	Klinikum der Universitat München, Studienzentrale fur Hematologie der Medizinischen Klinik II	München
Germany	Universitaetsklinikum Muenster	Münster
Germany	University Hospital Regensburg	Regensburg
Germany	University Hospital of Tuebingen	Tuebingen
Hungary	Del-Pesti Centrumkorhaz - Orszagos Hematologiai es Infektologiai Intezet	Budapest
Hungary	Debreceni Egyetem - Orvos es Egeszsegtudomanyi Centrum (DEOEC) (University of Debrecen Medical and Health Science Center)	Debrecen
Italy	Azienda Ospedaliera San Giovanni Battista Di Torino	Torino
Lithuania	VUH Santaros Klinikos	Vilnius
Netherlands	Amsterdam Universitaire Medische Centra (UMC) - locatie Amsterdam Medisch Centrum (AMC)	Amsterdam
Netherlands	University Medical Center Groningen	Groningen
Netherlands	Leiden University Medical Center (LUMC)	Leiden
Netherlands	Erasmus University Medical Center	Rotterdam
Poland	Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wroclawiu. Klinika Hematologii, Nowotworow Krwi i Transplantacji Szpiku	Wroclaw
Spain	Catalan Institute of Oncology (ICO) Hospitalet	Barcelona
Spain	Hospital Clinic de Barcelona - Institut Clinic de Malalties Hematologiques i Oncologiques (ICMHO)	Barcelona
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	Hospital Universitario Fundacion Jimenez Diaz	Madrid
Spain	Hospital Universitario Virgen De La Arrixaca (Huva)	Murcia
Spain	Clinica Universidad de Navarra	Pamplona
Spain	Hospital Clinico Universitario de Salamanca	Salamanca
Spain	Hospital Universitario Virgen del Rocio	Sevilla
Sweden	Onkologikliniken	Uppsala

Sponsors (2)

Lead Sponsor	Collaborator
Miltenyi Biomedicine GmbH	ICON plc

Countries where clinical trial is conducted

Austria,  Belgium,  Czechia,  France,  Germany,  Hungary,  Italy,  Lithuania,  Netherlands,  Poland,  Spain,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Event-free survival	Event-free survival (EFS), defined as the time between the date of randomisation and the date of objective disease progression, failure to achieve partial response (PR) or complete response (CR) at or beyond Week 8 after randomisation leading to a new anti-lymphoma therapy or death of any cause, whichever occurs first, based on independent review committee (IRC) assessment.	up to 30 weeks after randomisation
Secondary	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 IRC assessment.	up to 99 weeks after randomisation
Secondary	Best complete response rate	To evaluate the safety and toxicity of MB-CART2019.1 compared to SoC therapy.	up to 99 weeks after randomisation
Secondary	Duration of complete response	To evaluate the safety and toxicity of MB-CART2019.1 compared to SoC therapy.	up to 91 weeks
Secondary	Overall survival	To evaluate the safety and toxicity of MB-CART2019.1 compared to SoC therapy.	up to 99 weeks after randomisation