Informations générales (source: ClinicalTrials.gov)
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 (DALY 2-EU)
Interventional
Phase 2
Miltenyi Biomedicine GmbH (Voir sur ClinicalTrials)
août 2021
juillet 2029
05 avril 2025
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.
Etablissements
| Les établissements d'Île-de-France dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
|---|---|---|---|---|---|
| AP-HP - Hôpital Henri Mondor-Albert Chenevier | Contact (sur clinicalTrials) | ||||
| Les établissements sans correspondance certaine dans le répertoire FINESS dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| Centre Hospitalier Lyon Sud, Hospices Civils de Lyon Groupement Hospitalier Sud - 69495 - Lyon - France | Contact (sur clinicalTrials) | ||||
| Centre Hospitalier Universitaire de Bordeaux - Hopital Haut-Leveque - 33600 - Pessac - France | Contact (sur clinicalTrials) | ||||
| Centre Hospitalier Universitaire de Montpellier - Hopital Saint-Eloi - 34090 - Montpellier - France | Contact (sur clinicalTrials) | ||||
| Centre Hospitalier Universitaire de Nantes (CHU de Nantes) - Hopital Hotel Dieu - 44093 - Nantes - France | Contact (sur clinicalTrials) | ||||
| Centre Hospitalier Universitaire de Poitiers - 86000 - Poitiers - France | Contact (sur clinicalTrials) | ||||
| Centre Paoli Calmettes - 13273 - Marseille - France | Contact (sur clinicalTrials) | ||||
| CHRU de Lille - Hopital Claude Huriez - 59000 - Lille - France | Contact (sur clinicalTrials) | ||||
| CHU de Nancy Hopitaux de Brabois - 54500 - Vandœuvre-lès-Nancy - France | Contact (sur clinicalTrials) | ||||
| CHU de Rennes - Hopital de Pontchaillou - 35033 - Rennes - France | Contact (sur clinicalTrials) | ||||
| Hospital Saint-Louis - APHP - 75010 - Paris - France | Contact (sur clinicalTrials) | ||||
| Institut Universitaire du Cancer Service d´hématologie - 31059 - Toulouse - France | Contact (sur clinicalTrials) | ||||
Critères
Tous
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.
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.