This study has been transitioned to CTIS with ID 2023-506270-13-00 check the CTIS register for the current data. The primary objective is to determine superiority of MB CART2019.1 treatment compared to standard-of-care (SoC) therapy with R GemOx (…
ID
Source
Brief title
Condition
- Lymphomas non-Hodgkin's B-cell
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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 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.
Secondary outcome
Secondary Endpoints:
Key Efficacy Endpoints:
1. 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.
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 of any cause, 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.
• Time to new anti-lymphoma therapy 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 of any cause,
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 of any cause, 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 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.
Only for participants treated with MB-CART2019.1:
• 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 and
TNF).
• 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 months 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 within 12 months after randomisation.
FOR EXPLORATORY ENDPOINTS PLEASE REFER TO THE STUDY PROTOCOL
Background summary
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. The
CliniMACS Prodigy® performs all manufacturing steps in a single automated and
functionally closed system. The CD20/CD19 CAR transduced T cells (MB
CART2019.1) are to be administered for the treatment of relapsed/refractory (R
R) CD19 and CD20 expressing B cell non Hodgkin lymphoma (B NHL).
CARs have been generated against many cell surface molecules, including CD19,
CD20, CD22, human epidermal growth factor receptor 2, GD2, prostate specific
membrane antigen and mesothelin, and many of them are presently under
evaluation in over 370 Phase I or II clinical studies
(https://ClinicalTrials.gov/29.Sep.2020). To date, the most promising clinical
outcomes of this technology have been reported in patients treated with
autologous CAR transduced T cells targeting CD19. The first complete responses
(CR) to CAR T cell therapy were seen in participants with chronic lymphocytic
leukaemia (CLL). In pilot clinical studies, CAR T cells expressing second
generation CARs against CD19 produced durable remissions even in participants
with bulky lymphomas. Subsequent Phase I/II studies in children and adults with
relapsed and highly refractory acute lymphoblastic leukaemia (ALL) resulted in
high proportions of complete, mostly molecular remissions across 4
institutions, with follow up periods of up to 2 years reported. CAR-engineered
autologous and allogeneic T cells expanded and persisted in vivo and had
anti-leukaemic efficacy even in participants with large refractory leukaemia
burdens. Recently published results of Phase I/II studies in participants with
large B-cell lymphoma demonstrate best objective response (BOR) rates ranging
between 52% and 82% with a median progression free survival (PFS) ranging
between 3 and 5.9 months for all participants, whereas PFS for complete
responders was not reached. Grade 3 or worse cytokine release syndrome (CRS)
occurred in 11% to 22% and Grade 3 or worse neurologic events in 12% to 32% of
participants.
T cells transduced with a CAR directed against CD20 have also been used for
treatment of individuals with B-cell malignancies. In one Phase I study, 3 of 4
participants received CD20 CAR T cell infusions: 2 participants had no
evaluable disease after the treatment and remained progression free for 12 and
24 months, respectively; the third participant had an objective partial
remission at 6 months and relapsed at 12 months after infusions. CD20 CAR T
cells were detected by real time quantitative polymerase chain reaction (qPCR)
at tumour sites and up to 1 year in peripheral blood, albeit at low levels. No
evidence of host immune responses against infused cells was detected.
In another clinical study programme, CD20 CAR T cells were administered to
participants with resistant or chemotherapy refractory advanced diffuse large B
cell lymphoma (DLBCL) in a Phase I study and subsequently in a Phase IIa study.
The overall objective response rate (ORR) after 4 to 6 weeks in the latter
study was 9/11 (81.8%) participants with a median PFS of 6 months; no severe
toxicity was observed.
There was one ongoing study with a product consisting of CD20/19 CAR T cells,
conducted at the Medical College of Wisconsin, using the same lentiviral vector
and a nearly identical manufacturing process as used in all Miltenyi sponsored
studies (ClinicalTrials.gov Identifier: NCT03019055). First data have already
been published showing that 13/19 (68%) participants had a CR on Day 28.
Participants receiving fresh CAR T cells showed a numerical higher clinical
response rate (79%) than participants receiving cryopreserved CAR T cells (40%).
A Phase I/II safety, dose-finding and feasibility study of MB CART2019.1 in
participants with R R B-NHL clinical study is currently ongoing.
Indication
Haematological malignancies include a diverse group of lymphomas and leukaemia
that arise in cells of the immune and lymphatic systems. Aggressive B NHL are
rare diseases sharing a cell origin from the B cell lineage expressing B
lineage markers such as CD19, CD20 and CD22. According to the World Health
Organization (WHO) classification 2008 and its revision 2016, B NHL include
among others DLBCL, Burkitt lymphoma, mantle cell lymphoma and follicular
lymphoma, as well as CLL/SLL (chronic lymphocytic leukaemia/ small lymphocytic
lymphoma). Despite a high cure rate, a small subset of patients does not
respond to first line chemotherapy or relapse. Among patients with DLBCL - the
most common aggressive B NHL in adults - which are refractory to second line
chemotherapy, current salvage therapies are mostly ineffective; in patients
progressing after autologous stem cell transplantation (ASCT) or allogeneic
SCT, median overall survival (OS) is < 10%. Thus, there is a strong need for
alternative treatment options for patients with chemotherapy refractory and
relapsed aggressive B-NHL, not eligible for high-dose therapy/ASCT. Although
there has been a decline in the national trends in cancer death rates in
lymphoma and leukaemia from 2011 to 2015, an estimated 74,200 new cases of NHL
occurred in 2019, with 19,970 deaths due to this disease. Patients failing
first line therapy or relapsing post first line therapy who are not eligible to
receive a high dose chemotherapy (HDC) followed by an ASCT have a dismal
prognosis due to lack of effective treatments. This study is specifically
designed to address this unmet medical need.
Study objective
This study has been transitioned to CTIS with ID 2023-506270-13-00 check the CTIS register for the current data.
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 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 (ASCT).
Secondary Objectives:
• 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.
FOR EXPLORATORY OBEJCTIVES PLEASE REFER TO THE STUDY PROTOCOL
Study design
This is a pivotal Phase II randomised, open label, multi-centre study
evaluating the efficacy and safety of MB CART2019.1 versus SoC therapy in
participants with R R DLBCL, who are non eligible for high dose chemotherapy
(HDC) and ASCT. Adult participants with R R DLBCL after first line therapy will
be randomised in a 1:1 ratio to receive MB CART2019.1 or SoC therapy as
comparator. The comparator treatment is either a combination of rituximab,
gemcitabine and oxaliplatin (R GemOx) or a combination of bendamustine and
rituximab (BR) plus polatuzumab vedotin (Polivy®), with the latter accounting
for up to 10% of participants in the comparator arm.
Intervention
Single infusion of 2.5 × 106 CAR transduced autologous T cells per kg/body
weight (BW) (with a maximum dose equivalent to 100 kg for participants with a
body weight > 100 kg). The Investigational medicinal product (IMP) will be
administered over a period of approx. 15 minutes (slow intravenous [i.v.]
infusion via a large peripheral vein or central line). The IMP is only to be
administered after a lymphodepleting chemotherapy with fludarabine and
cyclophosphamide.
Comparators:
The participants will receive 8 cycles of 14 days each of R GemOx per i.v.
administration.
The participants will receive 6 cycles of 21 days each of BR plus polatuzumab
vedotin per i.v. administration.
Study burden and risks
Clinical results for the use of CD19 and CD20 CAR-transduced T cells have been
published. Therefore, all risks and benefits are estimated based on those data
and extrapolated to the use of this new CD20/CD19 CAR construct where only
limited data, mainly related to preclinical work, is available. CAR T-cell
administration carries substantial well-known risks that have to be weighed
against the risk of the malignancy as well as the consideration of other
treatment options. Based on the evaluations of risks and potential benefits and
bearing in mind that the participant population eligible for these studies has
already received approved and available treatment without success, the
benefit-risk ratio outweighs the above-mentioned potential risks.
Friedrich-Ebert-Straße 68
Bergisch Gladbach 51429
NL
Friedrich-Ebert-Straße 68
Bergisch Gladbach 51429
NL
Listed location countries
Age
Inclusion criteria
1. Histologically proven DLBCL and associated subtypes, according to the World
Health Organisation (WHO) 2016 classification.
2. Relapsed or refractory disease after first line chemoimmunotherapy.
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
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.
Men with non-pregnant WOCBP partners must agree to use highly effective
contraceptive measures
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.
FOR FULL LIST OF INCLUSION CRITERIA PLEASE REFER TO THE STUDY PROTOCOL
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 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.
FOR FULL LIST OF EXCLUSION CRITERIA PLEASE REFER TO THE STUDY PROTOCOL
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-506270-13-00 |
| EudraCT | EUCTR2020-003908-14-NL |
| CCMO | NL76282.000.21 |