This study has been transitioned to CTIS with ID 2024-511979-15-00 check the CTIS register for the current data. Primary objective: • To compare progression free survival (PFS, of patients randomized to investigational point-of-care (PoC) ARI-0001…
ID
Source
Brief title
Condition
- Lymphomas non-Hodgkin's B-cell
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• PFS from date of IMP infusion (if applicable)
Secondary outcome
• PFS from date of randomization
• Safety and toxicity assessment of ARI-0001 CAR T-cells and Axi cel per
AE reporting classified according to CTCAE Version 5 and CRS and ICANS
classified according to the ASTCT criteria
• Overall response rate (ORR, sum of CR and PR), as well as CR, PR, SD and
PD/relapse at 4 weeks, 12 weeks, 6, 12 and 24 months after infusion of CAR
T-cells
• Best overall response (BOR) rate at 4 weeks, 12 weeks, 6, 12 and 24 months
after infusion of CAR T-cells
• Duration of response (DOR)
• OS from date of randomization, and from date of CAR T-cell infusion (if
applicable)
• Patient Reported Outcome/Quality of Life (PRO/QOL)
• CAR T-cell expansion, persistence, and T-cell characteristics in both
treatment arms (ARI-0001 vs Axi-cel)
• PoC CAR T-cell production characteristics (e.g. number of viable T-cells,
transduction efficiency, T-cell subsets (activated T-cells, memory T-cells)),
including the functional characteristics (e.g. potency tests) between the
different production sites
• The association of the functional characteristics (e.g. potency tests) of the
CAR T-cell products (ARI-0001 CAR T-cells) with CAR T-cell expansion,
persistence, adverse events, response rates and progression free survival.
• Proportion of successful batches between the different production sites
• Number of days between leukapheresis and infusion of CAR T-cells
(vein-to-vein time)
• Fludarabine pharmacokinetics.
Background summary
Chimeric antigen receptor (CAR)T-cell therapy is an innovative form of adoptive
cell therapy that has proven its efficacy in the treatment of various
hematological malignancies, including B-cell non-Hodgkin lymphoma (NHL), and
B-cell acute lymphoblastic leukemia (ALL). CD19 has been the most studied
target antigen for CAR T-cell immunotherapy. Anti-CD19 CAR T-cell therapy has
shown durable responses in patients with different B-NHLs, including Diffuse
Large B-cell Lymphoma (DLBCL). Unfortunately, up to 50-60% of the patients do
not respond to CD19-directed CAR T-cell therapy. There are several shortcomings
of current CD19-directed CAR T-cell therapy, that likely underpin these,
namely:
i) Due to centralized production at commercial sites, the production is time
consuming (about 4 weeks), meaning that patients with rapidly progressive
lymphoma may not reach the moment of the infusion of the anti-CD19 CAR T-cells.
ii) Furthermore, for the current production processes, the autologous T-cells
need to be cryopreserved for shipment from the hospital to the production sites
and vice versa. This (double) cryopreservation process can decrease the quality
of the CAR T-cells.
This trial aims to address these shortcomings and will study the feasibility
and clinical efficacy of local manufacturing CD19-directed CAR T-cells,
(ARI-0001 CAR T-cells), in a completely closed system using the CliniMACS
Prodigy device. This randomized phase II study will compare the clinical
efficacy of locally produced CAR T-cells with commercially available CAR
T-cells (for example axicabtagene ciloleucel) in patients with relapsed or
refractory (R/R) diffuse large B-cell lymphoma (DLBCL).
This in-house (point-of-care) production process of ARI-0001 will take
approximately 7 or 12 days and thus will generate CAR T-cells *faster* which
will be infused in the patient preferably without cryopreservation (*fresh*).
Furthermore, the point-of-care production process can be replicated in academic
institutions with the appropriate cellular manufacturing facilities. If
successful, this study will show feasibility of local production of CAR T-cell
therapy, improving their rapid accessibility and quality.
Study objective
This study has been transitioned to CTIS with ID 2024-511979-15-00 check the CTIS register for the current data.
Primary objective:
• To compare progression free survival (PFS, of patients randomized to
investigational point-of-care (PoC) ARI-0001 CAR T-cells versus PFS of patients
randomized to commercial standard-of-care (SoC) (axicabtagene ciloleucel (Axi
cel, Yescarta)) CAR T-cells in patients with R/R DLBCL.
Secondary objectives:
• To evaluate response rates (ORR and CR)
• To evaluate safety and toxicity of ARI-0001 and Axi-cel
• To assess overall survival (OS)
• To evaluate quality of life (QoL)
• To assess costs associated with both treatment regimens (ARI-0001 vs
Axi-cel)
• To evaluate CAR T-cell expansion, persistence, and T-cell characteristics
in both treatment arms (ARI-0001 vs Axi-cel)
• To evaluate PoC CAR T-cell production characteristics (e.g. number of
viable T-cells, transduction efficiency, T-cell subsets (activated T-cells,
memory T-cells)), including the functional characteristics (e.g. potency tests)
between the different production sites
• To evaluate the association of the functional characteristics (e.g. potency
tests) of the CAR T-cell products (ARI-0001 CAR T-cells) with CAR T-cell
expansion, persistence, adverse events, response rates and progression free
survival
• To assess the proportion of successful batches between the different
production sites
• To evaluate the number of days between leukapheresis and infusion of CAR
T-cells (vein-to-vein time)
• To evaluate fludarabine pharmacokinetics.
Study design
Phase II, multi-center, randomized, open label, non-inferiority study.
Intervention
Patients are randomized between treatment with
- PoC CAR T-cell (ARI-0001)
- SoC CAR T-cell (Axi-cel)
Study burden and risks
All patients participating in this clinical trial are suffering from
progressive malignant B-cell lymphoma with no available approved curative
therapy. At this stage, patients are treated with palliative therapy or with
best supportive care. The survival rate and life expectancy are very poor.
Published clinical data lead to the assumption that a treatment with the IMP
could lead to tumor regression, response and long-term remission.
Anticipated risks
The risk of trial related procedures (blood sampling, leukapheresis, tumor
biopsies) are known and standard procedures will be applied to minimize risks.
The risks of the lympho-depleting chemotherapy with fludarabine (FLU) and
cyclophosphamide (CY) are known and include myelosuppression with neutropenia
and infections, gastrointestinal side effects with nausea and diarrhea,
alopecia and renal toxicities and cystitis.
Infusion of CAR T-cells can be associated with toxicities including high-grade
fever (usually starting about 24 h after CAR T cells infusion) and flu-like
symptoms such as myalgia, but can also lead to life-threatening complications
with hypotension and vascular leak, cytopenias, coagulopathy and renal and
respiratory failure, hypoxia, and neurologic disturbances. This syndrome of
toxicities has been termed cytokine release syndrome (CRS), likely related to a
progressive systemic inflammatory process initiated and maintained by the
infused CAR T-cells activated in vivo upon encounter with the targeted antigen.
In addition, neurotoxicity (immune effector cell-associated encephalopathy
(ICANS) eg encephalopathy, somnolence, aphasia) has been observed with CAR
T-cell therapy. Both CRS and ICANS are manageable, and the vast majority of
patients will recover from CRS and ICANS.
There will be no extra burden for the patients. because this trial will compare
treatment with commercial CAR T-cells with treatment with PoC CAR T-cells, and
in both arms standard of care (including lympho-depleting chemotherapy,
toxicity management, blood collections, cerebral spine fluid (CSF) collections,
and response evaluations) will be applied.
Hanzeplein 1
Groningen 9713 GZ
NL
Hanzeplein 1
Groningen 9713 GZ
NL
Listed location countries
Age
Inclusion criteria
Histologically confirmed DLBCL and associated subtypes, defined by WHO 2016
classification: DLBCL not otherwise specified (NOS), High-grade B-cell lymphoma
with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (DHL/THL) and
FL3B, T-cell/histocyte rich B-cell lymphoma, Primary mediastinal B-cell
lymphoma, EBV+ DLBCL, transformed lymphoma (transformed follicular) and R/R
after at least 2 lines of systemic therapy
• Age >= 18 years
• ECOG/WHO performance status >2
• Secondary central nervous system (CNS) involvement is allowed however, then
he/she must have
- No signs or symptoms of CNS involvement that would hamper adequate ICANS
assessment
• Estimated life expectancy of >3 months other than primary disease
• Patients of child-bearing or child-fathering potential must be willing to
practice birth control from the time of enrollment on this study and for four
months after receiving the preparative regimen
• Signed and dated informed consent before conduct of any trial-specific
procedure
• Patient is capable of giving informed consent
Exclusion criteria
• Absolute neutrophil count (ANC) <1.0x109/L
• Platelet count <50x109/L
• Absolute lymphocyte count <0.1x109/L
• Primary CNS lymphoma
• Known history of infection with hepatitis C or B virus unless treated and
confirmed to be PCR negative
• Active HIV infection with detectable viral load or CD4 T-cell count below
0.20x109/L
• Known history or presence of seizure activities or on active anti- seizure
medications within the previous 12 months
• Known history of CVA within prior 12 months
• Unstable neurological deficits
• Known history or presence of autoimmune CNS disease, such as multiple
sclerosis, optic neuritis or other immunologic or inflammatory disease
• Active systemic autoimmune disease for which immunnosupressive therapy is
required
• Presence of CNS disease that, in the judgment of the investigator, may impair
the ability to evaluate neurotoxicity, baseline dementia that would interfere
with therapy or monitoring, determined using mini-mental status exam at baseline
• Active systemic fungal, viral or bacterial infection
• Clinical heart failure with NYHA class >=2 or LVEF <40%
• Resting oxygen saturation <92% on room air
• Liver dysfunction as indicated by total bilirubin, AST and/or ALT >5 x
institutional ULN, unless directly attributable to the lymphoma or Gilbert
disease
• GFR <40 mL/min calculated according to the modified formula of Cockcroft and
Gault or by direct urine collection
• Pregnant or breast-feeding woman
• Active other malignancy requiring treatment
• Medical condition requiring prolonged use of systemic immunosuppressives with
exception of prednisolon<10 mg/day
• History of severe immediate hypersensitivity reaction against any drug or its
Ingredients/ impurities that is scheduled to be given during trial
participation e.g. as part of the mandatory lymphodepletion protocol,
premedication for infusion, or rescue medication/salvage therapies for
treatment related toxicities
• Any psychological, familial, sociological and geographical condition
potentially hampering compliance with the study protocol and follow-up schedule
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 | CTIS2024-511979-15-00 |
| EudraCT | EUCTR2021-000937-15-NL |
| CCMO | NL76854.000.21 |