Comparison of Point-of-care Produced CAR T-cell with Comm... | NCT05641428

ID	Type	Description	Link
2021-000937-15	EudraCT Number

Status Module

Name	Class
Stichting Hemato-Oncologie voor Volwassenen Nederland	OTHER

Description Module

Detailed Description

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 or relapse. There are several shortcomings of current CD19-directed CAR T-cell therapy, that are likely responsible for therapy failure, 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 of CD19-directed CAR T-cells (ARI-0001 CAR T-cells), in a completely closed system using the CliniMACS Prodigy device. This study will compare the clinical efficacy of locally produced CAR T-cells to commercial produced CAR T-cells (for example axicabtagene ciloleucel, a CD19 targeting commercially available CAR T-cell) in patients with relapsed or refractory (R/R) DLBCL.

This in-house (point-of-care) production process of ARI-0001 will take approximately 7-12 days and thus will generate CAR T-cells "faster" which will be infused in the patient without cryopreservation ("fresh", of note, a back-up cryopreserved product will also be manufactured). 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.

Label	Type	Description	Intervention Names
Arm A (ARI-0001)	Experimental	Infusion with Point of Care CAR T-cells	Drug: ARI-0001
Arm B (Axi-cel)	Active Comparator	Infusion with Standard of Care CAR T-cells	Drug: Axi-cel

Name	Type	Description	Arm Group Labels	Other Names
ARI-0001	Drug	Infusion with a single target dose of 2.0 x 10^6 Point of Care CAR T-cells/kg BW (range 1 -2.0x 10^6 CAR T-cells /kg BW).	Arm A (ARI-0001)

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Progression-free survival (PFS) from date of IMP infusion (if applicable)	PFS from date of IMP infusion is defined as the time from IMP infusion, until progression, relapse or death from any cause, whichever comes first. PFS reflects tumor growth and, therefore, occurs prior to the endpoint of OS. Progression is defined as the first date of documentation of a new lesion or enlargement of a previous lesion, or the date of the scheduled clinic visit immediately after radiologic assessment has been completed. If there is missing information, censoring of the data may be defined as the last date at which progression status was adequately assessed.	Approximately up to 60 months following first patient IMP infusion

Secondary Outcomes

Measure	Description	Time Frame
Progression-free survival (PFS) from date of randomization	PFS from date of randomization is defined as the time from enrollment, until progression, relapse or death from any cause, whichever comes first. PFS reflects tumor growth and, therefore, occurs prior to the endpoint of OS. Progression is defined as the first date of documentation of a new lesion or enlargement of a previous lesion, or the date of the scheduled clinic visit immediately after radiologic assessment has been completed. If there is missing information, censoring of the data may be defined as the last date at which progression status was adequately assessed.

Eligibility Module

Eligibility Criteria

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, transformed lymphoma (transformed follicular) and R/R after at least 2 lines of systemic therapy
Age ≥ 18
Eastern Cooperative Oncology Group (ECOG)/WHO performance status 0-2
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) <1.0x10^9/L
Platelet count <50x10^9/L
Absolute lymphocyte count <0.1x10^9/L
Primary CNS lymphoma
Known history of infection with hepatitis C or B virus unless treated and confirmed to be polymerase chain reaction (PCR) negative
Active HIV infection with detectable viral load or CD4 T-cell count below 0.20x10^9/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 immunosupressive 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 New York Heart Association class ≥2 (appendix F) or Left Ventricular Ejection Fraction (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 prednisolone <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

Facility	Status	City	State	ZIP	Country	Contacts
NL-Amsterdam-AMC	Recruiting	Amsterdam			Netherlands
NL-Groningen-UMCG

ID	Term
D015620	Histiocytic Disorders, Malignant
D009370	Neoplasms by Histologic Type
D009369	Neoplasms
D015614	Histiocytosis
D008206	Lymphatic Diseases
D006425	Hemic and Lymphatic Diseases