Comparison of Point-of-care Produced CAR T-cell with Commercial CAR T-cells in Patients with R/R LBCL

Official title

A Phase II Non-inferiority Study Comparing Point-of-care Produced CAR T-cell to Commercial CAR T-cells in Patients with Relapsed/refractory Non-Hodgkin Lymphoma

Overview

A phase II, multi-center study to compare the feasibility, and clinical efficacy of local manufacturing of CD19-directed CAR T-cells (ARI-0001 CAR T-cells) with 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.

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.

Interventions

• Drug ARI-0001
  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).
• Drug Axi-cel
  Infusion with a single target dose of 2.0 x 10\^6 Standard of Care CAR T-cells/kg BW (range 1 -2.0x 10\^6 CAR T-cells /kg BW).

Primary outcome measures

• Progression-free survival (PFS) from date of IMP infusion (if applicable) [Time frame: Approximately up to 60 months following first patient IMP infusion]

Secondary outcome measures (12)

• Progression-free survival (PFS) from date of randomization [Time frame: Approximately up to 60 months following first patient enrollment]
• Safety and toxicity assessment per AE reporting [Time frame: Approximately up to 60 months following first patient IMP infusion]
• Overall Response Rate (ORR) [Time frame: At 4 weeks, 12 weeks, 6, 12 and 24 months after infusion of CAR T-cells]
• Expansion of CAR T-cells [Time frame: Approximately up to 60 months following first patient IMP infusion]
• Phenotype of CAR T-cells [Time frame: Approximately up to 60 months following first patient IMP infusion]
• Persistence of CAR T-cells [Time frame: Approximately up to 60 months following first patient IMP infusion]
• Best Overall Response (BOR) [Time frame: 4 weeks, 12 weeks, 6, 12 and 24 months after infusion of CAR T-cells]
• Duration Of Response (DOR) [Time frame: Approximately up to 60 months following first patient IMP infusion]
• Overall Survival (OS) [Time frame: Approximately up to 60 months following first patient IMP infusion]
• Patient Reported Outcome/Quality of Life (PRO/QOL) EuroQol- 5 Dimension (EQ-5D) [Time frame: At 4 weeks, 12 weeks, 6, 12 and 24 months after infusion of CAR T-cells]
• Patient Reported Outcome/Quality of Life (PRO/QOL) Functional Assessment of Cancer Treatment-Lymphoma (FACT-Lym) [Time frame: At 4 weeks, 12 weeks, 6, 12 and 24 months after infusion of CAR T-cells]
• Patient Reported Outcome/Quality of Life (PRO/QOL) Quality of Life Questionnaire (QLQ-C30) [Time frame: At 4 weeks, 12 weeks, 6, 12 and 24 months after infusion of CAR T-cells]

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Netherlands · 7 centers

• NL-Amsterdam-AMC — Amsterdam
• NL-Groningen-UMCG — Groningen
• NL-Leiden-LUMC — Leiden
• NL-Maastricht-MUMC — Maastricht
• NL-Nijmegen-RADBOUDUMC — Nijmegen
• NL-Rotterdam-ERASMUSMC — Rotterdam
• NL-Utrecht-UMCUTRECHT — Utrecht

Identifiers

NCT: NCT05641428 · HO161 CAR T · 2021-000937-15

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗