COMparison of B-cell dePletion by rituximAb and anti-CD 19 CAR-T therapy in patients with rhEumatoid arthritis- The COMPARE TRIAL

Phase 1/2

Recruiting

• Conditions: Rheumatoid Arthritis

• Registration Number: 2024-514955-13-00
• Lead Sponsor: Charite Universitaetsmedizin Berlin KöR

Brief Summary

Primary objective phase I: To assess the safety of anti-CD19 CAR T cell therapy in subjects with active, ACPA positive and treatment refractory RA

Co-Primary objective phase II: To assess the safety of anti-CD19 CAR T cell therapy and of rituximab in subjects with active, ACPA positive and treatment refractory RA

Co-Primary objective phase II: To assess ACPA seroconversion after anti-CD19 CAR T cell or rituximab therapy in subjects with active, ACPA positive and treatment refractory RA

Detailed Description

This study aims to investigate the use of either rituximab as an established therapy or KYV101 (a fully human anti-CD19 CAR T cell therapy) in ACPA-positive RA patients who are refractory to previous treatments. This study is designed to determine and compare (i) the safety of these two B-cell targeted therapies, (ii) their clinical efficacy, (iii) their impact on the immunological status of the patient and in particular on ACPA positivity, and (iv) their ability to induce long-term (deep) clinical and molecular remission and drug-free survival.

The investigational product (IMP), KYV-101, is an autologous fully-human anti-CD19 CAR T-cell immunotherapy. . Before IMP infusion, patients will receive a premedication of 4 mg Dimetindenmaleat iv or equivalent antihistamine and 1000 mg oral acetaminophene. Prophylactic doses of acyclovir of 400mg 2x daily as well as cotrimoxazole 960mg 3x weekly will be administered orally following CAR T cell infusion until week 24. Tocilizumab 8mg/kg will be administered intravenously when required for treatment of IMP-related cytokine release syndrome. Dexamethasone as needed will be administered intravenously when required for treatment of neurological adverse event (ICANS).

In the control arm in phase II, rituximab will be administered. Rituximab, a chimeric monoclonal antibody targeting CD20, induces B cell depletion and is authorized for treatment of RA. A dose of 1000 mg will be administered intravenously at baseline and at day 14 as per summary of product characteristics. The need for further courses will be evaluated 24 weeks after baseline where retreatment of 1000 mg rituximab may be initiated if residual disease activity remains.

Follow-up time (both arms) is 52 weeks with regular visits at the site.

Study Timeline

• Study First Posted: 2024-11-01
• Last Update Posted: 2025-06-03

Recruitment & Eligibility

• Status: Ongoing, recruiting
• Sex: Not specified
• Target Recruitment: 16

Inclusion Criteria

Understand and voluntarily sign an informed consent form

Male subjects unless surgically sterile, must agree to use two accepta-ble methods for contraception (e.g. spermicide and condom) during the trial and refrain from fathering a child starting from the time of signing the Informed Consent Form (ICF) until 12 months after dosing of the IMP or rituximab

Females of childbearing potential (FCBP) must have a negative seum pregnancy test at screening and must agree to use a highly effective contraceptive method (Pearl index <1) starting from the time of signing the ICF and for 12 months after dosing of the IMP or rituximab

Updated vaccination record according to the STIKO recommendations for immunocompromised patients

Male or female, age ≥ 18 and ≤ 80 years at time of consent

Able to adhere to the study visits and protocol

Fulfilment of the 2010 ACR-EULAR RA classification criteria

ACPA positivity (cut off 20 mU/ml) at Screening

Disease Activity Score DAS28-ESR>3.2 at Screening

Failure (defined as inadequate response after at least 3 months of therapy) of at least one conventional DMARD and at least two tsDMARD/bDMARDs

At least one swollen joint with Power Doppler activity of at least grade 1 or B-mode activity of at least grade 2 at Screening

Willingness to participate in a synovial puncture and biopsy

Exclusion Criteria

ANC < 1.000/mm3, ALC < 500/mm3 or hemoglobin < 8g/dl, absolute CD3+T cell count < 100/µl

Females who are intending to conceive during the study

Known hypersensitivity to any drug components

Malignancy in the last 5 years before screening (except basal or squamous cell skin cancer)

Requirement for immunization with live vaccine during the study period or within 14 days preceding leukapheresis

Subjects who are younger than 18 years or are incapable to understand the aim, importance and consequences of the study and to give legal informed consent (according to § 40 Abs. 4 and § 41 Abs. 2 and Abs. 3 AMG)

Have a history of alcohol or substance abuse within the preceding 6 months that, in the opinion of the Investigator, may increase the risks associated with study participation or study agent administration, or may interfere with interpretation of results,

Subjects who possibly are dependent on the Sponsor, the Principal Investigator or Investigator (e.g. family members).

Subjects who are institutionalized by order of court or public authority

Subjects participating in another clinical trial with an investigational medicinal product or medical device (3 months before this trial)

Severely impaired renal (eGFR ≤ 30 ml/min/m2), liver (Child Pugh B or C), heart and pulmonary (NYHA IIIIV, blood oxygenation <92%) function

Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study

Prior treatment with anti-CD19 antibody therapy, adoptive T cell therapy or any prior gene therapy product (e.g. CAR T cell therapy)

Only in phase II: Prior treatment of rituximab < 7 months before baseline OR ≥ 7 months before baseline) and B cell level < 0.1/nl

History of bone marrow/ hematopoietic stem cell or solid organ transplantation

csDMARD other than MTX at baseline

Any concomitant severe active infection, e.g. HIV, hepatitis B or C, SARS-CoV-2 (COVID-19), or active tuberculosis as defined by a positive Quantiferon TB-test. If presence of latent tuberculosis is estab-lished then treatment according to local guidelines must have been initiated prior to enrollment

Pregnant or lactating females

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Safety (Phase I): Incidence and grading of severity (graded 0-4) of Cytokine Release Syndrome (CRS) and of Immune cCell Associated Neurotoxicity Syndrome (ICANS) as well as AE and SAE due to IMP within the first 4 weeks after anti-CD19 CAR T cell therapy. Participants of Phase I will continue to be observed over a total period of 52 weeks for AE and SAE, ACPA seroconversion and efficacy endpoints.		Safety (Phase I): Incidence and grading of severity (graded 0-4) of Cytokine Release Syndrome (CRS) and of Immune cCell Associated Neurotoxicity Syndrome (ICANS) as well as AE and SAE due to IMP within the first 4 weeks after anti-CD19 CAR T cell therapy. Participants of Phase I will continue to be observed over a total period of 52 weeks for AE and SAE, ACPA seroconversion and efficacy endpoints.
Safety (Phase II): AE and SAE due to IMP and rituximab throughout the whole study.		Safety (Phase II): AE and SAE due to IMP and rituximab throughout the whole study.
Efficacy (Phase II): Percentage of subjects with ACPA seroconversion = ACPA level <20 mU/ml at week 16.		Efficacy (Phase II): Percentage of subjects with ACPA seroconversion = ACPA level <20 mU/ml at week 16.

Secondary Outcome Measures

Name	Time	Method
Clinical secondary endpoint (Phase II): Drug free survival time (beginning of immunosuppression for RA treatment except for stable dosage of MTX in the control arm) from week 7 to 52		Clinical secondary endpoint (Phase II): Drug free survival time (beginning of immunosuppression for RA treatment except for stable dosage of MTX in the control arm) from week 7 to 52
Clinical secondary endpoint (Phase II): Time to relapse/flare from week 7 to week 52		Clinical secondary endpoint (Phase II): Time to relapse/flare from week 7 to week 52
Clinical secondary endpoint (Phase II): ACR 20/50/70 response at week 16, 24 and 52 weeks		Clinical secondary endpoint (Phase II): ACR 20/50/70 response at week 16, 24 and 52 weeks
Clinical secondary endpoint (Phase II): DAS28-CRP remission at 16, 24, and 52 weeks		Clinical secondary endpoint (Phase II): DAS28-CRP remission at 16, 24, and 52 weeks
Clinical secondary endpoint (Phase II): DAS28-CRP<3.2 at week 16, 24 and 52		Clinical secondary endpoint (Phase II): DAS28-CRP<3.2 at week 16, 24 and 52
Clinical secondary endpoint (Phase II): SDAI remission at 16, 24, and 52 weeks		Clinical secondary endpoint (Phase II): SDAI remission at 16, 24, and 52 weeks
Clinical secondary endpoint (Phase II): Boolean 2.0 remission at 16, 24, and 52 weeks		Clinical secondary endpoint (Phase II): Boolean 2.0 remission at 16, 24, and 52 weeks
Clinical secondary endpoint (Phase II): Change in DAS28-CRP at 16, 24, and 52 weeks		Clinical secondary endpoint (Phase II): Change in DAS28-CRP at 16, 24, and 52 weeks
Clinical secondary endpoint (Phase II): Change in ACR score components at 16, 24, and 52 weeks		Clinical secondary endpoint (Phase II): Change in ACR score components at 16, 24, and 52 weeks
Clinical secondary endpoint (Phase II): Change in SDAI and CDAI at 16, 24, and 52 weeks		Clinical secondary endpoint (Phase II): Change in SDAI and CDAI at 16, 24, and 52 weeks
Clinical secondary endpoint (Phase II): Number of flares until 16, 24 and 52 weeks		Clinical secondary endpoint (Phase II): Number of flares until 16, 24 and 52 weeks
Cellular and humoral response (Phase II): Percentage of subjects with ACPA seroconversion = ACPA level <20 mU/ml at week 24 and 52		Cellular and humoral response (Phase II): Percentage of subjects with ACPA seroconversion = ACPA level <20 mU/ml at week 24 and 52
Cellular and humoral response (Phase II): Duration of persistence of CAR T cells in the peripheral blood		Cellular and humoral response (Phase II): Duration of persistence of CAR T cells in the peripheral blood
Cellular and humoral response (Phase II): Duration of B cell depletion in the peripheral blood		Cellular and humoral response (Phase II): Duration of B cell depletion in the peripheral blood
Cellular and humoral response (Phase II): Expansion of CAR T cells in the patient over time		Cellular and humoral response (Phase II): Expansion of CAR T cells in the patient over time
Cellular and humoral response (Phase II): Change in ACPA levels (mU/ml) over time		Cellular and humoral response (Phase II): Change in ACPA levels (mU/ml) over time
Cellular and humoral response (Phase II): Change in RF levels (U/ml) over time		Cellular and humoral response (Phase II): Change in RF levels (U/ml) over time
Cellular and humoral response (Phase II): Change in ACPA levels (mU/ml) in HLA-defined subgroups over time		Cellular and humoral response (Phase II): Change in ACPA levels (mU/ml) in HLA-defined subgroups over time
Cellular and humoral response (Phase II): Change in levels of ACPA isotypes and IgG subclasses at week over time		Cellular and humoral response (Phase II): Change in levels of ACPA isotypes and IgG subclasses at week over time
Cellular and humoral response (Phase II): Change in total IgG, IgG subclasses and IgA, IgM immunoglobulins over time		Cellular and humoral response (Phase II): Change in total IgG, IgG subclasses and IgA, IgM immunoglobulins over time
Cellular and humoral response (Phase II): Change in the number of plasmablasts, B cell and T cell numbers over time in peripheral blood		Cellular and humoral response (Phase II): Change in the number of plasmablasts, B cell and T cell numbers over time in peripheral blood
additional endpoint (Phase II): Patient’s Global Assessment (PtGA) of disease activity (VAS 0-100mm)		additional endpoint (Phase II): Patient’s Global Assessment (PtGA) of disease activity (VAS 0-100mm)
additional endpoint (Phase II): Physician’s Global Assessment (PhGA) of disease activity (VAS 0-100mm)		additional endpoint (Phase II): Physician’s Global Assessment (PhGA) of disease activity (VAS 0-100mm)
additional endpoint (Phase II): Health Assessment Questionnaire – Disease Index (HAQ-DI)		additional endpoint (Phase II): Health Assessment Questionnaire – Disease Index (HAQ-DI)
additional endpoint (Phase II): Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT)		additional endpoint (Phase II): Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT)
additional endpoint (Phase II): Short Form 36 (SF-36, quality of life questionnaire)		additional endpoint (Phase II): Short Form 36 (SF-36, quality of life questionnaire)
additional endpoint (Phase II): Questionnaire on work productivity and activity impairment (WPAI)		additional endpoint (Phase II): Questionnaire on work productivity and activity impairment (WPAI)
additional endpoint (Phase II): Change in hand strength over time		additional endpoint (Phase II): Change in hand strength over time
additional endpoint (Phase II): Change in radiological Sharp-van-der-Heijde score (hands and feet)		additional endpoint (Phase II): Change in radiological Sharp-van-der-Heijde score (hands and feet)
additional endpoint (Phase II): Change in MRI RAMRIS score		additional endpoint (Phase II): Change in MRI RAMRIS score
additional endpoint (Phase II): Change of EULAR-OMERACT US synovitis scoring system		additional endpoint (Phase II): Change of EULAR-OMERACT US synovitis scoring system
Exploratory endpoint (Phase II): Change in ACPA specific plasmablasts and B cells		Exploratory endpoint (Phase II): Change in ACPA specific plasmablasts and B cells
Exploratory endpoint (Phase II): To analyze the changes in B cell receptor repertoire		Exploratory endpoint (Phase II): To analyze the changes in B cell receptor repertoire
Exploratory endpoint (Phase II): To evaluate the therapy-induced changes of B cell subsets		Exploratory endpoint (Phase II): To evaluate the therapy-induced changes of B cell subsets
Exploratory endpoint (Phase II): Characterizing B Cell and Plasma Cell Niches in Tissues		Exploratory endpoint (Phase II): Characterizing B Cell and Plasma Cell Niches in Tissues
Exploratory endpoint (Phase II): To evaluate the influence of therapy on auto-antigen-specific B cells		Exploratory endpoint (Phase II): To evaluate the influence of therapy on auto-antigen-specific B cells
Exploratory endpoint (Phase II): To evaluate the therapy-induced alterations of T cell compartments		Exploratory endpoint (Phase II): To evaluate the therapy-induced alterations of T cell compartments
Exploratory endpoint (Phase II): To evaluate the impact of therapy on Immunoglobulin glycosylation		Exploratory endpoint (Phase II): To evaluate the impact of therapy on Immunoglobulin glycosylation
Exploratory endpoint (Phase II): To evaluate changes in lymphocyte numbers and composition in bone marrow biopsy, synovial biopsy, lymph node biopsy and synovial fluid		Exploratory endpoint (Phase II): To evaluate changes in lymphocyte numbers and composition in bone marrow biopsy, synovial biopsy, lymph node biopsy and synovial fluid
Exploratory endpoint (Phase II): To repeat all statistical assessments using pooled data from CAR T patients in phase I and II		Exploratory endpoint (Phase II): To repeat all statistical assessments using pooled data from CAR T patients in phase I and II

Trial Locations

Locations (1)

Charite Universitaetsmedizin Berlin KöR; 🇩🇪 Berlin, Germany

Charite Universitaetsmedizin Berlin KöR

🇩🇪Berlin, Germany

David Simon

Site contact

+4930450513025

david.simon@charite.de