Comparison of B-cell Depletion by Rituximab and Anti-CD19 CAR-T Therapy in ACPA-Positive, Treatment-Refractory Rheumatoid Arthritis Patients
- Trial ID
- 2024-514955-13-00
- Protocol
- CCM-RNT-202401
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** of anti-CD19 CAR T cell therapy in patients with active, ACPA-positive, and treatment-refractory **Rheumatoid Arthritis** (RA). This assessment is crucial as it determines the potential risks associated with this novel therapeutic approach in a population that has not responded to conventional treatments. Additionally, in Phase II, the study aims to compare the safety of anti-CD19 CAR T cell therapy with rituximab, another treatment option for RA, and to assess ACPA seroconversion following these therapies. ACPA seroconversion is an important marker of disease activity and treatment response in RA.
The secondary objectives include evaluating the clinical efficacy, cellular and humoral immune responses, and changes in musculoskeletal imaging following treatment with either anti-CD19 CAR T cells or rituximab. These objectives are intended to provide a comprehensive understanding of the therapeutic effects and mechanisms of action of these treatments in RA, potentially guiding future therapeutic strategies.
Participants
The clinical trial focuses on evaluating the safety and efficacy of anti-CD19 CAR T cell therapy in individuals diagnosed with **Rheumatoid Arthritis**. The study population comprises both male and female participants, aged between 18 and 80 years, who are not part of a vulnerable population. Participants are required to have active, ACPA positive, and treatment-refractory rheumatoid arthritis, with a Disease Activity Score (DAS28-ESR) greater than 3.2 at screening. The trial includes individuals who have experienced inadequate responses to at least one conventional DMARD and at least two tsDMARD/bDMARDs. Participants must have 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. The sponsor has not provided information regarding the total number of participants. The selection criteria ensure that participants are capable of adhering to study visits and protocols, and they must have an updated vaccination record according to STIKO recommendations for immunocompromised patients. Lifestyle considerations such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is designed as a **randomized**, controlled, open-label, parallel-group study, conducted in two stages: Phase I and Phase II. The primary objective of Phase I is to assess the safety of anti-CD19 CAR T cell therapy in subjects with active, ACPA-positive, and treatment-refractory **rheumatoid arthritis**. Phase II aims to evaluate the safety of both anti-CD19 CAR T cell therapy and **rituximab**, as well as to assess ACPA seroconversion following these treatments. The trial is expected to commence recruitment on November 1, 2024, and conclude by March 31, 2027.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, ACPA positivity, and previous treatment failures. Following successful screening, participants will be randomized to receive either the investigational product KYV-101 or the comparator, Rixathon 500 mg concentrate for solution for infusion, both administered **intravenously**. The trial includes multiple follow-up visits to monitor safety and efficacy endpoints, with key assessments at weeks 16, 24, and 52. The end-of-study visit will finalize data collection and ensure participant safety.
The expected duration of participant involvement is approximately 52 weeks, with conditions for early termination including the occurrence of severe adverse events or withdrawal of consent. Safety endpoints will focus on the incidence and severity of Cytokine Release Syndrome and Immune Cell Associated Neurotoxicity Syndrome, while efficacy endpoints will include ACPA seroconversion rates and various clinical response measures. The trial will also explore secondary and exploratory endpoints related to drug-free survival, relapse rates, and changes in immunological markers.
Treatment
The clinical trial involves the administration of two experimental medications for the treatment of **rheumatoid arthritis**. The first medication, **Rixathon**, is a 500 mg concentrate for solution for infusion, containing the active substance **rituximab**. This pharmaceutical form is a solution for infusion, and it is administered intravenously. The administration schedule and dosage frequency are determined based on the study protocol, ensuring adherence to safety and efficacy standards. Participant compliance with the dosing regimen is monitored throughout the trial to ensure accurate assessment of the treatment's effects.
The second experimental medication is **KYV-101**, a suspension containing the active substance of the same name. This investigational product is also administered intravenously. KYV-101 is a structurally diverse substance used in cell therapy, developed by Kyverna Therapeutics Inc. The dosing schedule and frequency of administration are outlined in the study protocol, with careful monitoring of participant compliance to ensure the integrity of the trial data. Both medications are evaluated for their safety and efficacy in comparison to each other, with Rixathon serving as the comparator and KYV-101 as the test product in this randomized, controlled, open-label trial.
Efficacy
The efficacy of the clinical trial will be assessed through a series of predefined endpoints. The primary efficacy endpoint for Phase II is the percentage of subjects achieving **ACPA seroconversion**, defined as an ACPA level of less than 20 mU/ml at week 16. Secondary efficacy endpoints include various clinical and cellular measures. These include drug-free survival time from week 7 to 52, time to relapse or flare from week 7 to 52, and ACR 20/50/70 response rates at weeks 16, 24, and 52. Additionally, DAS28-CRP remission and scores, SDAI remission, and Boolean 2.0 remission will be evaluated at weeks 16, 24, and 52.
Further assessments will involve changes in DAS28-CRP, ACR score components, SDAI, and CDAI at specified time points. The trial will also monitor the number of flares and cellular and humoral responses, such as the duration of CAR T cell persistence and B cell depletion in peripheral blood. Changes in ACPA and RF levels, as well as immunoglobulin levels, will be tracked over time. Additional endpoints include patient and physician global assessments of disease activity, health-related quality of life measures, and changes in hand strength and radiological scores. Exploratory endpoints will analyze changes in B cell receptor repertoire and therapy-induced alterations in B cell and T cell compartments.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Understand and voluntarily sign an informed consent form
- 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
- 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
Exclusion Criteria
- ANC < 1.000/mm3, ALC < 500/mm3 or hemoglobin < 8g/dl, absolute CD3+T cell count < 100/µl
- 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
- 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)
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Recruiting | 01 Nov 2024 | 16 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Rixathon 500 mg concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | — | — | PRD6060692 |
KYV-101 | Test | SUSPENSION | INTRAVENOUS | — | — | PRD9974051 |