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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Charite Universitaetsmedizin Berlin KöR

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20], Diseases [C] - Musculoskeletal Diseases [C05]

Trial duration

29 Nov 2024 → ongoing

Decision date (initial)

2024-11-01

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Kyverna Therapeutics, Inc.

External identifiers

EU CT number

2024-514955-13-00

ClinicalTrials.gov

NCT06475495

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

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

Secondary objectives 1

1. To assess the clinical efficacy, the cellular and humoral response and the response in musculoskeletal imaging after anti-CD19 CAR T cell or rituximab therapy

Conditions and MedDRA coding

Rheumatoid Arthritis

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Understand and voluntarily sign an informed consent form
2. Male or female, age ≥ 18 and ≤ 80 years at time of consent
3. Able to adhere to the study visits and protocol
4. Fulfilment of the 2010 ACR-EULAR RA classification criteria
5. ACPA positivity (cut off 20 mU/ml) at Screening
6. Disease Activity Score DAS28-ESR>3.2 at Screening
7. Failure (defined as inadequate response after at least 3 months of therapy) of at least one conventional DMARD and at least two tsDMARD/bDMARDs
8. 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
9. Willingness to participate in a synovial puncture and biopsy
10. 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
11. 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
12. Updated vaccination record according to the STIKO recommendations for immunocompromised patients

Exclusion criteria 18

1. ANC < 1.000/mm3, ALC < 500/mm3 or hemoglobin < 8g/dl, absolute CD3+T cell count < 100/µl
2. Severely impaired renal (eGFR ≤ 30 ml/min/m2), liver (Child Pugh B or C), heart and pulmonary (NYHA IIIIV, blood oxygenation <92%) function
3. 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
4. Prior treatment with anti-CD19 antibody therapy, adoptive T cell therapy or any prior gene therapy product (e.g. CAR T cell therapy)
5. Only in phase II: Prior treatment of rituximab < 7 months before baseline OR ≥ 7 months before baseline) and B cell level < 0.1/nl
6. History of bone marrow/ hematopoietic stem cell or solid organ transplantation
7. csDMARD other than MTX at baseline
8. 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
9. Pregnant or lactating females
10. Females who are intending to conceive during the study
11. Known hypersensitivity to any drug components
12. Malignancy in the last 5 years before screening (except basal or squamous cell skin cancer)
13. Requirement for immunization with live vaccine during the study period or within 14 days preceding leukapheresis
14. 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)
15. 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,
16. Subjects who possibly are dependent on the Sponsor, the Principal Investigator or Investigator (e.g. family members).
17. Subjects who are institutionalized by order of court or public authority
18. Subjects participating in another clinical trial with an investigational medicinal product or medical device (3 months before this trial)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. 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.
2. Safety (Phase II): AE and SAE due to IMP and rituximab throughout the whole study.
3. Efficacy (Phase II): Percentage of subjects with ACPA seroconversion = ACPA level <20 mU/ml at week 16.

Secondary endpoints 40

1. 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
2. Clinical secondary endpoint (Phase II): Time to relapse/flare from week 7 to week 52
3. Clinical secondary endpoint (Phase II): ACR 20/50/70 response at week 16, 24 and 52 weeks
4. Clinical secondary endpoint (Phase II): DAS28-CRP remission at 16, 24, and 52 weeks
5. Clinical secondary endpoint (Phase II): DAS28-CRP<3.2 at week 16, 24 and 52
6. Clinical secondary endpoint (Phase II): SDAI remission at 16, 24, and 52 weeks
7. Clinical secondary endpoint (Phase II): Boolean 2.0 remission at 16, 24, and 52 weeks
8. Clinical secondary endpoint (Phase II): Change in DAS28-CRP at 16, 24, and 52 weeks
9. Clinical secondary endpoint (Phase II): Change in ACR score components at 16, 24, and 52 weeks
10. Clinical secondary endpoint (Phase II): Change in SDAI and CDAI at 16, 24, and 52 weeks
11. Clinical secondary endpoint (Phase II): Number of flares until 16, 24 and 52 weeks
12. Cellular and humoral response (Phase II): Percentage of subjects with ACPA seroconversion = ACPA level <20 mU/ml at week 24 and 52
13. Cellular and humoral response (Phase II): Duration of persistence of CAR T cells in the peripheral blood
14. Cellular and humoral response (Phase II): Duration of B cell depletion in the peripheral blood
15. Cellular and humoral response (Phase II): Expansion of CAR T cells in the patient over time
16. Cellular and humoral response (Phase II): Change in ACPA levels (mU/ml) over time
17. Cellular and humoral response (Phase II): Change in RF levels (U/ml) over time
18. Cellular and humoral response (Phase II): Change in ACPA levels (mU/ml) in HLA-defined subgroups over time
19. Cellular and humoral response (Phase II): Change in levels of ACPA isotypes and IgG subclasses at week over time
20. Cellular and humoral response (Phase II): Change in total IgG, IgG subclasses and IgA, IgM immunoglobulins over time
21. Cellular and humoral response (Phase II): Change in the number of plasmablasts, B cell and T cell numbers over time in peripheral blood
22. additional endpoint (Phase II): Patient’s Global Assessment (PtGA) of disease activity (VAS 0-100mm)
23. additional endpoint (Phase II): Physician’s Global Assessment (PhGA) of disease activity (VAS 0-100mm)
24. additional endpoint (Phase II): Health Assessment Questionnaire – Disease Index (HAQ-DI)
25. additional endpoint (Phase II): Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT)
26. additional endpoint (Phase II): Short Form 36 (SF-36, quality of life questionnaire)
27. additional endpoint (Phase II): Questionnaire on work productivity and activity impairment (WPAI)
28. additional endpoint (Phase II): Change in hand strength over time
29. additional endpoint (Phase II): Change in radiological Sharp-van-der-Heijde score (hands and feet)
30. additional endpoint (Phase II): Change in MRI RAMRIS score
31. additional endpoint (Phase II): Change of EULAR-OMERACT US synovitis scoring system
32. Exploratory endpoint (Phase II): Change in ACPA specific plasmablasts and B cells
33. Exploratory endpoint (Phase II): To analyze the changes in B cell receptor repertoire
34. Exploratory endpoint (Phase II): To evaluate the therapy-induced changes of B cell subsets
35. Exploratory endpoint (Phase II): Characterizing B Cell and Plasma Cell Niches in Tissues
36. Exploratory endpoint (Phase II): To evaluate the influence of therapy on auto-antigen-specific B cells
37. Exploratory endpoint (Phase II): To evaluate the therapy-induced alterations of T cell compartments
38. Exploratory endpoint (Phase II): To evaluate the impact of therapy on Immunoglobulin glycosylation
39. Exploratory endpoint (Phase II): To evaluate changes in lymphocyte numbers and composition in bone marrow biopsy, synovial biopsy, lymph node biopsy and synovial fluid
40. Exploratory endpoint (Phase II): To repeat all statistical assessments using pooled data from CAR T patients in phase I and II

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Charite Universitaetsmedizin Berlin KöR

Sponsor organisation

Charite Universitaetsmedizin Berlin KöR

Address

Chariteplatz 1, Mitte Mitte

City

Berlin

Postcode

10117

Country

Germany

Scientific contact point

Organisation

Charite Universitaetsmedizin Berlin KöR

Contact name

David Simon

Public contact point

Organisation

Charite Universitaetsmedizin Berlin KöR

Contact name

David Simon

Third parties 5

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 1 · Art. 52 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 6 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications