Anti-CD 19 CAR-T Cell Therapy in Patients with ANCA Vasculitis

NCT06590545 | Not Yet Recruiting Phase 1

• 2 other identifiers: CCM-RNT-2024022024-517303-36-00
• Study Type: interventional
• Target: 8
• Locations: 0 countries
• Sites: N/A

Brief Summary

The goal of this phase I/II clinical trial is to investigate anti-CD 19 chimeric antigen receptor T cell (CAR-T cell) therapy in patients with antineutrophil cytoplasmic antibodies (ANCA) immunoglobulin (IgG) positive ANCA associated vasculitis (AAV). The main questions it aims to answer are:

• To assess the safety of anti-CD19 CAR-T cell therapy in subjects with active, treatment refractory, ANCA-IgG-positive AAV
• To assess the clinical efficacy of anti-CD19 CAR-T cell therapy in subjects with active, treatment refractory ANCA-IgG-positive AAV
• To assess the ANCA seroconversion rate in subjects with active, treatment refractory ANCA-IgG-positive AAV Participants will receive a single dose of KYV-101 i.v., an autologous fully-human anti-CD19 CAR-T cell immunotherapy. Follow-up time is 52 weeks with regular visits at the site.

Conditions

ANCA-IgG-positive ANCA Associated Vasculitis

Keywords

ANCA; CAR-T-Cell; Vasculitis; Seroconversion; anti-CD19

Outcome Measures

Primary Outcomes (3)

• number of subjects experiencing a cytokine release syndrome

  The primary safety outcome in Phase I variable will be measured as the number of subjects experiencing a cytokine release syndrome (CRS) or an immune cell-associated neurotoxicity syndrome (ICANS) as well as adverse events (AE) and serious adverse events (SAE) due to investigational medical product (IMP) within the first 4 weeks.

  Screening up to week 4

• antineutrophil cytoplasmic antibodies (ANCA) seroconversion rate

  The primary efficacy outcome variable of Phase II will be the antineutrophil cytoplasmic antibodies (ANCA) seroconversion rate in subjects with active, treatment refractory ANCA-IgG-positive AAV at week 24.

  week 24

• adverse events and serious adverse events due to investigational medical product

  The primary safety outcome variable of Phase II will be measured as adverse events (AE) and serious adverse events (SAE) due to investigational medical product (IMP) throughout the whole study.

  up to 52 weeks

Secondary Outcomes (23)

• immunoglobulin IgG

  up to week 52

• immunoglobulin IgG subclasses

  up to week 52

• immunoglobulin IgA

  up to week 52

• immunoglobulin IgM

  up to week 52

• Change in PR3

  up to week 52

Study Arms (1)

KYV-101, anti-CD19 CAR T-cell immunotherapy.

EXPERIMENTAL

A dosage of 1x10\^8 KYV-101 CAR+ T cells will be administered intravenously as a single infusion.

Drug: KYV-101, an autologous fully-human anti-CD19 CAR T-cell immunotherapy

Interventions

KYV-101, an autologous fully-human anti-CD19 CAR T-cell immunotherapy DRUG

A dosage of 1x10\^8 KYV-101 CAR+ T cells will be administered intravenously as a single infusion.

KYV-101, anti-CD19 CAR T-cell immunotherapy.

Eligibility Criteria

• Age: 18 Years - 75 Years
• Gender Eligibility Details: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Understand and voluntarily sign an informed consent form
• Male or female, age ≥ 18 and ≤ 75 years at ti me of consent
• Able to adhere to the study visits and protocol
• Fulfilment of
• EITHER both of the following
• ACR-EULAR classification criteria for granulomatosis with polyangiitis (GPA)
• detectable anti-PR3 antibodies (≥ 20 AU/ml in CLIA) at screening
• OR both of the following
• ACR/EULAR classification criteria for microscopic polyangiitis (MPA)
• detectable anti-MPO antibodies (≥ 10 AU/ml in CLIA) at screening
• Active disease, defined as Clinical activity (BVAS ≥ 3) at screening
• Insufficient response or intolerance/contraindication to glucocorticoids and to at least one of the following treatments: rituximab, mycophenolate mofetil, azathioprine, methotrexate, cyclophosphamide, avacopan. Insufficient response is defined as having disease activity based on the definition explained in the previous bullet point
• Male subjects unless surgically sterile, must agree to use two acceptable 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
• Females of childbearing potential (FCBP) must have a negative urine pregnancy test at screening and must agree to use a highly effective contraceptive method (Pearl index less than 1) starting from the time of signing the ICF and for 12 months after dosing of the IMP
• Updated vaccination record according to the STIKO recommendations for immuno-compromised patients

You may not qualify if:

• ANC less than 500/µl, ALC less than 100/µl or hemoglobin less than 8g/dl, absolute CD3+T cell count less than 100/µl at screening
• Severely impaired renal (eGFR ≤ 30 ml/min/m2), liver (Child Pugh C), or heart or pulmonary (NYHA IV, blood oxygenation less than 92%) function
• Clinically relevant rapidly progressive glomerulonephritis or pulmonary alveolar hemorrhage
• 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)
• History of bone marrow/ hematopoietic stem cell or solid organ transplantation
• 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 established then treatment according to local guide-lines 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 adequately treated 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 (accord-ing 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 participa-tion 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).

Sponsors & Collaborators

• David Simon: lead
• Kyverna Therapeutics: collaborator

Related Publications (13)

• Hellmich B, Sanchez-Alamo B, Schirmer JH, Berti A, Blockmans D, Cid MC, Holle JU, Hollinger N, Karadag O, Kronbichler A, Little MA, Luqmani RA, Mahr A, Merkel PA, Mohammad AJ, Monti S, Mukhtyar CB, Musial J, Price-Kuehne F, Segelmark M, Teng YKO, Terrier B, Tomasson G, Vaglio A, Vassilopoulos D, Verhoeven P, Jayne D. EULAR recommendations for the management of ANCA-associated vasculitis: 2022 update. Ann Rheum Dis. 2024 Jan 2;83(1):30-47. doi: 10.1136/ard-2022-223764.

  PMID: 36927642 BACKGROUND

• Han WK, Choi HK, Roth RM, McCluskey RT, Niles JL. Serial ANCA titers: useful tool for prevention of relapses in ANCA-associated vasculitis. Kidney Int. 2003 Mar;63(3):1079-85. doi: 10.1046/j.1523-1755.2003.00821.x.

  PMID: 12631091 BACKGROUND

• Muller F, Taubmann J, Bucci L, Wilhelm A, Bergmann C, Volkl S, Aigner M, Rothe T, Minopoulou I, Tur C, Knitza J, Kharboutli S, Kretschmann S, Vasova I, Spoerl S, Reimann H, Munoz L, Gerlach RG, Schafer S, Grieshaber-Bouyer R, Korganow AS, Farge-Bancel D, Mougiakakos D, Bozec A, Winkler T, Kronke G, Mackensen A, Schett G. CD19 CAR T-Cell Therapy in Autoimmune Disease - A Case Series with Follow-up. N Engl J Med. 2024 Feb 22;390(8):687-700. doi: 10.1056/NEJMoa2308917.

  PMID: 38381673 BACKGROUND

• Schett G, Mackensen A, Mougiakakos D. CAR T-cell therapy in autoimmune diseases. Lancet. 2023 Nov 25;402(10416):2034-2044. doi: 10.1016/S0140-6736(23)01126-1. Epub 2023 Sep 22.

  PMID: 37748491 BACKGROUND

• Mackensen A, Muller F, Mougiakakos D, Boltz S, Wilhelm A, Aigner M, Volkl S, Simon D, Kleyer A, Munoz L, Kretschmann S, Kharboutli S, Gary R, Reimann H, Rosler W, Uderhardt S, Bang H, Herrmann M, Ekici AB, Buettner C, Habenicht KM, Winkler TH, Kronke G, Schett G. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med. 2022 Oct;28(10):2124-2132. doi: 10.1038/s41591-022-02017-5. Epub 2022 Sep 15.

  PMID: 36109639 BACKGROUND

• Mougiakakos D, Kronke G, Volkl S, Kretschmann S, Aigner M, Kharboutli S, Boltz S, Manger B, Mackensen A, Schett G. CD19-Targeted CAR T Cells in Refractory Systemic Lupus Erythematosus. N Engl J Med. 2021 Aug 5;385(6):567-569. doi: 10.1056/NEJMc2107725. No abstract available.

  PMID: 34347960 BACKGROUND

• Lodka D, Zschummel M, Bunse M, Rousselle A, Sonnemann J, Kettritz R, Hopken UE, Schreiber A. CD19-targeting CAR T cells protect from ANCA-induced acute kidney injury. Ann Rheum Dis. 2024 Mar 12;83(4):499-507. doi: 10.1136/ard-2023-224875.

  PMID: 38182404 BACKGROUND

• Treppo E, Binutti M, Agarinis R, De Vita S, Quartuccio L. Rituximab Induction and Maintenance in ANCA-Associated Vasculitis: State of the Art and Future Perspectives. J Clin Med. 2021 Aug 24;10(17):3773. doi: 10.3390/jcm10173773.

  PMID: 34501224 BACKGROUND

• Steinmetz OM, Velden J, Kneissler U, Marx M, Klein A, Helmchen U, Stahl RA, Panzer U. Analysis and classification of B-cell infiltrates in lupus and ANCA-associated nephritis. Kidney Int. 2008 Aug;74(4):448-57. doi: 10.1038/ki.2008.191. Epub 2008 Jun 4.

  PMID: 18528326 BACKGROUND

• Holden NJ, Williams JM, Morgan MD, Challa A, Gordon J, Pepper RJ, Salama AD, Harper L, Savage CO. ANCA-stimulated neutrophils release BLyS and promote B cell survival: a clinically relevant cellular process. Ann Rheum Dis. 2011 Dec;70(12):2229-33. doi: 10.1136/ard.2011.153890. Epub 2011 Aug 21.

  PMID: 21859691 BACKGROUND

• Falk RJ, Terrell RS, Charles LA, Jennette JC. Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc Natl Acad Sci U S A. 1990 Jun;87(11):4115-9. doi: 10.1073/pnas.87.11.4115.

  PMID: 2161532 BACKGROUND

• Kitching AR, Anders HJ, Basu N, Brouwer E, Gordon J, Jayne DR, Kullman J, Lyons PA, Merkel PA, Savage COS, Specks U, Kain R. ANCA-associated vasculitis. Nat Rev Dis Primers. 2020 Aug 27;6(1):71. doi: 10.1038/s41572-020-0204-y.

  PMID: 32855422 BACKGROUND

• Brudno JN, Lam N, Vanasse D, Shen YW, Rose JJ, Rossi J, Xue A, Bot A, Scholler N, Mikkilineni L, Roschewski M, Dean R, Cachau R, Youkharibache P, Patel R, Hansen B, Stroncek DF, Rosenberg SA, Gress RE, Kochenderfer JN. Author Correction: Safety and feasibility of anti-CD19 CAR T cells with fully human binding domains in patients with B-cell lymphoma. Nat Med. 2020 May;26(5):803. doi: 10.1038/s41591-020-0864-x.

  PMID: 32291416 BACKGROUND

MeSH Terms

Conditions

Vasculitis; HIV Seropositivity

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases; HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Central Study Contacts

David Nils Simon, Dr. med. habil.

CONTACT

+4930450513017; david.simon@charite.de

Jan Zernicke, Dr. rer. medic.

CONTACT

+4930450513227; jan.zernicke@charite.de

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator, Head of the Clinical Trial Unit

Model Details: this is a two-stage interventional, prospective, open-label study. This study has one treatment arm (open-label KYV101), but sequential treatment (two groups). Second group of participants are assigned to receive interventions based on the achievement of the previous milestone (28 days after treatment of the third patient of group 1). A data safety monitoring board (DSMB) will decide whether to proceed to phase II ≥ 28 days after treatment of the third subject.

Study Record Dates

• First Submitted: September 4, 2024
• First Posted: September 19, 2024
• Study Start: January 1, 2025
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): July 1, 2027
• Last Updated: September 19, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share