A Study of Anti-CD19 Chimeric Antigen Receptor T-Cell (CD19 CAR T) Therapy, in Subjects With Refractory Lupus Nephritis

A Phase 1/2, Open-Label, Multicenter Study of KYV-101, an Autologous Fully-Human Anti-CD19 Chimeric Antigen Receptor T-Cell (CD19 CAR T) Therapy, in Subjects With Refractory Lupus Nephritis (KYSA-1)

A Study of Anti-CD19 Chimeric Antigen Receptor T Cell Therapy for Subjects With Refractory Lupus Nephritis

Study Overview

• Status: Recruiting
• Conditions: Lupus Nephritis; Lupus Nephritis - World Health Organization (WHO) Class III; Lupus Nephritis - WHO Class IV
• Intervention / Treatment: Biological: KYV-101 anti-CD19 CAR-T cell therapy; Drug: Standard lymphodepletion regimen

Detailed Description

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by a wide spectrum of organ involvement and disease severity. Renal involvement (categorized as lupus nephritis [LN]) may occur in approximately 50% of SLE patients and is marked by proteinuria, microscopic hematuria, and varying degrees of renal insufficiency. B cells play a central role in the pathogenesis of SLE and LN, with autoantibodies developing as an early finding, and local, tissue resident B cells producing pathogenic autoantibodies and driving inflammation and tissue damage over time. CD19-targeted chimeric antigen receptor (CAR) T cells harness the ability of cytotoxic T cells to directly and specifically lyse target cells to effectively deplete B cells in the circulation and in lymphoid and potentially non-lymphoid tissues. KYV-101, a fully human anti-CD19 CAR T-cell therapy, will be investigated in adult subjects with refractory lupus nephritis.

• Study Type: Interventional
• Enrollment (Estimated): 32
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Kyverna Therapeutics; Phone Number: 510-925-2484; Email: medicalmonitor@kyvernatx.com

Study Locations

• United States
  • California
    • Palo Alto, California, United States, 94305
      • Recruiting
      • Stanford University Medical Center
      • Contact: Study Coordinator
  • Colorado
    • Denver, Colorado, United States, 80045
      • Recruiting
      • University of Colorado
      • Contact: Study Coordinator
  • Massachusetts
    • Worcester, Massachusetts, United States, 01655
      • Recruiting
      • University of Massachusetts Worcester
      • Contact: Study Coordinator
  • New York
    • Great Neck, New York, United States, 11021
      • Recruiting
      • Northwell Health
      • Contact: Study Coordinator
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Recruiting
      • Ohio State University Wexner Medical Center
      • Contact: Study Coordinator
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • University of Pennsylvania
      • Contact: Study Coordinator

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥18 years
2. Clinical diagnosis of SLE according to 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria
3. Biopsy-proven proliferative LN Class III or IV according to 2018 International Society of Nephrology/Renal Pathology Society (ISN/RPS) criteria
4. Positive anti-nuclear antibody (ANA) (titer ≥1:80 ), anti-dsDNA (≥30 IU/mL on enzyme-linked immunosorbent assay [ELISA]), or anti-Smith at screening or by documented medical history
5. Up to date on recommended vaccinations, including against coronavirus disease 2019 (COVID-19)/ severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), per Centers for Disease Control and Prevention (CDC) or institutional guidelines for immune compromised individuals

Exclusion Criteria:

1. Rapidly progressive glomerulonephritis; history of or currently active severe central nervous system (CNS) lupus, including cerebritis, cerebrovascular accident, and seizures
2. Prior treatment with cellular immunotherapy (CAR-T) or gene therapy product directed at any target
3. History of allogeneic or autologous stem cell transplant
4. Evidence of active hepatitis B or hepatitis C infection
5. Positive serology for HIV
6. Primary immunodeficiency
7. History of splenectomy
8. History of stroke, seizure, dementia, Parkinson's disease, coordination movement disorder, cerebellar diseases, psychosis, paresis, aphasia, and any other neurologic disorder investigator considers would increase the risk for the subject
9. Impaired cardiac function or clinically significant cardiac disease

10. Previous or concurrent malignancy with the following exceptions:

    1. Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is required prior to screening)
    2. In situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 3 years prior to screening
    3. A primary malignancy which has been completely resected, or treated, and is in complete remission for at least 5 years prior to screening

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: KYV-101 CAR-T cells with lymphodepletion conditioning (Phase 1); Dosing with KYV-101 CAR T cells	Biological: KYV-101 anti-CD19 CAR-T cell therapy; KYV-101 anti-CD19 CAR-T cell therapy; Drug: Standard lymphodepletion regimen; Standard lymphodepletion regimen; Other Names: Cyclophosphamide; Fludarabine
Experimental: KYV-101 CAR-T cells with lymphodepletion conditioning (Phase 2); Recommended Phase 2 Dose	Biological: KYV-101 anti-CD19 CAR-T cell therapy; KYV-101 anti-CD19 CAR-T cell therapy; Drug: Standard lymphodepletion regimen; Standard lymphodepletion regimen; Other Names: Cyclophosphamide; Fludarabine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence adverse events (AEs) and laboratory abnormalities (Phase 1 and Phase 2)		Up to 2 years
Frequency of dose limiting toxicities at each dose level (Phase 1)		Up to 2 years
To Evaluate efficacy (Phase 2)	Complete renal response rates (CRR)	Up to 52 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To characterize the pharmacokinetics (PK) (Phase 1 and Phase 2)	Levels of KYV-101 CAR-positive T cells in the blood	Up to 2 years
To characterize the pharmacodynamics (PD) (Phase 1 and Phase 2)	Levels of B cells in the blood	Up to 2 years
To characterize the pharmacodynamics (PD) (Phase 1 and Phase 2)	Levels of cytokines in serum	Up to 2 months
To evaluate disease related biomarkers (Phase 1 and Phase 2)	Levels of anti-double stranded DNA (anti-dsDNA) in serum	Up to 2 years
To evaluate disease related biomarkers (Phase 1 and Phase 2)	Levels of complement C3, C4 in serum	Up to 2 years
To evaluate efficacy (Phase 1 and Phase 2)	Complete renal response rates (CRR)	12, 24, and 52 weeks
To evaluate efficacy (Phase 1 and Phase 2)	Time to Complete renal response rates (CRR)	Up to 2 years
To evaluate efficacy (Phase 1 and Phase 2)	Time from first achieved CRR to disease worsening or end of study	Up to 2 years
To evaluate efficacy (Phase 2)	Duration of CRR to Week 52 but no less than 12 weeks (duration of remission)	Up to 52 weeks
To evaluate the immunogenicity (humoral response) of KYV-101 (Phase 1 and Phase 2)	Percentage of participants who develop anti-KYV-101 antibodies by immunoassays	Up to 2 years
To assess PRO after infusion of KYV-101 (Phase 1 and Phase 2)	Change from Baseline in SF-36	Up to 2 years
To assess PRO after infusion of KYV-101 (Phase 1 and Phase 2)	Change from Baseline in FACIT-F	Up to 2 years
To assess PRO after infusion of KYV-101 (Phase 1 and Phase 2)	Change from Baseline in Lupus QoL Questionnaire	Up to 2 years
To assess PRO after infusion of KYV-101 (Phase 1 and Phase 2)	Change from Baseline in WPAI	Up to 2 years
To define the Recommended Phase 2 Dose (RP2D) (Phase 1)		Up to 2 years

Collaborators and Investigators

• Sponsor: Kyverna Therapeutics
• Investigators: Study Director: MD, Kyverna Therapeutics

Publications and helpful links

General Publications

• 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. Safety and feasibility of anti-CD19 CAR T cells with fully human binding domains in patients with B-cell lymphoma. Nat Med. 2020 Feb;26(2):270-280. doi: 10.1038/s41591-019-0737-3. Epub 2020 Jan 20. Erratum In: Nat Med. 2020 May;26(5):803.
• 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. Erratum In: Nat Med. 2022 Nov 3;:

Study record dates

Study Major Dates

• Study Start (Actual): April 28, 2023
• Primary Completion (Estimated): August 1, 2025
• Study Completion (Estimated): August 1, 2026

Study Registration Dates

• First Submitted: October 11, 2022
• First Submitted That Met QC Criteria: July 7, 2023
• First Posted (Actual): July 10, 2023

Study Record Updates

• Last Update Posted (Actual): April 18, 2024
• Last Update Submitted That Met QC Criteria: April 16, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: cellular therapy; glomerulonephritis; autoimmune disease; KYV-101; anti-CD19 CAR-T therapy
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Kidney Diseases; Urologic Diseases; Connective Tissue Diseases; Glomerulonephritis; Lupus Erythematosus, Systemic; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Nephritis; Lupus Nephritis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Fludarabine
• Other Study ID Numbers: KYV101-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes