A Phase 1/2, Open-label, Safety and Dosing Study of Autologous CART Cells (Desmoglein 3 Chimeric Autoantibody Receptor T Cells [DSG3-CAART] or CD19-specific Chimeric Antigen Receptor T Cells [CABA-201]) in Subjects With Active, Pemphigus Vulgaris (RESET-PV)

Official title

A Phase 1/2, Open-label, Safety and Dosing Study of Autologous CART Cells (Desmoglein 3 Chimeric Autoantibody Receptor T Cells [DSG3-CAART] or CD19-specific Chimeric Antigen Receptor T Cells [CABA-201]) in Subjects With Active, Pemphigus Vulgaris

Overview

A phase 1/2, open-label, safety and dosing study of autologous CART cells (desmoglein 3 chimeric autoantibody receptor T cells \[DSG3-CAART\] or CD19-specific Chimeric Antigen Receptor T cells \[CABA-201\]) in subjects with active, pemphigus vulgaris

Detailed description

Pemphigus vulgaris (PV) is a B-cell mediated autoimmune disorder in which painful blisters are formed on the skin or mucosal membrane, including the mouth, nose, throat, eyelids, anus, and genitals.

This phase 1/2 study is being conducted in two parts. The first part is the main study conducted to find the maximum tolerated dose and optimal fractionated infusion schedule of an investigational cell therapy, DSG3-CAART, that can be given to patients with mucosal PV who are inadequately managed by standard therapies. This study is closed to enrollment.

The second part is a sub-study is being conducted to investigate if CABA-201, also called resecabtagene autoleucel, or "rese-cel", can be safely administered while achieving clinical responses without the need for preconditioning in mucosal-dominant PV (mPV) and mucocutaneous PV (mcPV) patients. This sub-study is open to enrollment.

DSG3-CAART or CABA-201 may potentially lead to complete and durable remission of disease.

Interventions

• Biological DSG3-CAART
  Intravenous infusions of DSG3-CAART alone at different doses and different fractionations, with or without intravenous immunoglobulin, cyclophosphamide, and/or fludarabine.
• Biological CABA-201
  Single intravenous infusion of CABA-201 at escalating doses, with or without preconditioning.

Primary outcome measures

• Adverse events, including Dose Limit Toxicity [Time frame: 3 months]
• For CABA-201 Sub-study: To evaluate adverse events reported by subjects [Time frame: Up to 28 days after CABA-201 infusion]

Secondary outcome measures (12)

• Percent of CAAR-transduced cells [Time frame: Baseline]
• Total DSG3-CAART positive cells [Time frame: Baseline]
• Cellular kinetics profile of DSG3-CAART [Time frame: Up to 36 months]
• Change in DSG3 autoantibody titer [Time frame: Up to 36 months]
• Serologic remission [Time frame: Up to 36 months]
• Pemphigus Disease Area Index (PDAI) [Time frame: Up to 36 months]
• Clinical remission: complete remission off therapy and complete remission on minimal therapy [Time frame: Up to 36 months]
• Time to clinical remission and time to serologic remission [Time frame: up to 36 months]
• Duration of clinical remission and duration of serologic remission [Time frame: up to 36 months]
• For CABA-201 Sub-study: To evaluate adverse events reported by subjects [Time frame: Up to 156 weeks after CABA-201 infusion]
• For CABA-201 Sub-study: To characterize the pharmacodynamics (PD) [Time frame: Up to 156 weeks]
• For CABA-201 Sub-study: To characterize the pharmacokinetics (PK) [Time frame: Up to 156 weeks]

Eligibility criteria

Inclusion Criteria for DSG3-CAART: Closed to enrollment

• Confirmed diagnosis of mPV by prior or screening biopsy and prior positive anti- DSG3 antibody ELISA
• mPV inadequately managed by at least one standard immunosuppressive therapies
• Active mPV at screening
• Anti-DSG3 antibody ELISA positive at screening

Inclusion Criteria for CABA-201 sub-study: Open to enrollment

• Age ≥18
• Confirmed diagnosis of PV by prior or screening biopsy and prior positive DSG3 ELISA, IIF, and/or DIF
• PV inadequately managed by at least one standard immunosuppressive therapy
• Active PV at screening
• DSG3 ELISA positive at screening

Exclusion criteria

• Active cutaneous lesions associated with PV that indicates mucocutaneous rather than mucosal-dominant disease
• Rituximab in last 12 months unless PV symptoms have recently worsened or anti-DSG3 antibody titers have recently increased
• Prednisone > 0.25mg/kg/day
• Other autoimmune disorder requiring immunosuppressive therapies
• Investigational treatment in last 3 months

Exclusion Criteria for CABA-201 sub-study

• Have paraneoplastic pemphigus or active malignancy (not including non-melanoma skin cancer) or malignancy diagnosed within the previous 5 years
• Have received rituximab or other anti-CD20 or anti-CD19 therapies in last 12 months unless anti-DSG3 antibody titers have recently increased or PV symptoms have recently worsened
• Prednisone > 0.25mg/kg/day
• Other autoimmune disorder requiring immunosuppressive therapies
• Treatment with any investigational agent within 4 weeks or 5 half-lives, whichever is longer.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 13 centers

• Stanford University, Dept. of Dermatology — Redwood City
• UC Davis, Dept. of Dermatology — Sacramento
• Yale University — New Haven
• Northwestern University — Chicago
• University of Iowa — Iowa City
• Brigham and Women's Hospital — Boston
• Mount Sinai - Icahn School of Medicine — New York
• Columbia University — New York
• … and 5 more centers

Publications

• Nunez D, Stadanlick J, Furmanak T, Goldenberg J, Choudhary GS, Ishikawa L, Werner M, Vorndran Z, Hadi-Nezhad F, Thompson D, Braccia D, Ellis A, Cicarelli J, Flanagan S, Williams J, Kobulsky D, Toreki A, Schreiber C, Bass N, Impagliazzo A, Lam Q, Dominguez A, Awan F, Zhou X, Brieva J, Abedi M, Maverakis E, Kresa-Reahl K, Tummala R, Chang D, Binder GK, Volkov J, Basu S. CD19 CAR T-cell therapy is fe PMID 42201777
• Shu J, Xie W, Chen Z, Offringa R, Hu Y, Mei H. The enchanting canvas of CAR technology: Unveiling its wonders in non-neoplastic diseases. Med. 2024 Jun 14;5(6):495-529. doi: 10.1016/j.medj.2024.03.016. Epub 2024 Apr 11. PMID 38608709

Identifiers

NCT: NCT04422912 · CAB-101

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗