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)

Официальное название

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

Обзор

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

Подробное описание

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.

Вмешательства

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

Первичные конечные точки

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

Вторичные конечные точки (12)

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

Критерии участия

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

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 13 центров

• 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
• … и ещё 5 центров

Публикации

• 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

Идентификаторы

NCT: NCT04422912 · CAB-101

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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