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Phase I study of ABBV-428, a mesothelin-CD40 bispecific, in patients with advanced solid tumors.
Luke, Jason J; Barlesi, Fabrice; Chung, Ki; Tolcher, Anthony W; Kelly, Karen; Hollebecque, Antoine; Le Tourneau, Christophe; Subbiah, Vivek; Tsai, Frank; Kao, Steven; Cassier, Philippe A; Khasraw, Mustafa; Kindler, Hedy L; Fang, Hua; Fan, Frances; Allaire, Kathryn; Patel, Maulik; Ye, Shiming; Chao, Debra T; Henner, William R; Hayflick, Joel S; McDevitt, Michael A; Fong, Lawrence.
Afiliação
  • Luke JJ; Cancer Immunotherapeutics Center, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA lukejj@upmc.edu.
  • Barlesi F; Multidisciplinary Oncology & Therapeutic Innovations Department, Aix-Marseille University, Assistance Publique Hôpitaux de Marseille, CNRS, INSERM, CRCM, CEPCM CLIP2, Marseille, France.
  • Chung K; Hematology and Oncology, PRISMA Health System, Greenville, South Carolina, USA.
  • Tolcher AW; Clinical Research, NEXT Oncology, San Antonio, Texas, USA.
  • Kelly K; UC Davis Comprehensive Cancer Center, University of California, Sacramento, California, USA.
  • Hollebecque A; Drug Development Department (DITEP), Gustave Roussy Cancer Campus, Villejuif, France.
  • Le Tourneau C; Department of Drug Development and Innovation (D3i), Curie Institute, Paris and Saint-Cloud, France.
  • Subbiah V; INSERM U900 Research Unit, Saint-Cloud, France.
  • Tsai F; Paris-Saclay University, Paris, France.
  • Kao S; Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
  • Cassier PA; Hematology/Oncology, HonorHealth Research Institute, Scottsdale, Arizona, USA.
  • Khasraw M; Medical Oncology, Chris O'Brien Lifehouse, Camperdown, New South Wales, Australia.
  • Kindler HL; Department of Medical Oncology, Centre Léon Bérard, Lyon, France.
  • Fang H; Department of Neurosurgery, Duke University, Durham, North Carolina, USA.
  • Fan F; Section of Hematology/Oncology, University of Chicago Medicine, Chicago, Illinois, USA.
  • Allaire K; Precision Medicine, AbbVie Inc, Redwood City, California, USA.
  • Patel M; Department of Medicine, University of California San Francisco, San Francisco, California, USA.
  • Ye S; Department of Medicine, University of California San Francisco, San Francisco, California, USA.
  • Chao DT; Clinical Pharmacology, AbbVie Inc, Redwood City, California, USA.
  • Henner WR; Oncology Discovery, AbbVie Inc, Redwood City, California, USA.
  • Hayflick JS; Search & Evaluation, Oncology, AbbVie Inc, Redwood City, California, USA.
  • McDevitt MA; Statistics, AbbVie Inc, Redwood City, California, USA.
  • Fong L; Oncology Early Development, AbbVie Inc, Redwood City, California, USA.
J Immunother Cancer ; 9(2)2021 02.
Article em En | MEDLINE | ID: mdl-33608377
BACKGROUND: CD40 agonist immunotherapy can potentially license antigen-presenting cells to promote antitumor T-cell activation and re-educate macrophages to destroy tumor stroma. Systemic administration of CD40 agonists has historically been associated with considerable toxicity, providing the rationale for development of tumor-targeted immunomodulators to improve clinical safety and efficacy. This phase I study assessed the safety, tolerability, preliminary antitumor activity, and preliminary biomarkers of ABBV-428, a first-in-class, mesothelin-targeted, bispecific antibody designed for tumor microenvironment-dependent CD40 activation with limited systemic toxicity. METHODS: ABBV-428 was administered intravenously every 2 weeks to patients with advanced solid tumors. An accelerated titration (starting at a 0.01 mg/kg dose) and a 3+3 dose escalation scheme were used, followed by recommended phase II dose cohort expansions in ovarian cancer and mesothelioma, tumor types associated with high mesothelin expression. RESULTS: Fifty-nine patients were treated at doses between 0.01 and 3.6 mg/kg. The maximum tolerated dose was not reached, and 3.6 mg/kg was selected as the recommended phase II dose. Seven patients (12%) reported infusion-related reactions. Treatment-related grade ≥3 treatment-emergent adverse events were pericardial effusion, colitis, infusion-related reaction, and pleural effusion (n=1 each, 2%), with no cytokine release syndrome reported. The pharmacokinetic profile demonstrated roughly dose-proportional increases in exposure from 0.4 to 3.6 mg/kg. Best response was stable disease in 9/25 patients (36%) treated at the recommended phase II dose. CD40 receptor occupancy >90% was observed on peripheral B-cells starting from 0.8 mg/kg; however, no consistent changes from baseline in intratumoral CD8+ T-cells, programmed death ligand-1 (PD-L1+) cells, or immune-related gene expression were detected post-ABBV-428 treatment (cycle 2, day 1). Mesothelin membrane staining showed greater correlation with progression-free survival in ovarian cancer and mesothelioma than in the broader dose escalation population. CONCLUSIONS: ABBV-428 monotherapy exhibited dose-proportional pharmacokinetics and an acceptable safety profile, particularly for toxicities characteristic of CD40 agonism, illustrating that utilization of a tumor-targeted, bispecific antibody can improve the safety of CD40 agonism as a therapeutic approach. ABBV-428 monotherapy had minimal clinical activity in dose escalation and in a small expansion cohort of patients with advanced mesothelioma or ovarian cancer. TRIAL REGISTRATION NUMBER: NCT02955251.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Anticorpos Biespecíficos / Antígenos CD40 / Antineoplásicos Imunológicos / Mesotelina / Neoplasias Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Anticorpos Biespecíficos / Antígenos CD40 / Antineoplásicos Imunológicos / Mesotelina / Neoplasias Idioma: En Ano de publicação: 2021 Tipo de documento: Article