Safety, pharmacokinetics, and antitumor activity of the anti-CEACAM5-DM4 antibody–drug conjugate tusamitamab ravtansine (SAR408701) in patients with advanced solid tumors: first-in-human dose-escalation study
| Autor: | A, Gazzah, P L, Bedard, C, Hierro, Y-K, Kang, A, Abdul Razak, M-H, Ryu, B, Demers, N, Fagniez, C, Henry, M, Hospitel, J-C, Soria, J, Tabernero |
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| Přispěvatelé: | Institut Català de la Salut, [Gazzah A] Drug Development Department, Gustave Roussy, Villejuif Cedex, Villejuif, France. [Bedard PL, Abdul Razak A] Division of Medical Oncology & Hematology, Department of Medicine, Princess Margaret Cancer Centre–University Health Network, University of Toronto, Toronto, Canada. [Hierro C] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Kang YK, Ryu MH] Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. [Tabernero J] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Medical Oncology Department, IOB-Quiron, UVic-UCC, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus |
| Rok vydání: | 2022 |
| Předmět: |
Adult
Immunoconjugates Adolescent Dose-Response Relationship Drug Maximum Tolerated Dose Farmacocinètica Càncer - Tractament Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores] diagnóstico::pronóstico::resultado del tratamiento [TÉCNICAS Y EQUIPOS ANALÍTICOS DIAGNÓSTICOS Y TERAPÉUTICOS] Antineoplastic Agents Bayes Theorem Hematology Other subheadings::Other subheadings::/drug therapy [Other subheadings] Physiological Phenomena::Pharmacological and Toxicological Phenomena::Pharmacological Phenomena::Dose-Response Relationship Drug [PHENOMENA AND PROCESSES] Diagnosis::Prognosis::Treatment Outcome [ANALYTICAL DIAGNOSTIC AND THERAPEUTIC TECHNIQUES AND EQUIPMENT] Antibodies Neoplasms [DISEASES] neoplasias [ENFERMEDADES] Treatment Outcome Oncology Neoplasms Avaluació de resultats (Assistència sanitària) Humans fenómenos fisiológicos::fenómenos farmacológicos y toxicológicos::fenómenos farmacológicos::relación dosis-respuesta de medicamentos [FENÓMENOS Y PROCESOS] Cell Adhesion Molecules |
| Zdroj: | Scientia |
| ISSN: | 0923-7534 |
| DOI: | 10.1016/j.annonc.2021.12.012 |
| Popis: | Antibody–drug conjugate; Dose-escalation study; Tusamitamab ravtansine Conjugado anticuerpo-fármaco; Estudio de escalada de dosis; Tusamitamab ravtansina Conjugat anticossos-fàrmac; Estudi d'escalada de dosi; Tusamitamab ravtansina Tusamitamab ravtansine (SAR408701) is an antibody–drug conjugate composed of a humanized monoclonal antibody that binds carcinoembryonic antigen-related cell adhesion molecule-5 (CEACAM5) and a cytotoxic maytansinoid that selectively targets CEACAM5-expressing tumor cells. In this phase I dose-escalation study, we evaluated the safety, pharmacokinetics, and preliminary antitumor activity of tusamitamab ravtansine in patients with solid tumors. Patients and methods Eligible patients were aged ≥18 years, had locally advanced/metastatic solid tumors that expressed or were likely to express CEACAM5, and had an Eastern Cooperative Oncology Group Performance Status of 0 or 1. Patients were treated with ascending doses of tusamitamab ravtansine intravenously every 2 weeks (Q2W). The first three dose levels (5, 10, and 20 mg/m2) were evaluated using an accelerated escalation protocol, after which an adaptive Bayesian procedure was used. The primary endpoint was the incidence of dose-limiting toxicities (DLTs) during the first two cycles, graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 criteria. Results Thirty-one patients received tusamitamab ravtansine (range 5-150 mg/m2). The DLT population comprised 28 patients; DLTs (reversible grade 3 microcystic keratopathy) occurred in three of eight patients treated with tusamitamab ravtansine 120 mg/m2 and in two of three patients treated with 150 mg/m2. The maximum tolerated dose was identified as 100 mg/m2. Twenty-two patients (71%) experienced ≥1 treatment-related treatment-emergent adverse event (TEAE), seven patients (22.6%) experienced ≥1 treatment-related grade ≥3 TEAE, and three patients (9.7%) discontinued treatment due to TEAEs. The most common TEAEs were asthenia, decreased appetite, keratopathy, and nausea. Three patients had confirmed partial responses. The mean plasma exposure of tusamitamab ravtansine increased in a dose-proportional manner from 10 to 150 mg/m2. Conclusions Tusamitamab ravtansine had a favorable safety profile with reversible, dose-related keratopathy as the DLT. Based on the overall safety profile, pharmacokinetic data, and Bayesian model recommendations, the maximum tolerated dose of tusamitamab ravtansine was defined as 100 mg/m2 Q2W. This work was supported by Sanofi, France (no grant number). |
| Databáze: | OpenAIRE |
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