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Isatuximab plus atezolizumab in patients with advanced solid tumors: results from a phase I/II, open-label, multicenter study
M. Simonelli, E. Garralda, F. Eskens, M. Gil-Martin, CJ. Yen, R. Obermannova, Y. Chao, S. Lonardi, B. Melichar, V. Moreno, ML. Yu, A. Bongiovanni, E. Calvo, S. Rottey, JP. Machiels, A. Gonzalez-Martin, L. Paz-Ares, CL. Chang, W. Mason, CC. Lin,...
Jazyk angličtina Země Anglie, Velká Británie
Typ dokumentu klinické zkoušky, fáze II, klinické zkoušky, fáze I, multicentrická studie, časopisecké články, práce podpořená grantem
NLK
Directory of Open Access Journals
od 2016
PubMed Central
od 2016
Europe PubMed Central
od 2016
Open Access Digital Library
od 2016-01-01
ROAD: Directory of Open Access Scholarly Resources
od 2016
- MeSH
- antigeny CD274 metabolismus MeSH
- forkhead transkripční faktory MeSH
- hepatocelulární karcinom * MeSH
- lidé MeSH
- nádorové mikroprostředí MeSH
- nádory jater * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze I MeSH
- klinické zkoušky, fáze II MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
BACKGROUND: The anti-CD38 antibody isatuximab is approved for the treatment of relapsed/refractory multiple myeloma, but there are no data on its efficacy in solid tumors. This phase I/II study (NCT03637764) assessed the safety and activity of isatuximab plus atezolizumab (Isa + Atezo), an anti-programmed death-ligand 1 (PD-L1) antibody, in patients with immunotherapy-naive solid tumors: epithelial ovarian cancer (EOC), glioblastoma (GBM), hepatocellular carcinoma (HCC), and squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Phase I assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and the recommended phase II dose (RP2D) of isatuximab 10 mg/kg intravenously (i.v.) every week for 3 weeks followed by once every 3 weeks + atezolizumab 1200 mg i.v. every 3 weeks. Phase II used a Simon's two-stage design to assess the overall response rate or progression-free survival rate at 6 months (GBM cohort). Interim analysis was carried out at 6 months following first dose of the last enrolled patient in each cohort. Pharmacodynamic biomarkers were tested for CD38, PD-L1, tumor-infiltrating immune cells, and FOXP3+ regulatory T cells (Tregs) in the tumor microenvironment (TME). RESULTS: Overall, 107 patients were treated (EOC, n = 18; GBM, n = 33; HCC, n = 27; SCCHN, n = 29). In phase I, Isa + Atezo showed an acceptable safety profile, no dose-limiting toxicities were observed, and RP2D was confirmed. Most patients experienced ≥1 treatment-emergent adverse event (TEAE), with ≤48.5% being grade ≥3. The most frequent TEAE was infusion reactions. The study did not continue to stage 2 based on prespecified targets. Tumor-infiltrating CD38+ immune cells were reduced and almost cleared after treatment. Isa + Atezo did not significantly modulate Tregs or PD-L1 expression in the TME. CONCLUSIONS: Isa + Atezo had acceptable safety and tolerability. Clinical pharmacodynamic evaluation revealed efficient target engagement of isatuximab via treatment-mediated reduction of CD38+ immune cells in the TME. Based on clinical data, CD38 inhibition does not improve responsiveness to PD-L1 blockade in these patients.
Cliniques Universitaires Saint Luc Brussels Belgium
Dana Farber Cancer Institute Harvard University Boston
Department of Biomedical Sciences Humanitas University Pieve Emanuele Italy
Department of Obstetrics and Gynecology Mackay Memorial Hospital Taipei Taiwan
Department of Oncology Palacky University Olomouc Czech Republic
Department of Oncology Taipei Veterans General Hospital Taipei Taiwan
Erasmus MC Cancer Institute Rotterdam the Netherlands
Gustave Roussy Villejuif France
Hospital Universitario 12 de Octubre Madrid Spain
Institut Català d'Oncologia IDIBELL L'Hospitalet Barcelona Spain
IRCCS Humanitas Research Hospital Rozzano Italy
IRCCS Istituto Romagnolo per lo Studio dei Tumori Dino Amadori Meldola Italy
Masaryk Memorial Cancer Institute Brno Czech Republic
National Cheng Kung University Tainan Taiwan
National Taiwan University Hospital Taipei Taiwan
Princess Margaret Cancer Centre Toronto Canada
START Madrid CIOCC Centro Integral Oncológico Clara Campal Madrid Spain
START Madrid FJD Hospital Fundación Jiménez Díaz Madrid Spain
Citace poskytuje Crossref.org
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