A Phase I Trial of CT900, a Novel α-Folate Receptor-Mediated Thymidylate Synthase Inhibitor, in Patients with Solid Tumors with Expansion Cohorts in Patients with High-Grade Serous Ovarian Cancer.

Autor:	Banerjee S; Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom.; Gynaecology Unit, The Royal Marsden NHS Foundation Trust, London, United Kingdom., Michalarea V; Drug Development Unit, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom., Ang JE; Drug Development Unit, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom., Ingles Garces A; Gynaecology Unit, The Royal Marsden NHS Foundation Trust, London, United Kingdom.; Drug Development Unit, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom., Biondo A; Drug Development Unit, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom., Funingana IG; Cambridge University Hospitals NHS Foundation Trust and University of Cambridge, Cambridge, United Kingdom., Little M; Experimental Cancer Medicine Team, The Christie NHS Foundation Trust, Manchester, United Kingdom., Ruddle R; Drug Development Unit, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom., Raynaud F; Drug Development Unit, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom., Riisnaes R; Drug Development Unit, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom., Gurel B; Drug Development Unit, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom., Chua S; Radiology and Nuclear Medicine Department, The Royal Marsden NHS Foundation Trust, London, United Kingdom., Tunariu N; Drug Development Unit, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom.; Radiology and Nuclear Medicine Department, The Royal Marsden NHS Foundation Trust, London, United Kingdom., Porter JC; UCL Respiratory, University College London and Interstitial Lung Disease Service, University College London NHS Foundation Trust, London, United Kingdom., Prout T; Drug Development Unit, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom., Parmar M; Drug Development Unit, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom., Zachariou A; Drug Development Unit, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom., Turner A; Drug Development Unit, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom., Jenkins B; Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, United Kingdom., McIntosh S; Carrick Therapeutics, Dublin, Ireland., Ainscow E; Carrick Therapeutics, Dublin, Ireland., Minchom A; Drug Development Unit, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom., Lopez J; Drug Development Unit, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom., de Bono J; Drug Development Unit, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom., Jones R; Cardiff University, School of Medicine, Velindre University NHS Trust, Cardiff, United Kingdom., Hall E; Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, United Kingdom., Cook N; Experimental Cancer Medicine Team, The Christie NHS Foundation Trust, Manchester, United Kingdom.; Division of Cancer Sciences, The University of Manchester, Manchester, United Kingdom., Basu B; Cambridge University Hospitals NHS Foundation Trust and University of Cambridge, Cambridge, United Kingdom., Banerji U; Drug Development Unit, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2022 Nov 01; Vol. 28 (21), pp. 4634-4641.
DOI:	10.1158/1078-0432.CCR-22-1268
Abstrakt:	Purpose: CT900 is a novel small molecule thymidylate synthase inhibitor that binds to α-folate receptor (α-FR) and thus is selectively taken up by α-FR-overexpressing tumors. Patients and Methods: A 3+3 dose escalation design was used. During dose escalation, CT900 doses of 1-6 mg/m2 weekly and 2-12 mg/m2 every 2 weeks (q2Wk) intravenously were evaluated. Patients with high-grade serous ovarian cancer were enrolled in the expansion cohorts. Results: 109 patients were enrolled: 42 patients in the dose escalation and 67 patients in the expansion cohorts. At the dose/schedule of 12 mg/m2/q2Wk (with and without dexamethasone, n = 40), the most common treatment-related adverse events were fatigue, nausea, diarrhea, cough, anemia, and pneumonitis, which were predominantly grade 1 and grade 2. Levels of CT900 more than 600 nmol/L needed for growth inhibition in preclinical models were achieved for >65 hours at a dose of 12 mg/m2. In the expansion cohorts, the overall response rate (ORR), was 14/64 (21.9%). Thirty-eight response-evaluable patients in the expansion cohorts receiving 12 mg/m2/q2Wk had tumor evaluable for quantification of α-FR. Patients with high or medium expression had an objective response rate of 9/25 (36%) compared with 1/13 (7.7%) in patients with negative/very low or low expression of α-FR. Conclusions: The dose of 12 mg/m2/q2Wk was declared the recommended phase II dose/schedule. At this dose/schedule, CT900 exhibited an acceptable side effect profile with clinical benefit in patients with high/medium α-FR expression and warrants further investigation. (©2022 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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