Data from 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
Year: 2023
Type: other
Abstract: 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.
Authors: Susana Banerjee, Vasiliki Michalarea, Joo Ern Ang, Alvaro Ingles Garces, Andrea Biondo, Ionut-Gabriel Funingana, Martin Little, Ruth Ruddle, Florence Raynaud, Ruth Riisnaes, Bora Gurel, Sue Chua, Nina Tunariu, Joanna C. Porter, Toby Prout, Mona Parmar, Anna Zachariou, Alison Turner, Ben Jenkins, Stuart McIntosh, Ed Ainscow, Anna Minchom, Juanita Lopez, Johann de Bono, Robert Jones, Emma Hall, Natalie Cook, Bristi Basu, Udai Banerji
Institutions: Royal Marsden NHS Foundation Trust, Institute of Cancer Research, University of Cambridge, Cambridge University Hospitals NHS Foundation Trust, The Christie NHS Foundation Trust, Royal Marsden Hospital, University College London, Velindre NHS Trust, Cardiff University, University of Manchester
Language: English
Subfield: Reproductive Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W4361950444