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Publication Detail
A phase I trial of CT900, a novel α-folate receptor-mediated thymidylate synthase inhibitor, with expansion cohorts in patients with high grade serous ovarian cancer
  • Publication Type:
    Journal article
  • Authors:
    Banerjee S, Michalarea V, Ang JE, Ingles Garces A, Biondo A, Funingana I-G, Little M, Ruddle R, Raynaud F, Riisnaes R, Gurel B, Chua S, Tunariu N, Porter JC, Prout T, Parmar M, Zachariou A, Turner A, Jenkins B, McIntosh S, Ainscow E, Minchom A, Lopez J, De Bono J, Jones R, Hall E, Cook N, Basu B, Banerji U
  • Publisher:
    American Association for Cancer Research (AACR)
  • Publication date:
    19/08/2022
  • Journal:
    Clinical Cancer Research
  • Status:
    Accepted
  • Country:
    United States
  • Print ISSN:
    1078-0432
  • PII:
    708154
  • Language:
    English
  • Notes:
    This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0).
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 tumours. 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 (HGSOC) 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, diarrhoea, cough, anaemia and pneumonitis, which were predominantly grade 1 and grade 2. Levels of CT900 greater than 600 nM 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 tumour 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.
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