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.


Banerjee, Susana ORCID: 0000-0002-8840-7934, Michalarea, Vasiliki ORCID: 0000-0002-3102-3534, Ang, Joo Ern ORCID: 0000-0003-2103-996X, Ingles Garces, Alvaro ORCID: 0000-0002-0073-4237, Biondo, Andrea ORCID: 0000-0003-0599-254X, Funingana, Ionut-Gabriel ORCID: 0000-0002-1197-2652, Little, Martin ORCID: 0000-0003-2592-1570, Ruddle, Ruth ORCID: 0000-0003-0025-8872, Raynaud, Florence ORCID: 0000-0003-0957-6279, Riisnaes, Ruth ORCID: 0000-0002-8924-302X et al (show 19 more authors) (2022) 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. Clinical cancer research : an official journal of the American Association for Cancer Research, 28 (21). pp. 4634-4641.

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Abstract

<h4>Purpose</h4>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.<h4>Patients and methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.

Item Type: Article
Uncontrolled Keywords: Humans, Neoplasms, Ovarian Neoplasms, Folic Acid, Thymidylate Synthase, Enzyme Inhibitors, Maximum Tolerated Dose, Female
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 07 Jul 2023 15:10
Last Modified: 07 Jul 2023 15:10
DOI: 10.1158/1078-0432.ccr-22-1268
Open Access URL: https://aacrjournals.org/clincancerres/article/28/...
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3171541
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