| Title: |
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. |
| Authors: |
Banerjee, Susana; Michalarea, Vasiliki; Ang, Joo Ern; Ingles Garces, Alvaro; Biondo, Andrea; Funingana, Ionut-Gabriel; Little, Martin; Ruddle, Ruth; Raynaud, Florence; Riisnaes, Ruth; Gurel, Bora; Chua, Sue; Tunariu, Nina; Porter, Joanna C; Prout, Toby; Parmar, Mona; Zachariou, Anna; Turner, Alison; Jenkins, Ben; McIntosh, Stuart; Ainscow, Ed; Minchom, Anna; Lopez, Juanita; de Bono, Johann; Jones, Robert; Hall, Emma; Cook, Natalie; Basu, Bristi; Banerji, Udai |
| Publisher Information: |
American Association for Cancer Research (AACR); Cancer Research UK Cambridge Institute; Department of Oncology; //doi.org/10.1158/1078-0432.ccr-22-1268 |
| Publication Year: |
2023 |
| Collection: |
Apollo - University of Cambridge Repository |
| Subject Terms: |
Humans; Female; Thymidylate Synthase; Maximum Tolerated Dose; Neoplasms; Enzyme Inhibitors; Ovarian Neoplasms; Folic Acid |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
https://www.repository.cam.ac.uk/handle/1810/348934 |
| Availability: |
https://www.repository.cam.ac.uk/handle/1810/348934 |
| Rights: |
Creative Commons Attribution Non Commercial-No Derivatives ; https://creativecommons.org/licenses/by-nc-nd/4.0/ |
| Accession Number: |
edsbas.C89C9B13 |
| Database: |
BASE |