| Source: |
Banerjee, S, Michalarea, V, Ang, J E, Garces, A I, Biondo, A, Funingana, I G, Little, M, Ruddle, R, Raynaud, F, Riisnaes, R, Gurel, B, Chua, S, Tunariu, N, Porter, J C, 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 2022, 'A Phase I Trial of CT900, a Novel a-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, vol. 28, no. .... |
| Description: |
Purpose: CT900 is a novel small molecule thymidylate synthase inhibitor that binds to a-folate receptor (a-FR) and thus is selectively taken up by a-FR–overexpressing tumors. Patients and Methods: A 3þ3 dose escalation design was used. During dose escalation, CT900 doses of 1–6 mg/m 2 weekly and 2–12 mg/m 2 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/m 2 /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/m 2 . 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/m 2 /q2Wk had tumor evaluable for quantification of a-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 a-FR. Conclusions: The dose of 12 mg/m 2 /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 a-FR expression and warrants further investigation. |