| Autor: |
Udai Banerji, Bristi Basu, Natalie Cook, Emma Hall, Robert Jones, Johann de Bono, Juanita Lopez, Anna Minchom, Ed Ainscow, Stuart McIntosh, Ben Jenkins, Alison Turner, Anna Zachariou, Mona Parmar, Toby Prout, Joanna C. Porter, Nina Tunariu, Sue Chua, Bora Gurel, Ruth Riisnaes, Florence Raynaud, Ruth Ruddle, Martin Little, Ionut-Gabriel Funingana, Andrea Biondo, Alvaro Ingles Garces, Joo Ern Ang, Vasiliki Michalarea, Susana Banerjee |
| Rok vydání: |
2023 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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