This research was conducted because CT900 is a novel small molecule thymidylate synthase inhibitor that specifically binds to the α-folate receptor (α-FR), making it available for uptake only by malignancies that overexpress this receptor. The doses were increased by a factor of 3 and 3. CT900 dosages as low as 1 mg/m2 weekly and as high as 12 mg/m 2 every 2 weeks (q2Wk) were tested during the dose-escalation phase. High-grade serous ovarian cancer patients were accepted into the cohort expansions. 

A total of 109 patients were enrolled, with 42 participating in the dose escalation and 67 in the expansion groups. Fatigue, nausea, diarrhea, cough, anemia, and pneumonitis were the most common treatment-related side effects at the dose/schedule of 12 mg/m2/q2Wk (with and without dexamethasone, n = 40), and they were mostly in grades 1 and 2. At a dosage of 12 mg/m2, CT900 concentrations greater than 600 nmol/L, which are necessary for growth inhibition in preclinical models, were maintained for more than 65 hours. The expansion cohorts had an ORR of 21.9%, with 14/64 responses. In the 12 mg/m2/q2Wk expansion cohorts, 38 patients with tumors amenable to evaluation had a response that could be evaluated. 

The objective response rate was 36% (9/25 patients) for those with high or medium expression against 1% (1 patient out of 13) for those with negative/very low or low expression of α-FR. This phase II dose and schedule, 12 mg/m2/q2Wk, has been deemed optimal. Patients with high/medium α-FR expression showed clinical benefit with CT900 at this dose/schedule, suggesting that it is safe and worth further study.