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.
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.
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DOI：
10.1158/1078-0432.ccr-22-1268
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发表时间：
2022-11-01
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影响因子：
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CT900是一种新的小分子胸苷合成酶抑制剂，可与α-叶酸受体(α-FR)结合，从而选择性地被α-FR过表达的肿瘤所摄取。采用3+3剂量递增设计。在剂量递增过程中，CT900每周1-6 mg/m2，每2周2-12 mg/m2，q2wk。高级别浆液性卵巢癌患者被纳入扩大队列。109例患者入选：剂量递增组42例，扩大队列组67例。在12 mg/m2/q2Wk的剂量/程序下(地塞米松和不加地塞米松，n=40)，与治疗相关的最常见的不良反应是乏力、恶心、腹泻、咳嗽、贫血和肺炎，主要是1级和2级。在临床前模型中，12 mg/m2的CT900水平超过了临床前模型中生长抑制所需的600nmol/L。在扩展队列中，总有效率为14/(21.9%)。在接受12 mg/m2/q2Wk治疗的扩展队列中，38名可评估疗效的患者的肿瘤可评估α-FR的定量。高或中等表达患者的客观有效率为9/25(36%)，而α-FR阴性/极低或低表达患者的客观有效率为1/13(7.7%)。12 mg/m2/q2wk的剂量被宣布为推荐的II期剂量/时间表。在这个剂量/时间表下，CT900在α-FR高/中表达的患者中表现出可接受的副作用，具有临床益处，值得进一步研究。
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. 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. 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. 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.
影响因子：
7.3
作者：
Tochowicz A;Dalziel S;Eidam O;O'Connell JD 3rd;Griner S;Finer-Moore JS;Stroud RM
通讯作者：
Stroud RM