Phase I Study of Ceralasertib (AZD6738), a Novel DNA Damage Repair Agent, in Combination with Weekly Paclitaxel in Refractory Cancer.
Phase I Study of Ceralasertib (AZD6738), a Novel DNA Damage Repair Agent, in Combination with Weekly Paclitaxel in Refractory Cancer.
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Ceralasertib（AZD 6738），一种新型DNA损伤修复剂，联合每周一次紫杉醇治疗难治性癌症的I期研究。
DOI：
10.1158/1078-0432.ccr-21-0251
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发表时间：
2021-09-01
期刊：
影响因子：
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通讯作者：
Lee J
中科院分区：
文献类型：
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作者：
Kim ST;Smith SA;Mortimer P;Loembé AB;Cho H;Kim KM;Smith C;Willis S;Irurzun-Arana I;Berges A;Hong JY;Park SH;Park JO;Park YS;Lim HY;Kang WK;Kozarewa I;Pierce AJ;Dean E;Lee J
Ceralasertib是一种有效和选择性的口服丝氨酸/苏氨酸蛋白激酶、共济失调、毛细血管扩张和RAD3相关(ATR)蛋白的抑制剂。符合条件的实体瘤患者，黑色素瘤丰富，接受Ceralasertib联合固定剂量的紫杉醇(80 mg/m2，d1，d8，d15)，28天为一个周期。在滚动的6个设计中，ceralasertib的剂量逐渐增加，达到MTD。Ceralasertib起始量为40 mg，qd。57名患者(33名之前PD1/L1治疗失败的黑色素瘤患者)被纳入7个剂量队列，剂量范围从40 mg qd到240 mg bd加每周紫杉醇。RP2D方案为Ceralasertib 240 mg，bd，d1-14，加紫杉醇80 mg/m2，d1，d8，d15，每28天1次。最常见的毒副反应是中性粒细胞减少(n=39，68%)、贫血(n=25，44%)和血小板减少(n=21，37%)。在57例患者的全组分析中，总有效率(ORR)为22.6%(95%CI，12.5~35.3)。在33例抗PD1治疗无效的黑色素瘤患者中，ORR为33.3%(95%CI，18.0~51.8)。在黑色素瘤亚组中，MPFS为3.6个月(95%CI，2.0~5.8)，中位有效时间为9.9个月(95%CI，3.7~23.2)，MOS为7.4个月(95%CI，5.7~11.9)。Ceralasertib联合紫杉醇在晚期恶性肿瘤患者中耐受性良好，并显示出抗肿瘤活性的证据。对抗PD1/L1治疗耐药的晚期皮肤、肢端和粘膜黑色素瘤患者观察到持久的反应。见Ashworth的相关评论，
Ceralasertib is a potent and selective oral inhibitor of the serine/threonine protein kinase ataxia telangiectasia and Rad3-related (ATR) protein. Eligible patients with solid tumors, enriched for melanoma, received ceralasertib in combination with a fixed dose of paclitaxel (80 mg/m2 on D1, D8, D15) in 28-day cycles. The dose of ceralasertib was escalated to reach an MTD in a rolling 6 design. The starting dose of ceralasertib was 40 mg QD. Fifty-seven patients (33 patients with melanoma who failed prior PD1/L1 treatment) were enrolled in 7 dose cohorts ranging from 40 mg QD to 240 mg BD plus weekly paclitaxel. The RP2D was established as ceralasertib 240 mg BD days 1–14 plus paclitaxel 80 mg/m2 on D1, D8, D15 every 28 days. The most common toxicities were neutropenia (n = 39, 68%), anemia (n = 25, 44%), and thrombocytopenia (n = 21, 37%). In the full analysis set of 57 patients, the overall response rate (ORR) was 22.6% (95% CI, 12.5–35.3). In 33 patients with melanoma, resistant to prior anti-PD1 therapy, the ORR was 33.3% (95% CI, 18.0–51.8). In the melanoma subset, the mPFS was 3.6 months (95% CI, 2.0–5.8), the median duration of response was 9.9 months (95% CI, 3.7–23.2), and the mOS was 7.4 months (95% CI, 5.7–11.9). Ceralasertib in combination with paclitaxel was well tolerated in patients with advanced malignancies and showed evidence of antitumor activity. Durable responses were observed in patients with advanced cutaneous, acral, and mucosal melanoma resistant to anti-PD1/L1 treatment. See related commentary by Ashworth,