Phase I study of oral rigosertib (ON 01910.Na), a dual inhibitor of the PI3K and Plk1 pathways, in adult patients with advanced solid malignancies.
Phase I study of oral rigosertib (ON 01910.Na), a dual inhibitor of the PI3K and Plk1 pathways, in adult patients with advanced solid malignancies.
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DOI：
10.1158/1078-0432.ccr-13-2506
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发表时间：
2014-03-15
期刊：
影响因子：
--
通讯作者：
Jimeno A
中科院分区：
文献类型：
--
作者：
Bowles DW;Diamond JR;Lam ET;Weekes CD;Astling DP;Anderson RT;Leong S;Gore L;Varella-Garcia M;Vogler BW;Keysar SB;Freas E;Aisner DL;Ren C;Tan AC;Wilhelm F;Maniar M;Eckhardt SG;Messersmith WA;Jimeno A
确定rigosertib口服制剂在晚期实体恶性肿瘤患者中的药代动力学（PK）、最大耐受剂量（MTD）、安全性和抗肿瘤活性。rigosertib是一种双磷酸肌肽3-激酶（PI3K）和脊髓样激酶1 （Plk1）途径抑制剂。晚期实体恶性肿瘤患者接受rigosertib治疗，每天2次，连续21天。剂量逐渐增加，直到无法忍受的≥2级毒性，此时扩大先前的剂量水平以定义MTD。对所有患者进行安全性、PK和反应评估。尿PK在MTD进行。档案肿瘤通过多重突变检测评估潜在的分子生物标志物。鳞状细胞癌（SCC）的一个子集进行了外显子组测序。48例患者接受了5个剂量水平的中位数为2个周期的治疗。Rigosertib暴露随着剂量的增加而增加。剂量限制性毒性为血尿和排尿困难。最常见的≥2级药物相关毒性涉及尿路上皮刺激。每日两次，每日每日560毫克。头颈部SCCs有活性（1例完全缓解，1例部分缓解），另外8例患者病情稳定≥12周。出现≥部分应答的肿瘤具有PI3K通路激活、p53失活以及与Wnt/β-catenin通路相互作用的两个基因ROBO3和FAT1的独特变异。推荐的II期口服rigosertib剂量为560mg，每日两次，连续给药。尿毒性是剂量限制性的，也是最常见的毒性。在未来的试验中，PI3K、p53和Wnt/β-catenin通路信号的改变应作为潜在的生物标志物进行研究。
To determine the pharmacokinetics (PK), maximum tolerated dose (MTD), safety, and antitumor activity of an oral formulation of rigosertib, a dual phosphoinositide 3-kinase (PI3K) and polo-like kinase 1 (Plk1) pathway inhibitor, in patients with advanced solid malignancies. Patients with advanced solid malignancies received rigosertib twice daily continuously in 21-day cycles. Doses were escalated until intolerable grade ≥ 2 toxicities, at which point the previous dose level was expanded to define the MTD. All patients were assessed for safety, PK, and response. Urinary PK were performed at the MTD. Archival tumors were assessed for potential molecular biomarkers with multiplex mutation testing. A subset of squamous cell carcinomas (SCC) underwent exome sequencing. Forty-eight patients received a median of 2 cycles of therapy at 5 dose levels. Rigosertib exposure increased with escalating doses. Dose-limiting toxicities were hematuria and dysuria. The most common grade ≥2 drug-related toxicities involved urothelial irritation. The MTD is 560 mg twice daily. Activity was seen in head and neck SCCs (1 complete response, 1 partial response) and stable disease for ≥ 12 weeks was observed in 8 additional patients. Tumors experiencing ≥partial response had PI3K pathway activation, inactivated p53, and unique variants in ROBO3 and FAT1, two genes interacting with the Wnt/β-catenin pathway. The recommended phase II dose of oral rigosertib is 560 mg twice daily given continuously. Urinary toxicity is the dose-limiting and most common toxicity. Alterations in PI3K, p53, and Wnt/β-catenin pathway signaling should be investigated as potential biomarkers of response in future trials.