A phase II clinical and pharmacodynamic study of e7070 in patients with metastatic, recurrent, or refractory squamous cell carcinoma of the head and neck: Modulation of retinoblastoma protein phosphorylation by a novel chloroindolyl sulfonamide cell cycle inhibitor
A phase II clinical and pharmacodynamic study of e7070 in patients with metastatic, recurrent, or refractory squamous cell carcinoma of the head and neck: Modulation of retinoblastoma protein phosphorylation by a novel chloroindolyl sulfonamide cell cycle inhibitor
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DOI：
10.1158/1078-0432.ccr-04-0229
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发表时间：
2004-07-15
影响因子：
11.5
通讯作者：
Shapiro, GI
中科院分区：
文献类型：
--
作者：
Haddad, RI;Weinstein, LJ;Shapiro, GI
目的：E7070是一种合成的磺胺类细胞周期抑制剂，在体外诱导视网膜母细胞瘤（Rb）蛋白的低磷酸化和G（1）阻滞。E7070治疗头颈部鳞状细胞癌（SCCHN）的疗效、安全性和药效学的II期研究。实验设计：转移性、复发性或难治性SCCHN患者，既往接受过不超过一次复发性疾病治疗，接受E7070 700 mg/m2，每3周一次，每次1小时。治疗前和治疗后的肿瘤细针抽吸物进行免疫组织化学与一组磷酸化特异性抗Rb抗体。终点包括无进展生存期，反应率和持续时间，总生存期，毒性特征，和抑制Rb磷酸化。结果：因为没有第一个15例患者实现无进展生存> 4个月，早期停止规则调用。11例患者患有口咽癌，12例为男性。中位年龄为59岁（范围：49-73岁）。输送了39个周期的E7070（中位数，2.6个周期/患者;范围，1-5个周期）。6例患者在2个周期后病情稳定，2例患者随后分别接受了1、2和3个额外周期，然后发生进展。3例患者的肿瘤细胞吸出物的免疫组化显示Rb磷酸化posttreatment.Conclusions减少：在这个剂量和时间表，E7070是不可能的上级单药化疗SCCHN。然而，数据表明肿瘤细胞中的cdk活性可以被抑制，从而导致治疗后Rb磷酸化的调节。在没有细胞毒性的情况下，可能需要更频繁地施用E7070来维持Rb低磷酸化和细胞生长抑制。
Purpose: E7070 is a synthetic sulfonamide cell cycle inhibitor that induces hypophosphorylation of the retinoblastoma (Rb) protein and G(1) arrest in vitro. This Phase II study was conducted to explore the efficacy, safety, and pharmacodynamics of E7070 in squamous cell carcinoma of the head and neck (SCCHN).Experimental Design: Patients with metastatic, recurrent, or refractory SCCHN, treated with no more than one prior therapy for recurrent disease, received E7070 at 700 mg/m(2) over 1 h every 3 weeks. Pre- and posttreatment tumor fine needle aspirates were subjected to inummohistochemistry with a panel of phospho-specific anti-Rb antibodies. End points included progression-free survival, response rate and duration, overall survival, toxicity profile, and inhibition of Rb phosphorylation.Results: Because none of the first 15 patients achieved progression-free survival > 4 months, the early stopping rule was invoked. Eleven patients had oropharyngeal cancer and 12 were male. Median age was 59 years (range, 49-73 years). Thirty-nine cycles of E7070 were delivered (median, 2.6 cycles/patient; range, 1-5 cycles). Six patients had stable disease after 2 cycles and 2 patients each subsequently received 1, 2, and 3 additional cycles, respectively, before experiencing progression. Immunohistochemistry of tumor cell aspirates from 3 patients demonstrated reduced Rb phosphorylation posttreatment.Conclusions: At this dose and schedule, E7070 is unlikely to be superior over single-agent chemotherapy in SCCHN. However, the data suggest that cdk activity can be inhibited in tumor cells, resulting in posttreatment modulation of Rb phosphorylation. In the absence of cytotoxicity, more frequent administration of E7070 may be required to sustain Rb hypophosphorylation and cytostatic growth arrest.