A phase II trial of perifosine, an oral alkylphospholipid, in recurrent or metastatic head and neck cancer
A phase II trial of perifosine, an oral alkylphospholipid, in recurrent or metastatic head and neck cancer
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DOI：
10.4161/cbt.5.7.2874
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发表时间：
2006-07-01
影响因子：
3.6
通讯作者：
Vokes, Everett
中科院分区：
文献类型：
--
作者：
Argiris, Athanassios;Cohen, Ezra;Vokes, Everett
背景资料：新的，有效的治疗方法是必要的复发性或转移性鳞状细胞癌的头部和颈部（SCCHN）的管理。哌立福新是一种口服的烷基磷脂，抑制AKT磷酸化，并已显示出临床前的抗肿瘤活性，在头部和颈部癌细胞系和xenografts.Patients和方法：我们进行了第二阶段试验哌立福新在患者不可治愈，复发或转移SCCHN。复发性或转移性疾病的既往治疗仅限于不超过一种既往化疗和一种既往靶向/生物制剂方案。患者必须有可测量的疾病、东部肿瘤协作组体能状态0-2和足够的实验室参数。哌立福新的负荷剂量为每6小时150 mg，前两天口服6剂，并进行止吐预防，随后不间断地口服100 mg/天。允许通过胃造口管给药。每两个周期（8周）评估一次肿瘤缓解。应用免疫组化方法，通过手工和自动化方法，检测了哌立福新可能影响肿瘤细胞凋亡途径的AKT、P-AKT、P38、p53和p21等生物标志物。未观察到客观缓解。1例患者的最佳缓解为疾病稳定，18例患者在首次评价时进展。中位总生存期为5.5个月，中位无进展生存期为1.7个月。最常见的毒性是胃肠道（便秘、恶心、呕吐）和疲乏。1例患者出现4级厌食症。虽然样本量很小，一个显着的相关性被检测到在基线肿瘤组织和更好的survival.Conclusions的P38和AKT的高表达之间：哌立福新的剂量和时间表使用缺乏单剂活性SCCHN。我们的数据不证明进一步研究perifosine作为单药在SCCHN。
Background: Novel, effective therapies are warranted in the management of recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Perifosine is an oral alkylphospholipid that inhibits AKT phosphorylation and has shown preclinical antitumor activity in head and neck cancer cell lines and xenografts.Patients And Methods: We conducted a phase II trial of perifosine in patients with incurable, recurrent or metastatic SCCHN. Previous therapy for recurrent or metastatic disease was limited to no more than one prior chemotherapy and one prior targeted/ biologic agent regimen. Patients had to have measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and adequate laboratory parameters. Perifosine was given as a loading dose of 150 mg every 6 hours x 6 doses orally in the first two days, with antiemetic prophylaxis, followed by 100 mg/day orally without interruption. Administration via gastrostomy tube was allowed. Tumor response was assessed every two cycles (eight weeks). Biomarkers in pathways potentially affected by perifosine, including AKT, P-AKT, P38, p53 and p21 were measured on tumor tissue by immunohistochemistry by manual and automated methods.Results: Nineteen patients were enrolled. No objective responses were observed. One patient had stable disease as best response and 18 patients progressed at first evaluation. The median overall survival time was 5.5 months and the median progression-free survival time was 1.7 months. The most frequent toxicities were gastrointestinal (constipation, nausea, vomiting) and fatigue. One patient developed grade 4 anorexia. Although the sample size was small, a significant correlation was detected between high expression of P38 and AKT in baseline tumor tissue and better survival.Conclusions: Perifosine in the doses and schedule used lacks single-agent activity in SCCHN. Our data do not justify further investigation of perifosine as a single agent in SCCHN.