Phase II basket trial of perifosine monotherapy for recurrent gynecologic cancer with or without PIK3CA mutations
Phase II basket trial of perifosine monotherapy for recurrent gynecologic cancer with or without PIK3CA mutations
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DOI：
10.1007/s10637-017-0504-6
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发表时间：
2017-12-01
影响因子：
3.4
通讯作者：
Kimura, Tadashi
中科院分区：
文献类型：
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作者：
Hasegawa, Kosei;Kagabu, Masahiro;Kimura, Tadashi
目的Perifosine通过抑制AKT的磷酸化而发挥抗肿瘤作用。这项II期篮子试验的目的是评估单药治疗卵巢癌、子宫内膜癌和宫颈癌的有效性和安全性。方法将复发性或持续性卵巢癌、子宫内膜癌、宫颈癌患者分为PIK3CA野生型和突变组。每个患者在第一天服用600毫克的潘生丁，然后每天服用100毫克的维持量。主要终点是疾病控制率；次要终点包括应答率、无进展存活率、总存活率和安全性。免疫组织化学染色和靶向测序被用来在这些患者中寻找新的生物标志物。结果PIK3CA野生型和突变型宫颈癌患者分别为卵巢癌患者16例和5例，子宫内膜癌患者17例和7例，宫颈癌患者18例和8例。卵巢癌、子宫内膜癌和宫颈癌的疾病控制率(野生型/突变型)分别为12.5/40.0%、47.1/14.3%和11.1/25.0%。最常见的3/4级毒性是贫血(22.5%)和厌食(11.3%)。免疫组织化学染色显示，PTEN表达阴性患者的疾病控制率为50.0%，阳性患者与阴性患者的优势比为0.24。结论Perifosine单药治疗耐受性好，但未达到预期疗效。PIK3CA突变的卵巢癌患者和PIK3CA野生型的子宫内膜癌患者的疗效不明显；PIK3CA野生型和突变型PIK3CA在宫颈癌中的疗效没有差异。PTEN表达缺失可能预示了单药治疗的临床疗效。
Objective Perifosine exhibits anti-tumor activity by inhibiting AKT phosphorylation. The purpose of this phase II basket trial was to evaluate the efficacy and safety of perifosine monotherapy for ovarian, endometrial, and cervical cancers. Methods Recurrent or persistent ovarian, endometrial, or cervical cancer patients were assigned to PIK3CA wild-type or mutant groups. Each patient received 600 mg oral perifosine on day 1 followed by a maintenance dose of 100 mg daily. The primary endpoint was disease control rate; secondary endpoints included response rate, progression-free survival, overall survival, and safety. Immunohistochemical staining and targeted sequencing were used to explore new biomarkers in such patients. Results Sixteen and 5 ovarian, 17 and 7 endometrial, and 18 and 8 cervical cancer patients with PIK3CA wild-type and mutant, respectively, were enrolled. Disease control rates (wild-type/mutant) were 12.5/40.0%, 47.1/14.3%, and 11.1/25.0% in ovarian, endometrial, and cervical cancer, respectively. The most common grade 3/4 toxicities were anemia (22.5%) and anorexia (11.3%). Immunohistochemical staining revealed that the disease control rate in patients with negative phosphatase and tensin homolog (PTEN) expression was 50.0%, and the odds ratio of positive to negative patients was 0.24 in all patients. Conclusions Perifosine monotherapy showed good tolerability but expected efficacy was not achieved. Modest efficacy was demonstrated in ovarian cancer patients with PIK3CA mutations and endometrial cancer patients with PIK3CA wild-type; no difference was observed between PIK3CA wild-type and mutant in cervical cancer. Absence of PTEN expression may be predictive of clinical efficacy with perifosine monotherapy.