A Multiinstitutional Phase 2 Trial of Pazopanib Monotherapy in Advanced Anaplastic Thyroid Cancer
A Multiinstitutional Phase 2 Trial of Pazopanib Monotherapy in Advanced Anaplastic Thyroid Cancer
复制标题
DOI：
10.1210/jc.2012-1520
复制
发表时间：
2012-09-01
影响因子：
5.8
通讯作者：
Erlichman, Charles
中科院分区：
文献类型：
--
作者：
Bible, Keith C.;Suman, Vera J.;Erlichman, Charles
背景/目标：帕唑帕尼是一种包括血管内皮生长因子受体在内的激酶抑制剂，在进行性转移性分化型甲状腺癌中表现出令人印象深刻的活性，促使其在未分化甲状腺癌（ATC）中进行评估。设计/设置/患者/干预/结局指标：临床前研究，随后进行多中心单臂2期试验，每天口服800 mg帕唑帕尼（设计为当真实应答率>5%时，在0.10显著性水平下提供90%的机会检测到应答率>20%）。主要试验终点是实体瘤反应评价标准（RECIST）responsibility.Results：帕唑帕尼显示在KTC 2 ATC异种移植模型中的活性，提示临床评价。16例试验患者入组; 15例接受治疗：66.7%为女性，中位年龄为66岁（范围45-77岁），15例患者中有11例通过既往全身治疗进展。招募被停止，这是由停止规则触发的，该规则要求33名潜在患者中的前14名患者中有一名以上确认的RECIST应答。4名患者需要减少1至2次剂量;严重毒性（国家癌症研究所常见毒性标准-不良事件3.0版等级>3）为高血压（13%）和咽喉疼痛（13%）。由于以下原因停止治疗：疾病进展（12例患者）、由于可能与治疗相关的肿瘤出血导致的死亡（1例患者）和不耐受（放射性回忆性气管炎和不受控制的高血压各1例患者）。尽管在几例患者中观察到一过性疾病消退，但没有确认的RECIST缓解。中位进展时间为62 d;中位生存时间为111 d。两名患者是活着的疾病登记后9.9和35个月，13死于disease.Conclusions：尽管在ATC的临床前体内活性，帕唑帕尼有最小的单药临床活性在先进的ATC。（临床内分泌代谢杂志97：3179-3184，2012）
Context/Objectives: Pazopanib, an inhibitor of kinases including vascular endothelial growth factor receptor, demonstrated impressive activity in progressive metastatic differentiated thyroid cancer, prompting its evaluation in anaplastic thyroid cancer (ATC).Design/Setting/Patients/Interventions/Outcome Measures: Preclinical studies, followed by a multicenter single arm phase 2 trial of continuously administered 800 mg pazopanib daily by mouth (designed to provide 90% chance of detecting a response rate of >20% at the 0.10 significance level when the true response rate is >5%), were undertaken. The primary trial end point was Response Evaluation Criteria in Solid Tumors (RECIST) response.Results: Pazopanib displayed activity in the KTC2 ATC xenograft model, prompting clinical evaluation. Sixteen trial patients were enrolled; 15 were treated: 66.7% were female, median age was 66 yr (range 45-77 yr), and 11 of 15 had progressed through prior systemic therapy. Enrollment was halted, triggered by a stopping rule requiring more than one confirmed RECIST response among the first 14 of 33 potential patients. Four patients required one to two dose reductions; severe toxicities (National Cancer Institute Common Toxicity Criteria-Adverse Events version 3.0 grades >3) were hypertension (13%) and pharyngolaryngeal pain (13%). Treatment was discontinued because of the following: disease progression (12 patients), death due to a possibly treatment-related tumor hemorrhage (one patient), and intolerability (radiation recall tracheitis and uncontrolled hypertension, one patient each). Although transient disease regression was observed in several patients, there were no confirmed RECIST responses. Median time to progression was 62 d; median survival time was 111 d. Two patients are alive with disease 9.9 and 35 months after the registration; 13 died of disease.Conclusions: Despite preclinical in vivo activity in ATC, pazopanib has minimal single-agent clinical activity in advanced ATC. (J Clin Endocrinol Metab 97: 3179-3184, 2012)