A Phase II, Randomized, Placebo-Controlled Study of Vismodegib as Maintenance Therapy in Patients with Ovarian Cancer in Second or Third Complete Remission
A Phase II, Randomized, Placebo-Controlled Study of Vismodegib as Maintenance Therapy in Patients with Ovarian Cancer in Second or Third Complete Remission
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DOI：
10.1158/1078-0432.ccr-12-1796
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发表时间：
2012-12-01
影响因子：
11.5
通讯作者：
Reddy, Josina C.
中科院分区：
文献类型：
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作者：
Kaye, Stanley B.;Fehrenbacher, Louis;Reddy, Josina C.
目的：通过阻断肿瘤-间质相互作用，抑制Hedgehog通路被认为是卵巢癌的一种潜在的维持治疗方法。Vismodegib是一种口服Hedgehog途径抑制剂，对晚期基底细胞癌和髓母细胞瘤具有临床活性。这项II期随机、双盲、安慰剂对照试验旨在提供对第二或第三次完全缓解(CR)的卵巢癌患者的疗效的初步评估。实验设计：第二次或第三次完全缓解(CR)中复发的上皮性卵巢癌、输卵管癌或原发性腹膜癌患者在完成化疗后3至14周被随机分为1：1的维莫吉组(GDC-0449，每天150 mg)或安慰剂组。治疗一直持续到放射学进展或中毒。结果：104例患者随机分为维莫地布组(n=52)和安慰剂组(n=52)，中位无进展生存期分别为7.5个月和5.8个月[HR 0.79；95%可信区间(CI)，0.461.35]。84例二期CR患者的HR为0.66(95%CI，0.36~1.20)，20例三期CR患者的HR为1.79(95%CI，0.50~6.48)。内脏肌臂最常见的不良事件是动作障碍/失语、肌肉痉挛和脱发。服用vismodegib的12名患者(23.1%)和服用安慰剂的6名患者(11.5%)发生了3/4级不良事件。在13.5%的档案组织中检测到hedgehog的表达。结论：在这项研究中，与安慰剂相比，在本研究中，卵巢癌患者在第二次或第三次CR中维持Vismodegib的PFS没有达到所要求的增加幅度。Hedgehog配体的表达频率低于预期。临床癌症资源；18(23)；6509-18。(C)2012年AACR。
Purpose: Hedgehog pathway inhibition has been suggested as a potential maintenance treatment approach in ovarian cancer through disruption of tumor-stromal interactions. Vismodegib is an orally available Hedgehog pathway inhibitor with clinical activity in advanced basal cell carcinoma and medulloblastoma. This phase II, randomized, double-blind, placebo-controlled trial was designed to provide a preliminary estimate of efficacy in patients with ovarian cancer in second or third complete remission (CR).Experimental Design: Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in second or third CR were randomized 1:1 to vismodegib (GDC-0449; 150 mg daily) or placebo three to 14 weeks after completing chemotherapy. Treatment continued until radiographic progression or toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS).Results: One hundred four patients were randomized to vismodegib (n = 52) or placebo (n 52); median PFS was 7.5 months and 5.8 months, respectively [HR 0.79; 95% confidence interval (CI), 0.461.35]. The HR was 0.66 (95% CI, 0.36-1.20) for second CR patients (n 84) and 1.79 (95% CI, 0.50-6.48) for third CR patients (n 20). The most common adverse events in the vismodegib arm were dysgeusia/ageusia, muscle spasms, and alopecia. Grade 3/4 adverse events occurred in 12 patients (23.1%) with vismodegib and six (11.5%) with placebo. Hedgehog expression was detected in 13.5% of archival tissues.Conclusions: In this study, the sought magnitude of increase in PFS was not achieved for vismodegib maintenance versus placebo in patients with ovarian cancer in second or third CR. The frequency of Hedgehog ligand expression was lower than expected. Clin Cancer Res; 18(23); 6509-18. (C) 2012 AACR.