Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors.
Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors.
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刺猬通路抑制剂 vismodegib (GDC-0449) 在难治性、局部晚期或转移性实体瘤患者中的 I 期试验。
DOI：
10.1158/1078-0432.ccr-10-2745
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发表时间：
2011-04-15
期刊：
影响因子：
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通讯作者：
Von Hoff DD
中科院分区：
文献类型：
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作者：
LoRusso PM;Rudin CM;Reddy JC;Tibes R;Weiss GJ;Borad MJ;Hann CL;Brahmer JR;Chang I;Darbonne WC;Graham RA;Zerivitz KL;Low JA;Von Hoff DD
刺猬蛋白 (Hh) 信号通路是发育过程中细胞生长和分化的关键调节因子，与某些癌症的发病机制有关。 Vismodegib (GDC-0449) 是一种平滑蛋白的小分子抑制剂，平滑蛋白是 Hh 信号传导的关键成分。该 I 期试验评估了 GDC-0449 对当前疗法难治或不存在标准疗法的实体瘤患者的治疗效果。 68 名患者接受 GDC-0449 治疗，剂量为 150 mg/d (n = 41)、270 mg/d (n = 23) 或 540 mg/d (n = 4)。评估了非受累皮肤中 GLI1 表达的不良事件、肿瘤反应、药代动力学和药效学下调。 68 名患者中，33 名患有晚期基底细胞癌 (BCC)，8 名患有胰腺癌，1 名患有髓母细胞瘤；还代表了 17 种其他类型的癌症。 GDC-0449 总体耐受性良好。 6 名患者 (8.8%) 经历了 7 起 4 级事件（低钠血症、疲劳、肾盂肾炎、先兆晕厥、可切除胰腺癌和高血糖偏执狂），27.9% 的患者经历了 3 级事件 [最常见的是低钠血症 (10.3%)、腹痛 (7.4%) 和疲劳 (5.9%)]。未达到最大耐受剂量。基于在此剂量下达到的最大血浆浓度和药效学反应，推荐的 II 期剂量为 150 mg/d。在 20 名患者中观察到肿瘤反应（19 名患有基底细胞癌，1 名髓母细胞瘤未确认反应），其中 14 名患者疾病稳定为最佳反应，28 名患者出现疾病进展。在非受累皮肤中观察到 GLI1 下调的证据。 GDC-0449 具有可接受的安全性，并且在晚期 BCC 和髓母细胞瘤中具有令人鼓舞的抗肿瘤活性。有必要对这些和其他癌症类型进行进一步研究。
The hedgehog (Hh) signaling pathway, a key regulator of cell growth and differentiation during development is implicated in pathogenesis of certain cancers. Vismodegib (GDC-0449) is a small-molecule inhibitor of smoothened, a key component of Hh signaling. This phase I trial assessed GDC-0449 treatment in patients with solid tumors refractory to current therapies or for which no standard therapy existed. Sixty-eight patients received GDC-0449 at 150 mg/d (n = 41), 270 mg/d (n = 23), or 540 mg/d (n = 4). Adverse events, tumor responses, pharmacokinetics, and pharmacodynamic down-modulation of GLI1 expression in noninvolved skin were assessed. Thirty-three of 68 patients had advanced basal cell carcinoma (BCC), 8 had pancreatic cancer, 1 had medulloblastoma; 17 other types of cancer were also represented. GDC-0449 was generally well-tolerated. Six patients (8.8%) experienced 7 grade 4 events (hyponatremia, fatigue, pyelonephritis, presyncope, resectable pancreatic adenocarcinoma, and paranoia with hyperglycemia), and 27.9% of patients experienced a grade 3 event [most commonly hyponatremia (10.3%), abdominal pain (7.4%), and fatigue (5.9%)]. No maximum tolerated dose was reached. The recommended phase II dose was 150 mg/d, based on achievement of maximal plasma concentration and pharmacodynamic response at this dose. Tumor responses were observed in 20 patients (19 with BCC and 1 unconfirmed response in medulloblastoma), 14 patients had stable disease as best response, and 28 had progressive disease. Evidence of GLI1 down-modulation was observed in noninvolved skin. GDC-0449 has an acceptable safety profile and encouraging anti-tumor activity in advanced BCC and medulloblastoma. Further study in these and other cancer types is warranted.