Phase I Trial of Pazopanib in Patients with Advanced Cancer

被引:343
作者
Hurwitz, Herbert I. [2 ]
Dowlati, Afshin [3 ]
Saini, Shermini [2 ]
Savage, Shawna [2 ]
Suttle, A. Benjamin [1 ]
Gibson, Diana M. [1 ]
Hodge, Jeffrey P. [1 ]
Merkle, Elmar M. [2 ]
Pandite, Lini [1 ]
机构
[1] GlaxoSmithKline Inc, Res Triangle Pk, NC 27709 USA
[2] Duke Univ, Med Ctr, Durham, NC USA
[3] Case Western Reserve Univ, Cleveland, OH 44106 USA
关键词
TUMOR VASCULATURE; INHIBITOR; KINASE; ANTITUMOR; GROWTH; SAFETY; PDGF; PHARMACODYNAMICS; PHARMACOKINETICS; VEGF;
D O I
10.1158/1078-0432.CCR-08-2740
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: The safety, pharmacokinetics, and clinical activity of pazopanib (GW786034), an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, were evaluated in patients with advanced-stage refractory solid tumors. Experimental Design: Patients were enrolled into sequential dose-escalating cohorts (50 mg three times weekly to 2,000 mg once daily and 300-400 mg twice daily). Escalation or deescalation was based on toxicities observed in the preceding dose cohort. Pharmacokinetic and biomarker samples were obtained. Clinical response was assessed every 9 weeks. Results: Sixty-three patients were treated (dose escalation, n = 43; dose expansion, n = 20). Hypertension, diarrhea, hair depigmentation, and nausea were the most frequent drug-related adverse events, the majority of which were of grade 1/2. Hypertension was the most frequent grade 3 adverse event. Four patients experienced dose-limiting toxicities at 50 mg, 800 mg, and 2,000 mg once daily. A plateau in steady-state exposure was observed at doses of >= 800 mg once daily. The mean elimination half-life at this dose was 31.1 hours. A mean target trough concentration (C-24) >= 15 mu g/mL (34 mu mol/L) was achieved at 800 mg once daily. Three patients had partial responses (two confirmed, one unconfirmed), and stable disease of 16 months was observed in 14 patients; clinical benefit was generally observed in patients who received doses of >= 800 mg once daily or 300 mg twice daily. Conclusion: Pazopanib was generally well tolerated and showed antitumor activity across various tumor types. A monotherapy dose of 800 mg once daily was selected for phase II studies.
引用
收藏
页码:4220 / 4227
页数:8
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