晚期肾细胞癌（RCC）一线治疗药物Tivozanib完胜多吉美

小马，tivozanib的剂量真的是每天1.5mg，每天一次呃。
1.5mg*2元=3元/天；那不是太好了吗？

Biologic and clinical activity of tivozanib (AV-951, KRN-951), a selective inhibitor of VEGF receptor-1, -2, and -3 tyrosine kinases, in a 4-week-on, 2-week-off schedule in patients with advanced solid tumors.

Clin Cancer Res. 2011 Nov 15;17(22):7156-63. Epub 2011 Oct 5.
Eskens FA, de Jonge MJ, Bhargava P, Isoe T, Cotreau MM, Esteves B, Hayashi K, Burger H, Thomeer M, van Doorn L, Verweij J.
SourceDepartment of Medical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands. f.eskens@erasmusmc.nl

Abstract
PURPOSE: To assess the maximum tolerated dose (MTD)/dose-limiting toxicities (DLT), safety, pharmacokinetics, and pharmacodynamics of tivozanib, a potent and selective oral VEGF receptor (VEGFR) tyrosine kinase inhibitor.

EXPERIMENTAL DESIGN: Dose levels of 1.0, 1.5, and 2.0 mg/d tivozanib for 28 days followed by 14 days of medication were explored in patients with advanced solid tumors.

RESULTS: Forty-one patients were enrolled. Animal data incorrectly predicted toxicity, resulting in DLTs at the starting dose (2.0 mg) consisting of grade 3 proteinuria and hypertension and grade 3 ataxia. At 1.0 mg, no DLT was observed. At an intermediate dose (1.5 mg), 1 patient experienced DLT consisting of grade 3 hypertension. This dose was determined as the MTD. Of 10 additional patients treated at 1.5 mg, 1 patient each experienced grade 3 hypertension and grade 3 fatigue, and 2 patients experienced grade 3 and 4 transaminase elevation. In 12 additional patients treated at 1.0 mg, no DLT was observed. Pharmacokinetics displayed long absorption time, dose proportional exposure, and a half-life of 4.7 days. Plasma levels of VEGF-A and soluble VEGFR-2 showed dose-dependent increases and decreases, respectively. Dynamic contrast-enhanced MRI indicated reduction in tumor perfusion. Clinical activity was observed in renal cell cancer, colorectal cancer, and other tumors.

CONCLUSION: Tivozanib was well tolerated with manageable side effects. The pharmacokinetics profile revealed that tivozanib was suitable for once-daily dosing. Encouraging and durable clinical activity was observed. The recommended daily dose of tivozanib in a 4-week-on and 2-week-off dosing regimen is 1.5 mg.

这药还有关于NSCLC的临床，已经结束了。
An Open-Label Study of QD Oral Administration of Tivozanib (AV-951) in Subjects With Non-Small Cell Lung Cancer (NSCLC)
Condition:         Carcinoma, Non-Small-Cell Lung
Intervention:         Drug: Tivozanib (AV-951)
=======================================
A Study of Tivozanib (AV-951), an Oral VEGF Receptor Tyrosine Kinase Inhibitor, in the Treatment of Renal Cell Carcinoma
Approximately 200 patients will be enroled into the initial, 16 week, open-label period using 1.5 mg/day dosing. Patients will receive tivozanib (AV-951) continuously for 3 weeks followed by 1 week off study drug. Patients will undergo disease assessment at baseline and after Cycles 2 and 4 and response will be determined by RESIST criteria.

还真是一天吃1.5mg，这样好便宜啊！

这药对Kras突变的非小肺癌也可能有效果。

这药对肺腺有用吗？

估计价格也是非常的昂贵！

主要的副作用：
Hypertension高血压，44.9%；Dysphonia发声困难，21.7%； Diarrhea腹泻，12.1%；Asthenia乏力，10.3%；Fatigue疲劳，8.1%；Dyspnoea呼吸困难，5.9%。
        52%的病人使用一种或二种降压药（钙拮抗剂硝苯地平、ACEI抑制剂依那普利）。4%的病人需要减量，5.5%的病人因无法耐受副作用退组。
其它临床试验中发现的副作用：Anorexia厌食，Nausea恶心，Thrombocytopenia血小板减少，Rash皮疹，Mucositis/Stomatitis粘膜炎/口腔炎, Vomiting呕吐，Hand-foot  syndrome手足反应，Elevations inγ-glutamic-transpeptidase γ-谷氨酰转肽酶升高，Elevations  of  alkaline  phosphatase 碱性磷酸酶升高，Lymphopenia 淋巴。
在1期临床试验中，吃四周停二周方案，2mg/d组出现1例3级asymptomatic proteinuria无症状性蛋白尿，1例3级intracranial hemorrhage颅内出血，1例4级intracranial hemorrhage颅内出血。

动物实验表明，Tivozanib (1mg/kg口服，一天二次，二周) 显著抑制大鼠异种移植模型乳腺癌 (MDA-MB-231，ZR-75-1),肠癌 (LoVo and LS174T),肝癌(SK-HEP-1), 卵巢癌 (OVCAR-3，SK-OV-3), 胰腺癌(BxPC-3) ，前列腺癌 (PC-3) ，非小细胞肺癌（Calu-6）。
Kras和EGFR驱动的中晚期肺腺癌对Tivozanib敏感，然而，一但停药，肿瘤迅速增长，重新使用Tivozanib治疗变得不那么敏感。这表示其它的抗血管生成机制形成，导致耐药。这种情况在乳腺癌的治疗中更明显。

Tivozanib在人体内半衰期的范围在3.8-4.7天，血药浓度约在2-3周后达到稳定状态。
JP Patent  Application Number 2002-306101
N-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-n'-(5-methyl-3-isoxaz- olyl)urea salt in crystalline form
http://appft1.uspto.gov/netacgi/ ... p;RS=DN/20060052415
        Tivozanib是一水合盐酸盐晶体。

up.