胡姨您好！张叔好！这是与癌共舞的马先生介绍的新型靶向药，您在美国了解一下其药效怎么样？是否适合张叔和我。张叔的化验结果出来告诉我。祝您们健康快乐！Tivozanib
英文名Tivozanib AV-951
别名 N-[2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl]-N'-(5-methyl-3-isoxazolyl)urea
产品名称 AV-951; N-[2-氯-4-[(6,7-二甲氧基-4-喹啉基)氧基]苯基]-N'-(5-甲基-3-异恶唑基)脲分子结构
分子式 C22H19ClN4O5 分子量 454.86 CAS 登录号 475108-18-0
Tivozanib是一种新型高选择抑制VEGFR的喹唑啉脲类化合物,体内外实验表明本品具有显著的抗血管生成和抑制抗肿瘤生长的活性。
http://google.brand.edgar-online ... nID=Pu71FShufhvanX7
临床试验数据：
1 Antitumor Activity and Safety of Tivozanib (AV-951) in a Phase II Randomized Discontinuation Trial in Patients With Renal Cell Carcinoma
http://jco.ascopubs.org/content/30/14/1678.abstract
服药方案：1.5mg每天，每三周休息一周。
结果：到参加研究的272例患者中，83％的患者有明确的细胞组织学，73％的患者曾接受肾切除术，54％的患者治疗无效。Tivozanib治疗16周后，118个随机患者的ORR为18％（14％至23％）。整个研究过程中，ORR为24％（19％至30％），并在总体研究人群中位PFS为11.7个月（8.3至14.3个月）。最常见的3级和4级的治疗相关的不良事件是高血压（12％）。
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。
2. An Open-Label Study of QD Oral Administration of Tivozanib (AV-951) in Subjects With Non-Small Cell Lung Cancer (NSCLC)（phase I、II）
服药方案：1.0mg和1.5mg每天，每四周。
3. A phase I QTc study of tivozanib in patients with advanced solid tumors.
服药方案：1.5mg每天，每三周休息一周。
4. Tivozanib Successfully Demonstrated Progression-Free Survival Superiority over Sorafenib in TIVO-1 Trial
All patients in TIVO-1 had clear cell RCC, had undergone a prior nephrectomy, and had not previously been treated with either a VEGF or mTOR therapy. Based on the top-line analysis of events in TIVO-1, determined by a blinded, independent review committee, key top-line findings include: tivozanib demonstrated a statistically significant improvement in PFS with a median PFS of 11.9 months compared to a median PFS of 9.1 months for sorafenib in the overall study population. Tivozanib demonstrated a statistically significant improvement in PFS with a median PFS of 12.7 months compared to a median PFS of 9.1 months for sorafenib in the pre-specified subpopulation of patients who were treatment naïve (no prior systemic therapy); this subpopulation was approximately 70% of the total study population.
Tivozanib demonstrated a well-tolerated safety profile consistent with the Phase 2 experience; the most commonly reported side effect was hypertension, a well established on-target and manageable effect of VEGFR inhibitors.
5. Tiv
5. Tivozanib, a pan-VEGFR tyrosine kinase inhibitor for the potential treatment of solid tumors
酪氨酸激酶靶点 IC50，nM（激酶活性检测） IC50，nM（磷酸化的诱导配体）
VEGFR-1 30 0.21
VEGFR-2 6.5 0.16
VEGFR-3 15 0.24
EphB2 24
PDGFR- α 40
PDGFR-β 49 1.72
c-Kit 78 1.63
Tie2 78
Flt-3 422
FGFR-1 299
c-met 1360
对FGFR-1, Flt-3, c-Met, EGFR, IGF-IR等抑制较弱
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。
专利：
1. U.S. Patent Application Number 61261252
Tivozanib and temsirolimus in combination
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。
Tivozanib是第一种可以与mTOR抑制剂Temsirolimus联合应用的VEGF抑制。剂量: 1.5 mg/day Tivozanib and 25 mg/week temsirolimus。
2.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。
3. US 7736861 B1 Tivozanib response prediction
http://ip.com/patent/US7736861
临床试验数据：
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