1-{2-Chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-3-(5-methylisoxazol-3-yl)urea
AV-951
Tivozanib (AV-951) is an oral VEGF receptor tyrosine kinase inhibitor. It is undergoing clinical trial investigation for the treatment of renal cell carcinomas.[1]
An oral quinoline urea derivative, tivozanib suppresses angiogenesis by being selectively inhibitory against vascular endothelial growth factor.[2] It was developed by AVEO Pharmaceuticals.[3]
It is designed to inhibit all three VEGF receptors.[4]
Phase III results on advanced renal cell carcinoma suggest a 30% or 3 months improvement in median PFS compared to sorafenib.[4]
AVEO Oncology and Astellas Pharma have announced FDA acceptance of tivozanib new drug application (NDA) filing for the treatment of advanced renal cell carcinoma (RCC).
According to the development and commercialization deal signed between the firms, NDA acceptance by the FDA has triggered a milestone payment worth $15m to AVEO from Astellas.
The efficacy and safety data from the Phase 3 TIvozanib Versus SOrafenib in 1st line Advanced RCC (TIVO-1) trial along with the data from 16 additional studies sponsored by AVEO conducted in more than 1,000 subjects administered with tivozanib are included in the NDA.
Safety and efficacy of the investigational compound Tivozanib with an anticipated brand name of Tivopath, is not completely established so far.
The review of kidney cancer pill that is not approved in any country is likely to be completed by 28 July 2013.
- A Study of Tivozanib (AV-951), an Oral VEGF Receptor Tyrosine Kinase Inhibitor, in the Treatment of Renal Cell Carcinoma, clinicaltrials.gov
- Campas, C., Bolos, J., Castaner, R (2009). “Tivozanib”. Drugs Fut 34 (10): 793.
- Aveo Kidney Cancer Drug Shows Success; Shares Up, By John Kell, Dow Jones Newswires
- “Phase III Results Lead Aveo and Astellas to Plan Regulatory Submissions for Tivozanib”. 3 Jan 2012.
AV-951 (Tivozanib, KRN-951) is a potent and selective VEGFR inhibitor for VEGFR1, VEGFR2 andVEGFR3 with IC50 of 0.21 nM, 0.16 nM and 0.24 nM, respectively.
| Molecular formula | C22H19ClN4O5 |
| Molar mass | 454.86 g mol−1 |
| Solubility (25°C) | DMSO 45 mg/mL |
| Water <1 mg/mL | |
| Ethanol <1 mg/mL |
Oral Abstract Session, Genitourinary Cancer (Nonprostate)Abstract No:4501
J Clin Oncol 30, 2012 (suppl; abstr 4501)
Tivozanib, a potent, selective, long half-life tyrosine kinase inhibitor targeting all three VEGF receptors, showed activity and tolerability in a Phase II trial (JCO 2011;29[18S]:4550). Methods: Patients (pts) with clear cell advanced renal cell carcinoma (RCC), prior nephrectomy, RECIST-defined measurable disease, and Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 were randomized 1:1 to tivozanib (T) 1.5 mg once daily for 3 weeks (wks) followed by 1 wk rest, or sorafenib (S) 400 mg twice daily continuously in a 4-wk cycle. Pts were treatment naïve or received no more than 1 prior systemic therapy for metastatic disease; pts receiving prior VEGF- or mTOR-targeted therapy were excluded. The primary endpoint was progression-free survival (PFS) per blinded, independent radiological review. 500 pts were to be enrolled to observe 310 events, yielding 90% power to detect medians of 9.7 and 6.7 months (m) with 5% type I error (2-sided). Results: A total of 517 pts were randomized to T (n=260) or S (n=257). Demographics were well balanced between the 2 groups, except ECOG 0 (T: 45% vs S: 54%, p=0.035). Median PFS was 11.9 m for T vs 9.1 m for S (HR=0.797, 95% CI 0.639–0.993; p=0.042). In the treatment-naïve stratum (70% of pts enrolled in each arm), the median PFS was 12.7 m for T vs 9.1 m for S (HR 0.756, 95% CI 0.580–0.985; p=0.037). In all pts, objective response rate (ORR) for T was 33% vs 23% for S (p=0.014). The most common adverse event (AE; all grades/≥grade 3) for T was hypertension (T: 46%/26% vs S: 36%/18%) and for S was hand-foot syndrome (T: 13%/2% vs S: 54%/17%). Other important AEs included diarrhea (T: 22%/2% vs S: 32%/6%), fatigue (T: 18%/5% vs S: 16%/4%), and neutropenia (T: 10%/2% vs S: 9%/2%). Patient-reported outcome data are being analyzed. Overall survival data are not mature.
Conclusions: Tivozanib demonstrated significant improvement in PFS and ORR compared with sorafenib as initial targeted treatment for advanced RCC. The safety profile of tivozanib is favorable, and includes a low incidence of fatigue, diarrhea, myelosuppression, and hand-foot syndrome.
References
| Sep 28, 2012 submission | AVEO and Astellas Announce Submission of New Drug Application for Tivozanib for the Treatment of Advanced Renal Cell Carcinoma |
http://www.aveooncology.com/our-product-candidates/tivozanib/
http://www.selleckchem.com/msds/AV-951-MSDS.html
http://www.ncbi.nlm.nih.gov/pubmed/21376230
Bayer/Onyx drug Nexavar (sorafenib) compare
others
1U.S. Cancer Statistics Working Group. United States Cancer Statistics: 1999–2007 Incidence and Mortality Web-based Report. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute; 2010. Available at:www.cdc.gov/uscs.
2Cancer Research UK. Available at: http://info.cancerresearchuk.org/cancerstats/world/the-global-picture/#Common;http://publications.cancerresearchuk.org/downloads/Product/cs_pdf_worldwide_2011.pdf
3American Cancer Society. Available at:http://www.cancer.org/Cancer/KidneyCancer/OverviewGuide/kidney-cancer–adult–renal-cell-carcinoma-overview-what-is-kidney-cancer.
4Bhargava, P., Robinson, M. Curr Oncol Rep (2011) 13:103–111
5Ravaud, A. Annals of Oncology 20 (Supplement 1): i7–i12, 2009
SEE ALSO
Figure VEGFR/multitargeted inhibitors approved for clinical use.\
Quinazoline and quinoline derivatives IN TRIALS
| Abbreviations Used | |
| VEGF | vascular endothelial growth factor |
| mTOR | mammalian target of rapamycin |
| TIMP-1 | tissue inhibitor of metalloproteinase 1 |
| PlGF | placenta growth factor |
| VEGFR | vascular endothelial growth factor receptor |
| TK | tyrosine kinase |
| Flt | fms-like tyrosine kinase |
| KDR | kinase insert domain |
| Flk | fetal liver kinase |
| JM | juxtamembrane |
| MAPK | mitogen activated protein kinase |
| Raf | rapidly accelerated fibrosarcoma |
| MEK | mitogen activated protein kinase/extracellular signal-regulated kinase kinase |
| ERK | extracellular signal-regulated kinase |
| FAK | focal adhesion kinase |
| PDGFR | platelet-derived growth factor receptor |
| CSFR | colony stimulating factor receptor |
| FLT3 | fms-like tyrosine kinase receptor 3 |
| FGF | fibroblast growth factor |
| HGF | hepatocyte growth factor |
| IL-8 | interleukin 8 |
| Tie-2 | tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2 |
| Eph | erythropoietin-producing human hepatocellular carcinoma receptor |
| PET | positron emission tomography |
| NSCLC | non-small-cell lung cancer |
| Bcr-Abl | breakpoint cluster region Abelson tyrosine kinase |
| RCC | renal cell carcinoma |
| HCC | hepatocellular carcinoma |
| GIST | gastrointestinal stromal tumor |
| EGFR | epidermal growth factor receptor |
| RET | rearranged during transfection |
| CD | catalytic domain |
| AML | acute myeloid leukemia |
| FGFR | fibroblast growth factor receptor |
| HUVEC | human umbilical vein endothelial cell |
| HER | human epidermal growth factor receptor |
| Lck | lymphoid cell kinase |
| ADME | adsorption, distribution, metabolism, and excretion |
| CML | chronic myeloid leukemia |
| PLK1 | polo-like kinase 1 |
| CDK | cyclin dependent kinase |
| eNOS | endothelial nitric oxide synthase |
