FDA accepts AVEO-Astellas tivozanib NDA filing for renal cell carcinoma, 29 nov 2012

Physical properties



 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.

  1. A Study of Tivozanib (AV-951), an Oral VEGF Receptor Tyrosine Kinase Inhibitor, in the Treatment of Renal Cell Carcinoma, clinicaltrials.gov
  2. Campas, C., Bolos, J., Castaner, R (2009). “Tivozanib”Drugs Fut 34 (10): 793.
  3. Aveo Kidney Cancer Drug Shows Success; Shares Up, By John Kell, Dow Jones Newswires
  4. “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 VEGFR1VEGFR2 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
475108-18-0, 682745-41-1 (ClH.H2O), 682745-43-3 (HCL)
Solubility (25°C) DMSO 45 mg/mL 
Water <1 mg/mL 
Ethanol <1 mg/mL 
Session Type and Session Title:

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.




Bayer/Onyx drug Nexavar (sorafenib)  compare


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


Abstract Image

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 synthasePhysical properties
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