Tivozanib: Status of Development

Abstract

Tivozanib is a potent and highly specific orally available, tyrosine kinase inhibitor that targets vascular endothelial growth factor (VEGF) receptor-1, VEGF receptor-2, and VEGF receptor-3 at very low concentrations with a long half-life (4 days). After its promising activity in xenograft and preclinical models, tivozanib was evaluated in early phase clinical trials in various solid tumors. The phase III trial (TIVO-1) compared tivozanib with sorafenib in metastatic clear cell renal cell carcinoma (RCC). Because of detrimental overall survival (OS), Oncology Drug Advisory Committee (ODAC) voted against its approval in RCC. Tivozanib is also being evaluated in various other solid tumors like breast, gastrointestinal cancers, hepatocellular cancer, sarcomas, and gynecological cancer. In BATON-CRC trial, low-serum neuropilin-1 (NRP-1) levels were associated with better progression-free survival (PFS) in patients treated with tivozanib. The NRP-1 will be evaluated as a biomarker for tivozanib response in future clinical trials. Ongoing clinical trial will further characterize activity of tivozanib in hepatocellular carcinoma, sarcomas, and gynecologic cancers.

Tivozanib mediated inhibition of c-Kit/SCF signaling on Tregs and MDSCs and reversal of tumor induced immune suppression correlates with survival of HCC patients

“…9,10 Additionally, antitumor efficacy of tivozanib has been evaluated in solid tumors such as gastrointestinal cancers and breast cancer. 8,10 Safety and tolerability profiles of tivozanib have been shown to be acceptable when used in combination therapy. 11 c-Kit signaling promotes cell proliferation and survival and this pathway has been shown to be aberrantly activated in cancer.…”

“… 9 Tivozanib specific progression-free survival in metastatic colorectal patients was associated with low-serum neuropilin-1 (NRP-1) levels and NRP-1 seemed to be a biomarker of tivozanib response in clinical trials. 9 , 10 Additionally, antitumor efficacy of tivozanib has been evaluated in solid tumors such as gastrointestinal cancers and breast cancer. 8 , 10 Safety and tolerability profiles of tivozanib have been shown to be acceptable when used in combination therapy.…”

“… 9 , 10 Additionally, antitumor efficacy of tivozanib has been evaluated in solid tumors such as gastrointestinal cancers and breast cancer. 8 , 10 Safety and tolerability profiles of tivozanib have been shown to be acceptable when used in combination therapy. 11 …”

Design, Synthesis and Structure-Activity Relationships of Novel Diaryl Urea Derivatives as Potential EGFR Inhibitors

“…It is reported that the lipophilic diaryl urea moiety served as a key structural fragment for binding with the hydrophobic pocket of the kinase domain through hydrogen bonds and hydrophobic interactions [5]. Subsequently, diverse diaryl urea derivatives were developed successively in the past decades, such as linifanib [6], tivozanib [7], and ki8751 [8] (Figure 1). Therein, thieno[3,2- d ]pyrimidine derivative S1 bearing diaryl urea moieties at the C-2 positon exhibited significant inhibition of tyrosine kinases, including c-Kit, orphan receptor tyrosine kinase (RET), and FLT3 for its prominent framework [9].…”

Light-assisted small-molecule screening against protein kinases

“…Two of these molecules (crizotinib and GSK-1120212) are known kinase inhibitors of hROS1 and pathway components. The third molecule (AV-951 12 ) was active specifically against hROS1 but not mFGFR1 or hEGFR ( Supplementary Fig. 10).…”