Tivozanib (AV-951)

Tivozanib is an inhibitor of tyrosine kinase with IC50 value of 160 pmol/L against VEGFR-2 [1].

Tivozanib is a quinoline-urea derivative. As a 2nd generation TKI, it has picomolar potency against VEGFR-1, -2 and -3, and minimal c-kit inhibition. Among this, Tivozanib has demonstrated a VEGFR-2 potency 2 orders of magnitude greater than sunitinib, sorafenib or pazopanib and a lower relative extent of off-target inhibition [1]. Tivozanib also shows to inhibit phosphorylation of the kinases PDGFRß and C-KIT at nanomolar level in cellular assays [2].

Tivozanib has shown antitumor activity in RCC xenograft models in addition to several other solid tumor models leading to its evaluation in clinical testing. The safety and efficacy of Tivozanib has been evaluated in several Phase I and Phase II trials. To compare the front-line use of tivozanib to sorafenib, a pivotal randomized Phase III trial has also been reported [3].

References:
[1] M.N. Fishman, S. Srinivas, R.J. Hauke, R.J. Amato, B. Esteves, M.M. Cotreau, A.L. Strahs, W.J. Slichenmyer, P. Bhargava, F.F. Kabbinavar. Phase Ib study of tivozanib (AV-951) in combination with temsirolimus in patients with renal cell carcinoma. European Journal of Cancer. 2013(49):2841-2850.
[2] Viktor Grunwald, Axel Stuart Merseburger. The progression free survival-plateau with vascular endothelial growth factor receptor inhibitors – Is there more to come? European Journal of Cancer. 2013(49):2504-2511.
[3] C Lance Cowey. Profile of tivozanib and its potential for the treatment of advanced renal cell carcinoma. Drug Design, Development and Therapy. 2013 (7): 519-527.

Phase Ib study of tivozanib (AV-951) in combination with temsirolimus in patients with renal cell carcinoma.[Pubmed:23726267]

Eur J Cancer. 2013 Sep;49(13):2841-50.

BACKGROUND: Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2 and -3, with a long half-life. Tivozanib has demonstrated clinical activity and acceptable tolerability in renal cell carcinoma (RCC). This phase Ib study determined the recommended phase II dose (RP2D) and evaluated the safety and clinical activity of tivozanib plus temsirolimus, a mammalian target of rapamycin inhibitor. PATIENTS AND METHODS: Patients with advanced RCC were administered open-label tivozanib 0.5, 1.0 or 1.5mg/d orally (3 weeks on/1 week off) and temsirolimus 15 or 25 mg/week intravenously in a 3+3 dose-escalation design and subsequent expansion cohort. RESULTS: Of 27 patients treated, 20 patients had received >/= 1 prior VEGF-targeted therapy. No dose-limiting toxicities occurred; the RP2D was determined to be tivozanib 1.5mg/d plus temsirolimus 25mg/week. Combination of tivozanib plus temsirolimus demonstrated acceptable tolerability and suggested no synergistic toxicity. The most common grade

Multicenter phase II study of tivozanib (AV-951) and everolimus (RAD001) for patients with refractory, metastatic colorectal cancer.[Pubmed:23580238]

Oncologist. 2013;18(4):377-8.

BACKGROUND: Treatments that target the vascular endothelial growth factor (VEGF) pathway have efficacy in colorectal cancer. We evaluated tolerability and efficacy of tivozanib (an oral VEGF receptor-1, -2, -3 inhibitor) plus everolimus (an oral mammalian target of rapamycin inhibitor). METHODS: The phase Ib study followed a 3 + 3 dose-escalation design with three dose levels. The primary objective in the follow-on phase II study was improvement in 2-month progression-free survival (PFS) from 30% (historical benchmark) to 50% in patients with refractory, metastatic colorectal cancer. RESULTS: Dose-limiting toxicities in the phase Ib study were grade 3 fatigue and dehydration. Oral tivozanib (1 mg daily for 3 of 4 weeks) and oral everolimus (10 mg daily continuously) were advanced to a 40-patient phase II study. The most common grade 3-4 adverse events were thrombocytopenia and hypophosphatemia. The 2-month PFS rate was 50%, with 20 of 40 patients having stable disease (SD). Seven (18%) patients were treated for >/=6 months. Median PFS and overall survival (OS) times were 3.0 months (95% confidence interval [CI]: 1.9-3.6 months) and 5.6 months (95% CI: 4.4-10.6 months), respectively. Patients who developed grade 1+ hypertension had increased SD rates (65.2% vs. 29.4%) and longer OS times (10.6 vs. 3.7 months). CONCLUSIONS: The oral combination of tivozanib and everolimus was well tolerated, with stable disease achieved in 50% of patients with refractory, metastatic colorectal cancer.

Tivozanib (AV-951; KRN951) is a highly potent and selective VEGFR 1/2/3 inhibitor with IC50s of 0.21, 0.16, and 0.24 nM in cell assay, respectively.

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