1591P - Translational study for mechanisms of synergy and toxicity of tivozanib in combination with capecitabine in a population-based murine tumor model

Date 28 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anti-Cancer Agents & Biologic Therapy
Complications of Treatment
Basic Science
Presenter Jie Lin
Citation Annals of Oncology (2014) 25 (suppl_4): iv546-iv563. 10.1093/annonc/mdu358
Authors J. Lin1, G. Li2, F. Jiang2, L. Shen2, J. Gyuris2
  • 1Clinical Research, AVEO Oncology, 02142 - Cambridge/US
  • 2Clinical Research, AVEO Oncology, Cambridge/US

Abstract

Aim

Clinical trials combining vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) and capecitabine have been promising but often met with increased toxicities requiring dose reductions. Tivozanib is a highly selective VEGFR TKI with demonstrated antitumor activity. Translational studies were conducted using a genetically diverse population of tumor models to understand tivozanib+capecitabine potential synergistic responses and possible toxicities.

Methods

The antitumor activity of tivozanib+capecitabine at various dose levels was assessed in multiple tumors that exhibited partial or no response to either agent alone. Tumor growth, cell proliferation, angiogenesis, and the effect of tivozanib on capecitabine conversion to 5-fluorouracil (FU) were investigated.

Results

The combination of tivozanib+capecitabine enhanced antitumor activity of capecitabine and blocked inflammatory and angiogenic reactions triggered by capecitabine monotherapy. A subset of tumors exhibited strong synergistic response to the combination treatment and complete tumor growth inhibition was achieved at capecitabine doses reduced to as low as 25% of maximum tolerated dose. RT-PCR analysis of the treated tumors revealed that tivo significantly induced the expression of thymidine phosphorylase (TP), an enzyme for cape conversion in the body. Increased TP expression in tumors was associated with elevated local 5-FU concentration, suggesting a pharmacokinetic mechanism of synergy. In addition, TP expression was induced by tivozanib treatment in both the epidermis of treated mice and in cultured human keratinocytes suggesting increased capecitabine conversion in the skin.

Conclusions

These results indicate tivozanib TP induction may be a key mechanism of synergistic response to the combination treatment and suggests clinical antitumor activity may be achieved with a reduced capecitabine dose. The elevated epidermal TP expression may provide a mechanistic explanation for increased Hand-Foot Syndrome observed in phase 1 trial patients treated with tivozanib+capecitabine (NCT01306630). Further exploration is warranted.

Disclosure

J. Lin: AVEO Oncology employee • Stock • Salary Other financial relationships • None; G. Li: AVEO Oncology employee • Stock • Salary Other financial relationships • None; F. Jiang: AVEO Oncology employee • Stock • Salary Other financial relationships • None; L. Shen: AVEO Oncology employee • Stock • Salary Other financial relationships • None; J. Gyuris: AVEO Oncology employee • Stock • Salary Other financial relationships • None.