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Dual antiangiogenic inhibition: a phase I dose escalation and expansion trial targeting VEGF-A and VEGFR in patients with advanced solid tumors

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Summary

Purpose Angiogenesis plays a pivotal role in tumor growth and metastasis. Sorafenib, a tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR), combined with bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF-A), would vertically inhibit VEGF/VEGFR signaling. A phase I trial was performed to assess safety, maximum tolerated dose (MTD), and clinical correlates. Experimental design Patients with advanced solid tumors refractory to standard therapy were eligible. In cohorts of escalating doses, patients received sorafenib daily for 28 days and bevacizumab every two weeks. Clinical correlates included VEGF polymorphisms. Expansion cohorts of responding tumor types were enrolled. Results One hundred fifteen patients were treated, and the MTD was identified as 200 mg twice daily sorafenib and 5 mg/kg bevacizumab every two weeks. Median number of prior therapies was four. Twenty-nine patients (25 %) achieved stable disease ≥6 months; six patients (5 %) achieved a partial response (total SD ≥ 6 months/PR=35 (30 %)). 76 patients (66 %) experienced adverse events of grade 2 or higher, most commonly hand and foot syndrome (n = 27, 24 %) and hypertension (n = 24, 21 %). Dose-limiting toxicity occurred in eight patients (7 %), and 45 patients (39 %) required dose reduction for toxicity. Grade 3 and 4 hypertension was associated with longer time to treatment failure, overall survival, and higher response rate. Conclusions Combination sorafenib and bevacizumab was well-tolerated and demonstrated antitumor activity in heavily pretreated patients with advanced solid tumors.

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Acknowledgments

We would like to thank the patients and their families for their participation in this clinical trial. We would also like to thank Goran Cabrilo for assistance with lab sample collection. This work was supported by the Paul Calabresi Career Development Award for Clinical Oncology K12 CA088084.

Ethical standards

The experiments performed in this study comply with the current laws of the country in which they were performed.

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The authors declare that they have no conflict of interest.

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Paul Calabresi Career Development Award for Clinical Oncology K12 CA088084

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Correspondence to Gerald S. Falchook.

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Falchook, G.S., Wheler, J.J., Naing, A. et al. Dual antiangiogenic inhibition: a phase I dose escalation and expansion trial targeting VEGF-A and VEGFR in patients with advanced solid tumors. Invest New Drugs 33, 215–224 (2015). https://doi.org/10.1007/s10637-014-0176-4

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