Faculty Collaboration Database

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 2015 Feb;33(1):215-24

Date

11/05/2014

Pubmed ID

25363205

Pubmed Central ID

PMC4477529

DOI

10.1007/s10637-014-0176-4

Scopus ID

2-s2.0-84922005567 (requires institutional sign-in at Scopus site)   9 Citations

Abstract

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.

Author List

Falchook GS, Wheler JJ, Naing A, Piha-Paul SA, Fu S, Tsimberidou AM, Hong DS, Janku F, Zinner R, Jiang Y, Huang M, Lin Q, Parkhurst K, Kurzrock R

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Aged, 80 and over
Angiogenesis Inhibitors
Antibodies, Monoclonal, Humanized
Antineoplastic Combined Chemotherapy Protocols
Bevacizumab
Class I Phosphatidylinositol 3-Kinases
Female
Humans
Male
Middle Aged
Mutation
Neoplasms
Niacinamide
PTEN Phosphohydrolase
Phenylurea Compounds
Phosphatidylinositol 3-Kinases
Polymorphism, Single Nucleotide
Proto-Oncogene Proteins
Receptors, Vascular Endothelial Growth Factor
Tumor Suppressor Protein p53
Vascular Endothelial Growth Factor A