Targeting hypoxia-inducible factor-1α (HIF-1α) in combination with antiangiogenic therapy: a phase I trial of bortezomib plus bevacizumab. Oncotarget 2014 Nov 15;5(21):10280-92
Date
11/07/2014Pubmed ID
25373733Pubmed Central ID
PMC4279372DOI
10.18632/oncotarget.2163Scopus ID
2-s2.0-84916912453 (requires institutional sign-in at Scopus site) 49 CitationsAbstract
PURPOSE: We hypothesized that bortezomib, an agent that suppresses HIF-1α transcriptional activity, when combined with bevacizumab, would obviate the HIF-1α resistance pathway. The objectives of this phase I trial were to assess safety and biological activity of this combination.
EXPERIMENTAL DESIGN: Patients with advanced, refractory malignancies were eligible. Patients received bevacizumab and bortezomib (3-week cycle) with dose expansions permitted if responses were seen and for assessing correlates. Pharmacodynamic assessment included plasma VEGF, VEGFR2, 20S proteasome inhibition, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and HIF-1α tumor expression.
RESULTS: Ninety-one patients were treated (median=6 prior treatments). The FDA-approved doses of both drugs were safely reached, and the recommended phase 2 dose (RP2D) is bevacizumab 15 mg/kg with bortezomib 1.3 mg/m(2). Four patients attained partial response (PR) and seven patients achieved stable disease (SD) ≥ 6 months (Total SD ≥ 6 months/PR=11 (12%)). The most common drug-related toxicities included thrombocytopenia (23%) and fatigue (19%). DCE-MRI analysis demonstrated no dose-dependent decreases in K(trans) although analysis was limited by small sample size (N=12).
CONCLUSION: Combination bevacizumab and bortezomib is well-tolerated and has demonstrated clinical activity in patients with previously treated advanced malignancy. Pharmacodynamic assessment suggests that inhibition of angiogenic activity was achieved.
Author List
Falchook GS, Wheler JJ, Naing A, Jackson EF, Janku F, Hong D, Ng CS, Tannir NM, Lawhorn KN, Huang M, Angelo LS, Vishwamitra D, Hess K, Howard AN, Parkhurst KL, Amin HM, Kurzrock RAuthor
Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdultAged
Antibodies, Monoclonal, Humanized
Antineoplastic Combined Chemotherapy Protocols
Bevacizumab
Boronic Acids
Bortezomib
Breast Neoplasms
Carcinoma, Renal Cell
Fatigue
Female
Humans
Hypoxia-Inducible Factor 1, alpha Subunit
Kidney Neoplasms
Magnetic Resonance Imaging
Male
Middle Aged
Neoplasm Staging
Neovascularization, Pathologic
Proteasome Endopeptidase Complex
Pyrazines
Thrombocytopenia
Treatment Outcome
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factor Receptor-2
