Targeting hypoxia-inducible factor-1α (HIF-1α) in combination with antiangiogenic therapy: a phase I trial of bortezomib plus bevacizumab.
Oncotarget
; 5(21): 10280-92, 2014 Nov 15.
Article
em En
| MEDLINE
| ID: mdl-25373733
ABSTRACT
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. EXPERIMENTALDESIGN:
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Pirazinas
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Ácidos Borônicos
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Neoplasias da Mama
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Carcinoma de Células Renais
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Protocolos de Quimioterapia Combinada Antineoplásica
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Subunidade alfa do Fator 1 Induzível por Hipóxia
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Anticorpos Monoclonais Humanizados
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Neoplasias Renais
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Neovascularização Patológica
Tipo de estudo:
Clinical_trials
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Etiology_studies
Limite:
Adult
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Aged
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Oncotarget
Ano de publicação:
2014
Tipo de documento:
Article