Dataset Information

Targeting hypoxia-inducible factor-1? (HIF-1?) in combination with antiangiogenic therapy: a phase I trial of bortezomib plus bevacizumab.

ABSTRACT:

Purpose

We hypothesized that bortezomib, an agent that suppresses HIF-1? transcriptional activity, when combined with bevacizumab, would obviate the HIF-1? 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-1? 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.

SUBMITTER: Falchook GS

PROVIDER: S-EPMC4279372 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Targeting hypoxia-inducible factor-1α (HIF-1α) in combination with antiangiogenic therapy: a phase I trial of bortezomib plus bevacizumab.

Falchook Gerald S GS Wheler Jennifer J JJ Naing Aung A Jackson Edward F EF Janku Filip F Hong David D Ng Chaan S CS Tannir Nizar M NM Lawhorn Kristie N KN Huang Mei M Angelo Laura S LS Vishwamitra Deeksha D Hess Kenneth K Howard Adrienne N AN Parkhurst Kristin L KL Amin Hesham M HM Kurzrock Razelle R

Oncotarget 20141101 21

<h4>Purpose</h4>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.<h4>Experimental design</h4>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 ...[more]

PMID: 25373733

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Project description:IntroductionSystemic sclerosis is an autoimmune disease characterized by tissue fibrosis and microangiopathy. Vascular changes such as a decrease in capillary density diminish blood flow and impair tissue oxygenation. Reliable ways to monitor disease activity and predict disease progression are desired in the process of patient selection for clinical trials and to optimize individual patient outcomes. Hypoxia-inducible factor-1 (HIF-1) is a dimeric protein complex that plays an integral role in the body's response to hypoxia. Our study aimed to investigate the potential abnormalities of HIF-1α plasma concentration and its possible association with disease activity and vascular abnormalities in patients with systemic sclerosis.MethodsBlood plasma levels of HIF-1α were measured in patients with systemic sclerosis (n = 50) and in healthy individuals (n = 30) using commercially available ELISA test kits.ResultsThe results showed a marked increase in HIF-1α levels in patients with systemic sclerosis (3.042 ng/ml [2.295-7.749]) compared to the control group (1.969 ng/ml [1.531-2.903] p < 0.01). Patients with diffuse cutaneous SSc (2.803 ng/ml, IQR 2.221-8.799) and limited cutaneous SSc (3.231 ng/ml, IQR 2.566-5.502) exhibited elevated serum HIF-1α levels compared to the control group (p < 0.01). We found a notable increase in HIF-1α plasma concentration in patients with an "active" pattern (6.625 ng/ml, IQR 2.488-11.480) compared to those with either an "early" pattern (2.739, IQR 2.165-3.282, p < 0.05) or a "late" pattern (2.983 ng/ml, IQR 2.229-3.386, p < 0.05). Patients with no history of digital ulcers had significantly higher levels of HIF-1α (4.367 ng/ml, IQR 2.488-9.462) compared to patients with either active digital ulcers (2.832 ng/ml, IQR 2.630-3.094, p < 0.05) or healed digital ulcers (2.668 ng/ml, IQR 2.074-2.983, p < 0.05).ConclusionsOur results indicate that HIF-1α may serve as a biomarker in assessing microcirculatory changes in individuals with systemic sclerosis.