Skip to main content
eScholarship
Open Access Publications from the University of California

UC San Diego

UC San Diego Previously Published Works bannerUC San Diego

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

  • Author(s): Falchook, Gerald S;
  • Wheler, Jennifer J;
  • Naing, Aung;
  • Jackson, Edward F;
  • Janku, Filip;
  • Hong, David;
  • Ng, Chaan S;
  • Tannir, Nizar M;
  • Lawhorn, Kristie N;
  • Huang, Mei;
  • Angelo, Laura S;
  • Vishwamitra, Deeksha;
  • Hess, Kenneth;
  • Howard, Adrienne N;
  • Parkhurst, Kristin L;
  • Amin, Hesham M;
  • Kurzrock, Razelle
  • et al.
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.

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.

Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.

Main Content
For improved accessibility of PDF content, download the file to your device.
Current View