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

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/m². 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.