Journal
ONCOTARGET
Volume 5, Issue 21, Pages 10280-10292Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.2163
Keywords
bevacizumab; bortezomib; phase 1; proteasome; HIF-1 alpha
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Funding
- Paul Calabresi Career Development Award for Clinical Oncology K12 [CA088084]
- American Society of Clinical Oncology Young Investigator Award
- MD Anderson Cancer Center [P30 CA016672]
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Purpose: We hypothesized that bortezomib, an agent that suppresses HIF-1 alpha transcriptional activity, when combined with bevacizumab, would obviate the HIF-1 alpha 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-1a 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.
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