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

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.

• Authors: Gerald S Falchook, Jennifer J Wheler, Aung Naing, Edward F Jackson, Filip Janku, David Hong, Chaan S Ng, Nizar M Tannir, Kristie N Lawhorn, Mei Huang, Laura S Angelo, Deeksha Vishwamitra, Kenneth Hess, Adrienne N Howard, Kristin L Parkhurst, Hesham M Amin, Razelle Kurzrock
• Journal: Oncotarget (Oncotarget) Vol. 5 Issue 21 Pg. 10280-92 (Nov 15 2014) ISSN: 1949-2553 [Electronic] United States
• PMID: 25373733 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Humanized
• Boronic Acids
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Pyrazines
• Vascular Endothelial Growth Factor A
• Bevacizumab
• Bortezomib
• KDR protein, human
• Vascular Endothelial Growth Factor Receptor-2
• Proteasome Endopeptidase Complex

Topics

• Adult
• Aged
• Antibodies, Monoclonal, Humanized (administration & dosage, adverse effects)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Bevacizumab
• Boronic Acids (administration & dosage, adverse effects)
• Bortezomib
• Breast Neoplasms (drug therapy)
• Carcinoma, Renal Cell (drug therapy)
• Fatigue (etiology)
• Female
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors, genetics, metabolism)
• Kidney Neoplasms (drug therapy)
• Magnetic Resonance Imaging
• Male
• Middle Aged
• Neoplasm Staging
• Neovascularization, Pathologic (drug therapy)
• Proteasome Endopeptidase Complex (drug effects)
• Pyrazines (administration & dosage, adverse effects)
• Thrombocytopenia (etiology)
• Treatment Outcome
• Vascular Endothelial Growth Factor A (immunology, metabolism)
• Vascular Endothelial Growth Factor Receptor-2 (metabolism)