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


METHODS
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).


CONCLUSIONS
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.
Sarah Cannon Research Institute, Denver, CO 80218.
Gerald S
GS
Falchook
Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
Jennifer J
JJ
Wheler
Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
Aung
A
Naing
Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705.
Edward F
EF
Jackson
Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
Filip
F
Janku
Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
David
D
Hong
Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
Chaan S
CS
Ng
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
Nizar M
NM
Tannir
Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
Kristie N
KN
Lawhorn
Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
Mei
M
Huang
Department of Immunology, Allergy, and Rheumatology, The Center for Human Immunobiology, Texas Children's Hospital/Baylor College of Medicine, Houston, TX 77030.
Laura S
LS
Angelo
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
Deeksha
D
Vishwamitra
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
Kenneth
K
Hess
Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
Adrienne N
AN
Howard
Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
Kristin L
KL
Parkhurst
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
Hesham M
HM
Amin
Center for Personalized Cancer Therapy, Moores Cancer Center, University of California, San Diego, San Diego, CA 92093.
Razelle
R
Kurzrock
D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D001897:Boronic Acids / Q000008:administration & dosage* / Q000009:adverse effects; D000069286:Bortezomib; D001943:Breast Neoplasms / Q000188:drug therapy*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D005221:Fatigue / Q000209:etiology; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D011719:Pyrazines / Q000008:administration & dosage* / Q000009:adverse effects; D013921:Thrombocytopenia / Q000209:etiology; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D061067:Antibodies, Monoclonal, Humanized; D001897:Boronic Acids; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011719:Pyrazines; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D000069286:Bortezomib; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D046988:Proteasome Endopeptidase Complex