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

// Gerald S Falchook 1 , Jennifer J Wheler 2 , Aung Naing 2 , Edward F Jackson 3 , Filip Janku 2 , David Hong 2 , Chaan S Ng 4 , Nizar M Tannir 5 , Kristie N Lawhorn 6 , Mei Huang 2 , Laura S Angelo 7 , Deeksha Vishwamitra 8 , Kenneth Hess 9 , Adrienne N Howard 2 , Kristin L Parkhurst 2 , Hesham M Amin 8 , Razelle Kurzrock 10 1 Sarah Cannon Research Institute, Denver, CO 80218 2 Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, Houston, TX 77030 3 Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705 4 Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 5 Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 6 Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 7 Department of Immunology, Allergy, and Rheumatology, The Center for Human Immunobiology, Texas Children's Hospital/Baylor College of Medicine, Houston, TX 77030 8 Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 9 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 10 Center for Personalized Cancer Therapy, Moores Cancer Center, University of California, San Diego, San Diego, CA 92093 Correspondence to: Gerald Falchook, e-mail: gerald.falchook@scresearch.net Keywords: bevacizumab, bortezomib, phase 1, proteasome, HIF-1α Received: April 29, 2014      Accepted: June 23, 2014      Published: November 08, 2014 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/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.