Hypoxia-inducible factor-1α (HIF-1α) modulation in combination with anti-angiogenic therapy

3555 Background: HIF-1α mediates adaptive responses to hypoxic conditions induced by anti-angiogenic therapy. Bortezomib has demonstrated the ability to inhibit transcriptional activity of HIF-1α. We hypothesized that the addition of bortezomib to bevacizumab would augment response, and we performed this phase I trial to assess safety, MTD, and correlative studies of anti-angiogenic activity. Methods: Patients with advanced malignancy refractory to standard therapy were eligible. Cohorts of 6 patients received bevacizumab and bortezomib on a 3-week cycle, with a stair-step dose escalation design. Pharmacodynamic assessment included plasma VEGF, VEGFR2, 20S proteasome inhibition, DCE-MRI, and tumor expression of HIF-1α, VEGF, VEGFR2, and polymorphisms of VEGF and VEGFR2. Results: 71 patients were treated, and the MTD was identified at the highest dose level (bevacizumab 15 mg/kg, bortezomib 1.3 mg/m2). Two partial responses were observed in patients with renal cell carcinoma (RCC) (Total patients with RCC ...