Hypoxia-inducible factor-1alpha modulation in combination with anti-angiogenic therapy.

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Author(s): G. S. Falchook, J. J. Wheler, N. M. Tannir, A. Naing, E. Jackson, D. Hong, K. N. Lawhorn, C. Ng, H. Amin, R. Kurzrock; M. D. Anderson Cancer Center, Houston, TX



Background: HIF-1alpha mediates adaptive responses to hypoxic conditions induced by anti-angiogenic therapy. Bortezomib has demonstrated the ability to inhibit transcriptional activity of HIF-1alpha. 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-1alpha, 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 = 6). Minor responses or stable disease lasting ?4 months was achieved in 8 patients, including RCC (1), breast (1), leiomyosarcoma (1), nasopharyngeal (2), hepatocellular (1), neuroendocrine (1), lacrimal gland adenocystic carcinoma (1). The most common drug-related toxicities observed included hypertension (36%), fatigue (34%), thrombocytopenia (29%), and myalgia (19%). 22 patients (31%) experienced no drug-related toxicities greater than grade 1. 56 patients (79%) experienced no drug-related toxicities greater than grade 2. One DLT (G5 bleeding) was observed at the MTD. Plasma VEGF levels demonstrated decreases at 1 and 4 hours post-infusion, followed by increases to levels above baseline on days 2, 3, and at the end of cycle 1. DCE-MRI analysis demonstrated decreases in Ktrans on days 2 and 3. Analysis of HIF-1alpha expression in biopsies is underway.


Conclusions: Combination bevacizumab and bortezomib is well-tolerated and has demonstrated clinical activity in patients with previously treated, advanced malignancy. Pharmacodynamic assessment with biomarkers and DCE-MRI suggests that inhibition of angiogenic activity was achieved. Updated clinical and biomarker data will be presented.