A randomized phase II efficacy and safety study of vandetanib (ZD6474) in combination with bicalutamide versus bicalutamide alone in patients with chemotherapy naïve castration-resistant prostate cancer

• Published in: Investigational new drugs Vol. 32; no. 4; pp. 746 - 752
• Main Authors: Azad, Arun A., Beardsley, Emma K., Hotte, Sebastian J., Ellard, Susan L., Klotz, Lawrence, Chin, Joseph, Kollmannsberger, Christian, Mukherjee, Som D., Chi, Kim N.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.08.2014; Springer; Springer Nature B.V
• Subjects: Aged; Androgens; Anilides - administration & dosage; Anilides - adverse effects; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Cancer therapies; Chemotherapy; Correlation analysis; Drug dosages; Drug therapy; Epidermal growth factor; FDA approval; Gynecology. Andrology. Obstetrics; Health sciences; Humans; Inhibitor drugs; Kinases; Male; Male genital diseases; Medical sciences; Medicine; Medicine & Public Health; Metastasis; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Nephrology. Urinary tract diseases; Nitriles - administration & dosage; Nitriles - adverse effects; Oncology; Patients; Pharmaceuticals; Pharmacology. Drug treatments; Pharmacology/Toxicology; Phase II Studies; Piperidines - administration & dosage; Plasma; Prostate cancer; Prostate-Specific Antigen - metabolism; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - metabolism; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Quinazolines - administration & dosage; Scintigraphy; Statistical analysis; Testosterone; Tosyl Compounds - administration & dosage; Tosyl Compounds - adverse effects; Toxicity; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Canada; Castration-resistant prostate cancer; Vandetanib; Bicalutamide; VEGFR-2; EGFR; Antineoplastic agent; Prostate disease; Toxicity; Antihormone; Epidermal growth factor receptor; Randomization; Castration; Phase II trial; Antiangiogenic agent; Vascular endothelial growth factor receptor 2; Non steroid compound; Male genital diseases; Protein-tyrosine kinase; Human; Drug combination; Urinary system disease; Enzyme; Tyrosine kinase inhibitor; Transferases; Treatment efficiency; Enzyme inhibitor; Antiandrogen; Malignant tumor; Resistance; Chemotherapy; Treatment; Multikinase inhibitor; Prostate cancer; Comparative study; Cancer
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-014-0091-8

Summary Purpose To investigate the efficacy and safety of combining vandetanib, an orally available multi-targeted tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR), with bicalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods This was an open-label, randomized phase II multi-center study. Eligible patients had rising PSA on androgen deprivation therapy, minimal symptoms and were chemotherapy-naïve. Protocol therapy was either vandetanib 300 mg oral daily plus bicalutamide 50 mg oral daily (Arm A) or bicalutamide 50 mg oral daily alone (Arm B) with cross-over to vandetanib monotherapy at progression. The primary endpoint was PSA response (≥ 50 % decline from baseline). Results Thirty-nine patients were recruited, 19 in Arm A and 20 in Arm B. PSA response was comparable in Arm A and Arm B (18 vs. 19 %). Time to PSA progression was 3.16 months (95 % confidence interval (CI): 1.09, not reached (NR)) for Arm A and 3.09 months (95 % CI: 1.22, NR) for Arm B. Treatment discontinuation due to adverse events was more common in Arm A compared to Arm B (42 vs. 5 %; p  = 0.019). Treatment with vandetanib was associated with a reduction in soluble VEGFR-2 levels after two cycles but an increase in plasma VEGF levels. Conclusion The combination of vandetanib and bicalutamide was associated with considerable toxicity and did not have superior efficacy over bicalutamide alone. Further evaluation of this combination is not warranted in mCRPC.