Phase II evaluations of cilengitide in asymptomatic patients with androgen-independent prostate cancer: scientific rationale and study design.
Two randomized trials demonstrated an improvement in survival with docetaxel-based chemotherapy for patients with metastatic, androgen-independent prostate disease. However, the effect of current therapy is suboptimal in that it is complicated by toxicities and has no curative potential. Cilengitide (EMD121974; NSC 707544), is a potent selective alphavbeta3 and alphavbeta5 integrin antagonist. Integrins are cell surface receptors that mediate a variety of cell activities including endothelial cell proliferation and migration. Blocking the ligation of integrins by antagonists promotes apoptosis of proliferative angiogenic cells, thereby suspending new blood vessel formation, which is essential for the growth of malignant disease. In prostate cancer specifically, integrins are known to be involved in metastases with differential expression on tumor cells. Tumors and vascular endothelial cells produce factors, such as vascular endothelial growth factor and basic fibroblast growth factor, that promote neovascularization, which has been implicated in prostate cancer progression. Cilengitide has been shown to inhibit alphavbeta3- and alphavbeta5-mediated cell adhesion and block in vitro endothelial cell migration. In vivo experiments demonstrated that cilengitide inhibited cytokine-induced basic fibroblast growth factor- and vascular endothelial growth factor-mediated angiogenesis in a dose-dependent manner. Cilengitide also inhibited tumor growth in various in vivo systems. Two Cancer Therapy Evaluation Program-sponsored, multicenter, phase II trials are designed to evaluate the safety and efficacy of this agent in patients with androgen-independent prostate cancer. National Cancer Institute trial 6735 is evaluating cilengitide at 2000 mg in patients with nonmetastatic androgen-independent prostate cancer, and National Cancer Institute trial 6372 is evaluating 2 dose levels of cilengitide, 500 mg or 2000 mg, intravenously twice weekly in patients with metastatic prostate cancer.
Beekman
Kathleen W
KW
Genitourinary Oncology Service, Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, 48109, USA.
Colevas
A Dimitrios
AD
Cooney
Kathleen
K
Dipaola
Robert
R
Dunn
Rodney L
RL
Gross
Mitchell
M
Keller
Evan T
ET
Pienta
Kenneth J
KJ
Ryan
Charles J
CJ
Smith
David
D
Hussain
Maha
M
D000728:Androgens / Q000502:physiology; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017322:Clinical Trials, Phase II as Topic; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016032:Randomized Controlled Trials as Topic; D012107:Research Design; D012910:Snake Venoms / Q000494:pharmacology / Q000627:therapeutic use*
D000728:Androgens; D000970:Antineoplastic Agents; D016023:Integrins; D012910:Snake Venoms; C422910:Cilengitide