Evaluation of the safety, pharmacokinetics and treatment effects of an alpha(nu)beta(3) integrin inhibitor on bone turnover and disease activity in men with hormone-refractory prostate cancer and bone metastases.
OBJECTIVE
This study aimed to evaluate the safety, pharmacokinetics and treatment effects of an alpha(nu)beta(3) integrin inhibitor on bone turnover and disease activity in men with hormone-refractory prostate cancer (HRPC) and bone metastases.


METHODS
A total of 21 patients with bone metastases and HRPC were randomized to receive MK-0429 200 mg b.i.d. or 1600 mg b.i.d. for 4 weeks. Toxicity, pharmacokinetics and markers of bone turnover and tumor activity were examined.


RESULTS
Nausea was the most common adverse event: one (200-mg group) and 11 (1600-mg group) patients. At 4 weeks, mean AUC(0-12 h) was 210 mmol*h (200-mg group) and 673 mmol*h (1600-mg group); mean C(max) values were 42 mmol/L (200-mg group) and 154 mmol/L (1600-mg group). Urinary cross-linked N-telopeptides of type I collagen to creatinine ratio (uNTx), a bone turnover biomarker, showed a change from baseline of -43.4 percent (200-mg group) and -34.1 percent (1600-mg group). There was an increase in serum prostate specific antigen (PSA), a marker for disease activity, of 54.1 percent (200-mg group) and 44.5 percent (1600-mg group).


CONCLUSIONS
MK-0429 was generally well tolerated, with the most common side-effect being nausea. There was some evidence of an early reduction of bone turnover, indicating a potential for clinical use in the treatment of MBD although serum PSA was unexpectedly increased during the study.
Rosenthal
Mark A
MA
Royal Melbourne Hospital, Melbourne, Australia. mark.rosenthal@mh.org.au
Davidson
Peter
P
Rolland
Frederic
F
Campone
Mario
M
Xue
Lingling
L
Han
Tae H
TH
Mehta
Anish
A
Berd
Yuliya
Y
He
Weili
W
Lombardi
Antonio
A
D000368:Aged; D050071:Bone Density Conservation Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001859:Bone Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000556:secondary; D001842:Bone and Bones / Q000187:drug effects*; D004311:Double-Blind Method; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
D050071:Bone Density Conservation Agents; D016023:Integrins; D017430:Prostate-Specific Antigen