Saracatinib (
AZD0530) is an orally active once-daily
Src kinase inhibitor which modulates key signaling pathways in
cancer cells. In a Phase I study in patients with advanced solid
malignancies resistant to standard treatment we assessed the effect of
saracatinib on bone turnover. Fifty-one patients were randomized into three parallel groups to receive
saracatinib 50, 125 or 175 mg/day. After a single dose followed by a 7-day washout, patients received once-daily doses for 21 days. Bone turnover markers were measured in serum and urine samples collected before dosing on days 1, 2, 3, 17 and 28. Samples were available at baseline and more than one other time point for 44 patients.
Bone resorption markers were significantly decreased by
saracatinib. Serum cross-linked
C-terminal telopeptide of type I collagen (sCTX) changed in the 50, 125 and 175 mg/day groups by -36% (95% CI -58, -4), -64% (95% CI -75, -48) and -75% (95% CI -83, -61), respectively, at day 28. Urinary cross-linked N-terminal telopeptide of
type I collagen/
creatinine ratio (uNTX/Cr) changed in the 50, 125 and 175 mg/day groups by; -13% (95% CI -33, 13), -48% (95% CI -59, -34) and -50% (95% CI -62, -35), respectively, at day 28. The significant decreases in
bone resorption markers indicate that suppression of
Src kinase inhibits osteoclast activity in patients with advanced
cancer. This result suggests that
saracatinib may have therapeutic benefit in metastatic
bone disease.