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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.

OBJECTIVE To investigate, in a phase II trial, the use of the epidermal growth factor receptor (EGFR) inhibitor gefitinib as monotherapy in patients with non-metastatic hormone refractory prostate cancer (HRPC), as current treatment options for this disease are limited, and agents which target the EGFR should be assessed because EGFR is highly expressed in prostate cancer and associated with a poor prognosis. PATIENTS AND METHODS Patients with histologically or cytologically confirmed cancer of the prostate with no evidence of metastatic disease were enrolled into this open-label, multicentre study of monotherapy with gefitinib 500 mg/day. The primary endpoint of the study was biochemical response, defined as a ≥50% decrease in serum prostate-specific antigen (PSA) level. RESULTS Fifty-eight men were enrolled across 10 centres in the USA; none of the 40 evaluable patients had a PSA response. Gefitinib was generally well tolerated, with diarrhoea being the most common treatment- related adverse event, in 71% of patients. There was treatment-related grade 3 diarrhoea in 5% of patients, with no grade 4 adverse events or deaths during the course of the study. CONCLUSIONS Gefitinib has no single-agent activity in non-metastatic HRPC, as assessed by decreases in serum PSA level. This phase II study also confirmed the well-established favourable tolerability profile of gefitinib monotherapy.

3520 Background: Agents that specifically inhibit the invasive phenotype of cancers are urgently required. AZD0530 is a potent, orally administered inhibitor of Src that has been shown preclinically to prevent phosphorylation of downstream mediators of motility and invasion, paxillin (Pax) and focal adhesion kinase (FAK), with inhibition of metastasis in vivo. Although Src activation is associated with poor prognosis, inhibition of Src activity in human cancers has never been demonstrated. Methods: Patients with cancer received AZD0530 in dose cohorts of 50 mg to 250 mg daily in this 2-part Phase I study. Paired tumor biopsies were acquired for investigation of Src inhibition. Part A defined MTD, toxicity profile and PK. Part B expanded the 50 mg, 125 mg and 175 mg cohorts to characterize changes in phosphorylation of the Src substrates Pax and FAK by evaluating intensity and localization of staining by IHC. Biopsy samples were assigned as pre- or post-AZD0530 treatment by an independent pathology panel blinded to treatment status, and tested for 80% concordance at a 10% alpha. Markers of bone turnover were collected. Results: There were 81 patients evaluable for safety assessment. The median number of prior therapies was 5 (1–27). Part A: DLTs occurred in 3 patients at 250 mg (leukopenia; septic shock (grd5) with renal failure; asthenia) and in 2 patients at 200 mg (febrile neutropenia; dyspnea). Part B confirmed the 50, 125 and 175 mg doses to be tolerable. The mean duration of AZD0530 treatment was 44 days (6–217); 11 patients were treated for longer than 3 months. The pathology panel found consistent modulation of phosphorylation and/or cellular localization of tumor Pax (P=0.067) and FAK (P=0.002) consequent to AZD0530 therapy. There was a dose response trend for reductions in Pax phosphorylation. Bone biomarker and PK data will be presented. Conclusion: For the first time, biomarkers have confirmed inhibition of Src in human cancers. AZD0530 is well tolerated at doses that demonstrate significant inhibition of Src activity. The trend for dose response changes in biomarkers of Src inhibition indicates that the MTD should be taken forward in further development. AZD0530 has a potential role in the prevention of metastases and invasion. No significant financial relationships to disclose.

Two large, randomized, placebo-controlled trials (IRESSA NSCLC Trial Assessing Combination Therapy; INTACT 1 and 2) in non-small-cell lung cancer (NSCLC) failed to show survival benefit for gefitinib (IRESSA) in combination with first-line platinum-based chemotherapy. Epidermal growth factor receptor (EGFR) staining was assessed retrospectively in relation to survival response to gefitinib in combination with chemotherapy.Tumor biopsies obtained prior to start of therapy were assessed by immunohistochemistry for EGFR using the Dako EGFR pharmDx assay (Dako, Denmark). Analyses were stratified by trial and performed independently for patients randomized to placebo and gefitinib as well as for both treatment groups combined. A restricted backwards elimination Cox regression analysis was conducted to identify independent EGFR factors that were statistically significant (P0.10), and these were also tested for treatment interaction to assess if they served as predictive factors.Analyses found two statistically significant EGFR-based prognostic factors representing growth pattern and percent membrane staining in patients treated with gefitinib (P = 0.0023), placebo (P = 0.0128), and both combined (P0.0001). The prognostic effect was independent of other known prognostic factors. There was no predictive effect of either the growth pattern or membrane staining variable.While some previous studies indicate that higher EGFR expression correlates with poor survival, our analyses provide statistically significant evidence that the combination of EGFR expression and growth pattern is a strong prognostic indicator for improved survival within this setting. The effects of membrane staining and growth pattern are still significant when adjusting for mutation.