The objectives of this phase I study were to determine the safety, pharmacokinetics (PK), pharmacodynamics and efficacy of brivanib combined with full-dose cetuximab in patients with advanced gastrointestinal malignancies. Patients with advanced gastrointestinal malignancies who had failed prior therapies received brivanib (320, 600 or 800 mg daily) plus cetuximab (400 mg m–2 loading dose then 250 mg m–2 weekly). Assessments included adverse events, PK, tumour response, 2[18F]fluoro-2-deoxyglucose positron-emitting tomography and K-Ras mutation analyses. Toxicities observed were manageable; the most common treatment-related toxicities (>10% of patients) were fatigue, diarrhoea, anorexia, increase in aspartate aminotransferase and alanine aminotransferase, acneiform dermatitis, headache, mucosal inflammation, nausea, dry skin, vomiting, hypertension, pruritus, proteinuria and weight loss. Of 62 patients, 6 (9.7%) had objective radiographic partial responses, with an overall response rate of 10%. Median duration of response was 9.2 months; median progression-free survival was 3.9 months. The acceptable toxicity profile and efficacy of brivanib observed in this study were promising. These findings are being further evaluated in a phase III study of brivanib plus cetuximab vs cetuximab alone in patients previously treated with combination chemotherapy for K-Ras wild-type advanced metastatic colorectal cancer.

BACKGROUND This study was designed to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of brivanib in patients with advanced/metastatic solid tumors. PATIENTS AND METHODS Ninety patients enrolled in this two-part, phase I open-label study of oral brivanib alaninate. The primary objectives of this study were (in part A) dose-limiting toxicity, maximum tolerated dose (MTD) and the lowest biologically active dose level and (in part B) the optimal dose/dose range. The secondary objectives of this study were preliminary evidence of antitumor activity, PK and PD. RESULTS Across part A (open-label dose escalation and MTD) and part B (open-label dose optimization), 68 patients received brivanib alaninate. Brivanib demonstrated a manageable toxicity profile at doses of 180-800 mg. Most toxic effects were mild. Systemic exposure of the active moiety brivanib increased linearly ≤1000 mg/day. The MTD was 800 mg/day. Forty-four patients were treated at the MTD: 20 with 800 mg continuously, 11 with 800 mg intermittently and 13 with 400 mg b.i.d. doses. Partial responses were confirmed in two patients receiving brivanib ≥600 mg. Dynamic contrast-enhanced magnetic resonance imaging demonstrated statistically significant decreases in parameters reflecting tumor vascularity and permeability after multiple doses in the 800-mg continuous q.d. and 400-mg b.i.d. dose cohorts. CONCLUSION In patients with advanced/metastatic cancer, brivanib demonstrates promising antiangiogenic and antitumor activity and manageable toxicity at doses ≤800 mg orally q.d., the recommended phase II study dose.

3506 Background: Many tumors express the FGFR ligand FGF2, and increased levels of FGF are correlated with poor prognosis in pts with RCC, HCC, NSCLC, esophageal, and pancreatic cancer. Brivanib is an oral prodrug of BMS-540215, a dual tyrosine kinase inhibitor of VEGFR and FGFR signaling. Brivanib inhibits FGF-stimulated and FGF-dependent cell lines. Methods: An open-label Phase I dose- escalation study of brivanib was conducted in pts with cancer who failed prior therapy (ASCO #3559, 2007). Tumor response (modified WHO) was evaluated q 8 weeks. Immunohistochemistry was used to assess expression of FGF2 in archival tumor tissue. Pts were scored positive if ≥10% of tumor cells had weak staining and negative if <10% of tumor cells had positive staining. Plasma samples were collected pretreatment (x2) and on select days during treatment. Plasma PD markers collagen IV (COL IV) and sVEGFR2 were measured using ELISA. Results: 43 evaluable pts with available archival tumor tissue were analyzed for correlations between FGF2 status (+ or -) and treatment dose with tumor response, PFS, and changes in PD plasma markers. 19 pts were FGF2- and 24 pts were FGF2+. Low (<600 mg) and high (≥600 mg) doses of brivanib were given to 17 and 26 pts, respectively. All groups of pts except high-dose FGF2+ pts had an increased average change in mean tumor size. Median PFS was longer in FGF2+ pts than FGF2- pts (Table). A greater decline from baseline in COL IV was measured in FGF2+ pts than FGF2- pts. Differences in tumor responses, PR, and SD ≥8 wks for FGF2+ and FGF2- pts are shown in the table. Conclusions: Whereas FGF overexpression is typically correlated with poor prognosis, FGF2+ tumor expression is associated with a trend for improved tumor response, PFS, and changes in plasma PD markers following treatment with brivanib compared with pts whose tumors do not express FGF2. Mean change in tumor size (%) (∼8 wks) Median PFS (days) COL IV change from baseline (%) (Day 26) (n = 42) sVEGFR2 change from baseline (%) (Day 26) (n = 39) PR SD ≥8 wks PD Low (<600 mg) (n = 17) High (≥600 mg) (n = 26) Low (<600 mg) (n = 17) High (≥600 mg) (n = 26) FGF2- (n = 19) 71 24 54 56 -16 -15 0 5 14 FGF2+ (n = 24) 28 0.9 71 107 -30 -23 2 13 9 P value 0.03* 0.075† 0.029* 0.138* * Wilcoxon rank-sum test (combined low and high dose assessing FGF2- vs FGF2+). † Log-rank test (combined low and high dose assessing FGF2- vs FGF2+). Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb

2525 Background: Ixabepilone (BMS-247550) is a microtubule stabilizing agent with demonstrable therapeutic value in taxane- refractory breast cancer (BC) patients. Biomarkers to predict either ixabepilone or paclitaxel activity in BC patients have previously been reported. However, markers that differentiate response to the two agents have yet to be identified. This study sought to discover predictive markers that will enable patient selection to differentially enhance response to ixabepilone or paclitaxel in ER-negative (ER-) patients. Materials and Methodologies: Pre-treatment gene expression profiles were generated for 62 ER- patients treated with ixabepilone in clinical study CA163080, and 51 ER- patients treated with T/FAC (paclitaxel and fluorouracil-doxorubicin-cyclophosphamide) in clinical study MDA133. Biomarkers differentially predictive of complete pathological response in breast were identified through gene set enrichment analysis (GSEA) or classification by threshold gradient descent (TGD). Gene knockdown by siRNA was used to study some of these candidate markers. Results: Four candidate models that differentiate response to ixabepilone treatment and taxane-containing therapy were identified. Two of the models, found by GSEA, are based on expression levels for single microtubule-related genes: transforming, acidic coiled-coil containing protein 3 (TACC3) and chromosome condensation protein G (HCAP-G). The potential of HCAP-G as a differential marker was supported by siRNA studies. Two of the models, found by TGD, are based on expression levels for 26 and 20 genes. Areas under the ROC curves for the models applied to each study separately are given in the table . Conclusions: We have identified four predictive models that differentiate response in a clinical trial of ixabepilone from that in a trial of T/FAC. A clinical trial is under way to further evaluate their utility for differentiating response to ixabepilone- and taxane-containing regimens. [Table: see text] [Table: see text]