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1028 Background: T and P are humanized recombinant monoclonal antibodies (MoAB) that target different epitopes of HER2 extracellular domain. P blocks HER2’s ability to heterodimerize with other HER/ErbB receptors. Methods: This Ph II trial evaluates the efficacy and safety of T with P in patients (pts) with HER2+ (FISH +) MBC who had progressive disease (PD) on T-based therapy. Eligible pts must have had = 3 T-based regimens, normal (nl) left ventricular ejection fraction (EF=55%) and without significant cardiac history. Pts received IV T (6mg/kg) and P (420 mg) every 3 weeks (wks). EKG plus echocardiogram (ECHO) or cardiac MRI and tumor response were assessed every 3 and 6 wks, respectively. Results: Eleven pts received 39 (1 to 13) cycles, 1 pt achieved a partial response (PR) and 3 pts had stable disease. A total of 68 ECHOs and 8 cardiac MRIs were performed. Left ventricular systolic dysfunction (LVSD) with nl EKG was seen in 5 pts; Grade (Gr) 1 (n = 2) (EF 50–55%), Gr 2 (n = 2) (EF 40–50%) and Gr 3 (n = 1) (EF20–40%). Gr 2–3 events were associated with global hypokinesis. Gr 3 event was associated with symptomatic CHF. All 5 pts had received 240mg/m2 cumulative dose of doxorubicin, 2 pts (Gr 2–3) received chest wall radiation, and 1 pt (Gr 1) had HTN. Two pts with Gr 1–2 LVSD had a history of reduced EF during prior T-based treatment, which reversed to nl upon stopping T. Reduced EF appeared within 1–2 cycles, which returned to nl in 3 pts within 1wk to 3 months (mo) post discontinuing T/P. One pt had persistent Gr 2 LVSD 3 mo after the initial event. The pt with Gr 3 LVSD had extensive chest wall disease and died of PD and possibly CHF 2 mo after treatment termination. Conclusions: We observed Gr 1–3 LVSD in patients with HER2+ MBC who received dual MoAB treatment directed at HER2, in which very strict cardiac surveillance guidelines were required. One of 11 pts achieved PR and 1 pt had symptomatic CHF thus far. It is unknown whether the other events would have become symptomatic if treatment had continued. Further evaluation of the efficacy of combination T with P is required to define the overall risk and benefit. No significant financial relationships to disclose.

651 Background: Ixabepilone, an epothilone B analog, stabilizes microtubules by binding to tubulin. The response rate (RR) in taxane-pretreated patients at our institution was 22%. Methods: Patients (pts) were eligible if they had MBC previously untreated with taxanes and measurable disease by RECIST criteria. Ixabepilone was given at 6mg/m2/d intravenously days 1–5 every 3 weeks until unacceptable toxicity or disease progression. Primary objectives included RR and toxicity. Pts underwent pre and/or post treatment tumor biopsies for correlative studies. Acetylated α-tubulin, Tau-1, and p53 were stained with anti-acetylated α-tubulin, anti-Tau-1, and anti-p53 antibodies in samples from 13 pts. Staining was scored quantitatively using the Automated Cellular Imaging System. Results: Twenty-three pts received 197 cycles (C). Median of 7C (range 2–22) per pt were administered. Median age was 55 (range 22–79). Seven pts received 1 prior metastatic chemotherapy regimen. Ten of 23 or 43% (exact 95% confidence interval: 23.2% to 65.5%) pts had partial responses (PR), 9 (39%) stable disease (SD) (2 unconfirmed PRs), and 4 (17%) progressive disease (PD). Median time to progression was 5.3 months; median duration of response was 5.4 months from date of best response. Four pts required dose reductions for neutropenia, neuropathy or fatigue. Grade 3/4 toxicities included neutropenia (22%), fatigue (13%), anorexia (9%), infection without neutropenia (9%), motor neuropathy (4%), and muscle weakness (4%). No grade 3/4 sensory neuropathy was seen, but 35% and 13% of pts had grades 1 and 2 neuropathy respectively. Median acetylated α-tubulin at baseline was 0.2 in responders and 17.6 in non-responders (p=0.069). There were no differences in response according to Tau-1 or p53 expression at baseline. Conclusion: Ixabepilone is an effective treatment for MBC with a 43% RR in 23 pts previously untreated with taxanes. There was minimal hematologic toxicity and no grade 3 sensory neuropathy. The use of baseline level of acetylated α-tubulin to predict response may warrant further study. No significant financial relationships to disclose.

13003 Background: VEGFR-2 is a principal mediator of angiogenesis. The effects on sVEGFR-2 after anti-angiogenesis therapy are unknown. Methods: Twenty-one patients (pts) with breast cancer underwent neoadjuvant treatment with BV for 1 cycle (C1) followed by 6 cycles of BV, CT and filgrastim. Blood was collected at baseline (BL), post-cycles 1, 4 and 7. Objectives were to correlate sVEGFR-2 changes after treatment with response, assess wound healing complications, and evaluate for tumor VEGFR-2 mutations. sVEGFR-2 levels were measured by ELISA. Exons 17–26 were sequenced on tissue samples from 20 pts at BL and post C1 to evaluate for VEGFR-2 mutations. Statistical testing is non-parametric. All p-values are two-tailed, with a p < 0.01 interpreted as a statistically significant difference. Results: Thirteen pts had a partial response (PR), 1 unconfirmed PR, 5 stable disease (SD), and 2 progressive disease (PD). Median sVEGFR-2 levels increased by 16% from BL to post C1 (p = 0.0003) and decreased by 19% post C1 to post C4 (p = 0.048). sVEGFR-2 levels were not associated with clinical response. sVEGFR-2 levels at BL did not correlate with other BL parameters: Ki67, microvessel density, VEGF-A, pVEGFR-2, VEGFR-2 or TUNEL (apoptosis). A moderate-weak correlation was seen between post C1 levels of sVEGFR-2 and pVEGFR-2 (r = 0.43). A moderate inverse correlation was seen in the relative difference of sVEGFR-2 and TUNEL from BL to post C1 (r = −0.59). Comparing pts with (n = 5) and without (n = 16) wound healing problems, median sVEGFR-2 levels were 11322 ng/ml and 7524 ng/ml at BL (p = 0.019), 13928 ng/ml and 10148 ng/ml post C1 (p = 0.029), and 10965 ng/ml and 7932 ng/ml post C4 (p = 0.042). In 40 samples where tumor VEGFR-2 sequencing was obtained, no mutations were seen compared to the reference sequence. Conclusion: sVEGFR-2 levels rose significantly following BV alone but were not associated with response. There is a suggestion that sVEGFR-2 may correlate with activated VEGFR2 and a decrease in apoptosis. sVEGFR-2 levels were higher in pts with wound healing problems and may predict pts at higher risk of this complication. There were no mutations of VEGFR2. [Table: see text]