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289 Background: Amplification of the FGFR1 gene occurs in ≈ 10% of BC, correlates with FGFR1 overexpression, and is mainly observed in estrogen receptor (ER)-positive human epidermal growth factor receptor 2 (HER2)- BCs. Dovitinib (TKI258) is a multitargeted tyrosine kinase inhibitor that demonstrated potent antitumor activities in FGFR1-amplified tumor cell lines. This phase 2 study evaluated the efficacy and safety of dovitinib in metastatic HER2- BC. Methods: Patients were stratified into 4 groups based on FGFR1 and hormone receptor (HR) tumor subtype: 1) FGFR1+, HR+; 2) FGFR1+, HR-; 3) FGFR1-, HR+; 4) FGFR1-, HR-. Screening for FGFR1 status was performed by fluorescence/chromogenic in situ hybridization (cutoff ≥ 6 gene copies). Dovitinib (500 mg) was administered once daily on a 5-day-on/ 2-day-off schedule. The primary endpoint was RECIST best overall response rate in patients with measurable disease per external radiology review. Results: Data from 77 of 81 treated patients were available as of January 2011 (n=21, n=34, n=22 in groups 1, 3, 4, respectively). Median number of prior therapies in the metastatic setting was 2 chemotherapy lines (all patients) and 2 endocrine therapy lines (HR+ patients). Liver metastases were present in 58% of patients (81%, 50%, 50% in groups 1, 3, 4, respectively). Most common adverse events included vomiting (75%; grade 3 [g3]: 6%), diarrhea (72%; g3: 6%), nausea (62%; g3: 5%), and asthenia (61%; g3: 17%). Median dovitinib exposure was 1.7 (range, 0-8.2) months, including 8 patients with > 4 months of therapy. Of patients with measurable disease at baseline, in group 1, 13% had unconfirmed partial responses and 44% had stable disease ≥ 4 months (SD4). In groups 3 and 4, 29% and 11% had SD4. Conclusions: This is the first trial reporting efficacy of an FGFR1 inhibitor in patients with FGFR1-amplified BC. Dovitinib showed antitumor activity in patients with HR+, FGFR1- amplified BC and disease stabilization in other subgroups. FGFR1 is likely a relevant target in BC, and FGFR1 amplification may define a segment of dovitinib-sensitive disease. Further evaluation of dovitinib in patients with HR+ BC is planned.

508 Background: Amplification of the FGFR1 gene occurs in ≈ 10% of breast cancers (BC), correlates with FGFR1 overexpression, and is mainly observed in ER+/Her2− BCs. Preclinical (pc) studies suggest that FGFR1 is a candidate therapeutic target in BC. Dovitinib (TKI258) is a tyrosine kinase inhibitor that targets FGFR, VEGFR, and PDGFR. In pc models, dovitinib demonstrated potent antitumor activities in FGFR1−amplified tumor cell lines. Methods: A 2-stage, phase 2 study to determine the efficacy and safety of dovitinib in 4 groups (gps) of metastatic BC patients (pts): (gp 1: FGFR1+, HR+), (gp 2: FGFR1+, HR−) (gp 3: FGFR1−, HR+), (gp 4: FGFR1−, HR−). Pt selection was performed according to FISH/CISH for FGFR1 (cut-off ≥ 6 gene copies). Dovitinib (500 mg) was administered once daily on a 5-day on/ 2-day off schedule. The primary endpoint was RECIST best overall response rate in pts with measurable disease per external radiology review. Results: As of January 2011, 81 pts were treated, with data for 77 pts ...

1081 Background: PI3K pathway alterations (receptor tyrosine kinase amplification, activating mutations of PIK3CA or PTEN loss) are frequent in breast cancer (BC). In hormone receptor (HR) + / HER2...

TPS110 Background: Activation of the PI3K/AKT/mTOR pathway is common in breast cancer. Preclinical studies indicate that the dual inhibition of IGFR and mTOR may be additive or synergistic and abro...

3105 Background: AZD8931 is an oral, equipotent inhibitor of ErbB1, ErbB2 and ErbB3 receptor signaling. Methods: This open-label (3+3 design) study (NCT00900627) evaluated the MTD, safety, tolerabi...

590 Background: Retaspimycin hydrochloride (IPI-504) is a potent, intravenously-administered heat shock protein 90 (Hsp90) chaperone inhibitor. Hsp90 helps maintain the stability of key oncoproteins, including HER2. Preclinical studies have demonstrated the activity of IPI-504 plus trastuzumab in xenograft mouse models using trastuzumab-sensitive and trastuzumab-resistant HER2-positive cell lines. Methods: In our single-arm, phase 2 study, the overall response rate and tolerability of IPI-504 plus trastuzumab in pts with previously treated, locally advanced or metastatic HER2-positive breast cancer were evaluated. Prior treatment with trastuzumab was required and no limit of previous lines was specified. The trial used a Simon two-stage design; if the DLT rate was ≤25% and at least 2 responses were observed, the trial would be expanded. Results: 26 pts were initially treated with 300 mg/m2 IPI-504 once weekly in combination with 6 mg/kg trastuzumab once every 3 weeks. The median age was 52.5 years (range ...

1064 Background: Ixa is active in taxane-refractory metastatic and neoadjuvant BC. In the neoadjuvant ixa study CA163-080 (080), pre-treatment (tx) and post-tx tumor specimens were assessed by gene...

e11058 Background: The PI3K/Akt/mTOR pathway, a key regulator of cellular proliferation, cellular metabolism, and angiogenesis, is constitutively activated in aromatase inhibitor–resistant breast c...

3043 Background: PI3K pathway is frequently altered in cancer and can have an impact on tumor survival and proliferation. BKM120 is a potent and highly specific oral pan-class I PI3K inhibitor with...

3011 Background: Activated TGF-b signaling has been associated with poor survival in several tumors, including glioma, hepatocellular and pancreatic cancer. TGF-b inhibitors are expected to improve...

554 Background: Gene expression profiling can be used to predict the likelihood of achieving a pathological complete response (pCR) to neoadjuvant chemotherapy (CT) in patients with primary breast ...

3066 Background: BEZ235 is a potent and highly specific oral dual mTOR/PI3K inhibitor. BEZ235 hard-gelatin capsule (Burris, ASCO 2010) and SDS capsule (Rodon, SABCS 2010) were reported previously. ...

TPS124 Background: SOR is an oral multikinase inhibitor with antiangiogenic/antiproliferative activity. A randomized Ph 2b screening trial (SOLTI 0701) that compared SOR+CAP vs PL+CAP in patients (...

3056 Background: BEZ235 is a novel pan-class I PI3K/mTOR inhibitor with proven apoptotic effect (Brachman et al 2009), antiangiogenic effect (Schnell et al 2009) and clinical activity especially in...

1074 Background: Few data are available on the cardiotoxic effect of NPLD in pts previously treated with A. Several studies have reported predictive factors associated with cardiotoxicity and A but...

TPS116 Background: Despite advances in the treatment of HER2 overexpressed MBC, nearly all patients develop progressive disease and innovative well-tolerated HER2-directed therapies are needed. T-DM1 is a unique antibody-drug conjugate that combines the antitumor activities of trastuzumab with intracellular delivery of the highly potent cytotoxic agent, DM1 (derivative of maytansine). In two phase II studies (TDM4258g; TDM4374g) single-agent T-DM1 3.6 mg/kg IV q3w showed substantial efficacy in patients with HER2-positive MBC who had received prior chemotherapy and ≥1 HER2-directed therapy for MBC (Burris JCO 2010; Krop ESMO 2010) providing strong rationale to assess T-DM1 in the phase III setting. In addition, comparable response rates and improved safety relative to trastuzumab and docetaxel were reported in a randomized phase II study of T-DM1 in first-line MBC (Perez ESMO 2010). Methods: EMILIA (TDM4370g, registry #NCT00829166) is an international, phase III study evaluating the safety and efficacy of...

1113 Background: VT has proven active in HER2+ MBC: Response rate (RR) and time to progression (TTP) in first- and second-line therapy: 51-84%, 7.5-17 months (m) and 51-66%, 3.5-9 m, respectively. However, all pts included in such studies were T-naive. In contrast, few data regarding the efficacy of VT in pts with prior T treatment (Tpt) has been reported and preclinical data do not support a synergism of V and T in T-resistant cell lines. Our aim was to describe the efficacy of VT in Tpt pts compared to a T-naive group and to study predictive factors of TTP in both groups. Methods: Medical reports of all pts receiving VT for MBC between 2001 and 2009 were selected. Those previously treated with T for MBC and/or relapsing ≤ 6 m after completion of adjuvant T constituted the Tpt group. Pts without previous exposure to T formed the T-naive subset. RR, clinical benefit rate (CBR), and TTP were analyzed. Baseline characteristics, along with time of prior T treatment in Tpt group, were analyzed as potential va...

1534 Background: Modulation of response to chemotherapy and prediction of efficacy to certain targeted therapies in TNBC is highly associated to BRCA1/2 mutations. We aimed to identify if TN phenotype in BC female patients added to family history is a useful predictor for detecting the presence of any of these mutations. Methods: We analyzed the mutation status of 227 consecutive unrelated female BC patients (probands) referred to our High Risk and Cancer Prevention Unit who had undergone full genetic testing of BRCA1/2 (direct sequencing and large rearrangements analysis). Univariate analyses were performed to compare the prevalence of mutations between TNBC and non-TNBC according to family history (breast/ovarian cancer in first/second degree relatives) and age at diagnosis (dichotomized at 50). A multivariate analysis was performed to identify predictors of finding a mutation. Results: Overall, 58/227 (26%) had a TNBC, 184 (81%) had a family history, and 190 (84%) were diagnosed before 50y. Twenty-one ...

1083 Background: We reported data from SOLTI-0701 demonstrating a clinical benefit with the oral regimen of SOR+CAP vs. PL+CAP in pts with advanced BC for progression-free survival (median, 6.4 vs. 4.1 mo; hazard ratio 0.58; 1-sided p=0.0006). Toxicities were comparable between treatment arms except for HFSR/HFS, which was not unexpected as HFSR and HFS are associated with SOR and CAP, respectively. Here we describe HFSR/HFS toxicity during this study. Methods: SOLTI-0701 is a multinational (Brazil, France, Spain) phase 2b study in HER2-negative pts with locally advanced or metastatic BC and ≤1 prior chemo regimen for advanced BC (n=229). Pts were randomized (1:1) to receive CAP (1,000 mg/m2 po, twice daily [BID], 14 of every 21 days) with PL or SOR (400 mg po, BID). The protocol recommended managing HFSR/HFS with symptomatic therapy, study drug (SOR, PL, CAP) interruption for grade (G) 2 toxicity, study drug interruption and dose reduction for recurrent G2 or G3 toxicity, and discontinuation for persiste...

1112 Background: In pts with MBC, retreatment with chemotherapy agents given previously in the early disease setting is a valid therapeutic option. Re-introduction of anthracyclines is limited by the risk of accumulative cardiotoxicity. Since NPLD is less cardiotoxic, administration of NLPD could be a potential strategy to re-introduce anthracyclines in MBC. In order to explore this hypothesis, we have analyzed the cardiotoxicity NPLD-containing regimes in pts with MBC previously exposed to D 360 mg/m2. Methods: Pts had PS 0-2, basal left ventricular ejection fraction (LVEF) >50%, adequate organ function, and prior exposure of D in the (neo)adjuvant setting at a dose of 360 mg/m2. No prior liposomal anthracyclines were allowed. LVEF was measured before initiating treatment with NPLD and at least at the time of treatment discontinuation. Cardiac events were defined as type A in case of signs and/or symptoms of congestive heart failure plus grade 3/4 LVEF decline; or type B including asymptomatic LVEF decli...

1073 Background: Two phase IIb trials in pts with advanced BC demonstrated activity for SOR plus standard chemotherapy for the primary endpoint of PFS. In Study A, median PFS for SOR + capecitabine (CAP) versus PL+CAP was 6.4 versus 4.1 mo (hazard ratio [HR] 0.58; 1-sided p=0.0006). In Study B, median PFS for SOR + paclitaxel (PAC) versus PL+PAC was 6.9 versus 5.6 mo (HR 0.79; 1-sided p=0.09). In both studies, randomization was stratified by visceral status with slight imbalances in some covariates. We performed MVA to assess the impact of imbalances and prognostic factors on PFS. Methods: Study A: Pts (N=229) with ≤1 prior chemo regimen for advanced BC were randomized to CAP (1,000 mg/m2 po, twice daily [BID], 14 of 21 days) + SOR (400 mg po, BID) or PL. Study B: Pts (N=237) with no prior chemo for advanced BC were randomized to PAC (90 mg/m2/wk IV, 3 wk on/1 wk off) + SOR (400 mg po, BID) or PL. MVA: Cox proportional hazards models of PFS stratified by visceral status were used for each study. Additiona...

2500 Background: LDE225 is a potent and selective inhibitor of Smo, a key signaling protein in the hedgehog (Hh) pathway. Activation of the Hh pathway is implicated in the pathogenesis of a wide ra...

3008 Background: RIDA is a non-prodrug rapamycin analog mTOR inhibitor, and DALO is a humanized monoclonal antibody targeting the IGF-1R receptor. In preclinical models, dual mTOR/IGF1-R inhibition...

3102 Background: Preclinical studies show that evasion of death receptor (DR)-mediated apoptosis may depend on intact growth factor signaling. DR agonists have not previously been combined with IGF-1R inhibitors in published clinical studies. The combination may yield synergistic targeted antitumor activity without added toxicity. This study combined 2 investigational, fully human monoclonal antibodies: conatumumab, a human DR5 agonist; and AMG 479, an IGF-1R antagonist. Methods: Eligible pts had locally advanced or metastatic chemotherapy refractory solid tumors, ECOG PS of 0 or 1, and adequate glycemic control if diabetic. Pts enrolled into 3 sequential dose cohorts and received conatumumab 1, 3, or 15 mg/kg IV and AMG 479 18 mg/kg IV on day 1 of each Q3W cycle. Dose escalation was based on

1043 Background: The use of bevacizumab, a vascular endothelial growth factor inhibitor, has been associated with an increase in risk of arterial thromboembolic events (ATE) and venous thromboembolic events (VTE) in some clinical trials. The aim of this systematic review and meta-analysis of randomized trials was to assess the overall risk of both grade 3-5 ATE and VTE associated with bevacizumab in patients with metastatic breast cancer (MBC). Methods: We selected all randomized phase III trials which compared chemotherapy with or without bevacizumab in MBC. For the analysis, we used a fixed-effects and random effects models to calculate the pooled event-based relative risk ratios (RR) with 95% confidence interval (CI). The Cochran's Q statistic and I2 statistics were first calculated to assess the heterogeneity among the proportions of the included trials. For this study, we collected all grade 3-5 events reported in these trials. We analyzed the overall RR for vascular events (ATE + VTE) because differ...

e11065 Background: Breast-conserving surgery (BCS) aims to obtain pathologically negative resection margins. Pts with PM may require S2. According to different series, the timing of aRx is related to BC pt prognosis. This study evaluated the impact of re-excision for PM on initiation of aRx and its correlation with pt prognosis. Methods: BCS patients with PM treated between 2000 and 2009 at Vall d'Hebron Hospital were identified. Clinical and pathological characteristics were collected; the time of S2 and aRx calculated from initial surgery (S1), and univariate analysis performed. Results: Of 53 pts, median age 53 yrs (range 29-87), 6 pts (11%) had immediate re-excision; 47 pts underwent S2: 18 (38%) had wider re-excision and 29 (62%) mastectomy. The median time from S1 to S2 was 3.13 weeks (range 0–18) and 8.83 weeks (range 2–24) from S1 to aRx. The median time to aRx for the 23 pts with early-S2 (≤ 3 weeks) versus the 30 pts with delayed-S2 (>3 weeks) was 6.98 weeks (range 2-17) and 8.98 weeks (range 3-...

601 Background: TNBC comprises 15%-20% of all breast cancers (BCs) and is associated with a poor prognosis. In the ixabepilone (Ixa) study CA163-080 (-080) (n = 161), 26% of the patients (pts) had ...

3030 Background: XL765 is a potent and selective inhibitor of class I PI3K isoforms, TORC1, and TORC2. XL765 has shown dose-dependent target modulation and tumor growth inhibition or shrinkage in multiple human xenografts. Methods: Pts receive XL765 twice daily (bid) or daily (qd) for 28-day cycles. Dose escalation follows a standard 3 + 3 design. PK and pharmacodynamic biomarker analyses are performed. Tumor response is assessed by RECIST every 8 weeks. A cohort of lymphoma pts will be enrolled to explore the potential utility of combined inhibition of PI3K and TORC1/2 in this disease setting. Results: 79 pts have been dosed with XL765; 52 pts on a bid regimen (30-240 mg/day) and 27 pts on a qd regimen (70-100 mg/day). On the bid schedule, 25 subjects have been treated at the established maximum tolerated dose (MTD) of 50 mg bid. The maximum administered dose (MAD) is 120 mg bid. On the qd schedule, the MAD is 100 mg and the preliminary MTD is 90 mg. The most common related adverse events (> 10% of pts) ...

3003 Background: The PI3K pathway is the most frequently aberrantly hyperactivated pathway in cancer. PI3K pathway inhibition is expected to have a strong impact on tumor survival and proliferation...

3005 Background: The PI3K pathway plays a major role in cancer cell growth and survival, and is frequently aberrantly hyperactivated in tumors. BEZ235 is a potent and highly selective reversible PI3K pathway inhibitor with antiproliferative and apoptotic activity in cancer cells. BEZ235 strongly inhibited activation of downstream effectors (e.g. Akt) and displayed antitumor activity in xenograft models harboring PI3K pathway alterations. In preclinical toxicology studies, BEZ235 treatment was well tolerated. Methods: This phase I, multicenter, open-label, single-agent, dose-escalation, study was conducted in pts with histologically confirmed, advanced, unresectable solid tumors. BEZ235 was administered once daily as a gelatin capsule either fasted or fed (10-1,100 mg) until unacceptable toxicity or disease progression. Dose escalation was guided by a Bayesian logistic regression model with overdose control. Anti-tumor activity of BEZ235 was assessed by CT and PET. Early efficacy data are based on central ...

1066 Background: Pertuzumab (P), a fully humanized monoclonal antibody, targets the dimerization epitope of human epidermal growth factor receptor (HER) 2, preventing dimerization of HER2 with othe...

3004 Background: XL147 is a selective inhibitor of class I PI3K isoforms. In preclinical cancer models, XL147 is cytostatic or cytoreductive as monotherapy and enhances the efficacy of targeted agents and chemotherapeutics. This open label, phase I dose escalation study assesses the safety, pharmacokinetics, pharmacodynamics and activity of XL147 in pts with advanced solid tumors and lymphoma. Methods: Using a standard 3 + 3 design, pts with solid tumors receive once daily XL147 on days 1-21 (21/7) or as a continuous daily dose (CDD) in 28-day cycles. Cycle 1 safety data determine dose-limiting toxicities (DLTs). Disease assessments occur every 8 weeks. The potential utility of pan-Class I PI3K inhibition in lymphoma pts will be explored. Results: 68 solid tumor pts have been treated: 41 on 21/7, 21 on CDD using capsules, and 6 on CDD using tablets. The MTD for 21/7 and preliminary MTD for CDD was 600 mg; MTD expansion in NSCLC and other solid tumor pts at 600 mg XL147 CDD is ongoing. Drug-related skin ra...

1036 Background: Improvement in progression-free (PFS: HR: 0.73; p=0.008) and overall survival (OS: HR: 0.74; p=0.026) was demonstrated with the combination of lapatinib (L) plus trastuzumab (T) in...

1091 Background: Bevacizumab, a vascular endothelial growth factor inhibitor, has shown to be active in patients with metastatic breast cancer (MBC) as first or second line therapy. In some tumor types, the addition of bevacizumab to chemotherapy increase the risk of gastrointestinal (GI) perforation compared with controls. The aim of this systematic review and meta-analysis of randomized trials was to assess the overall risk of GI perforation associated with bevacizumab in MBC. Methods: We selected all randomized trials which compared chemotherapy with or without bevacizumab in MBC. For the analysis, we used a fixed-effects and random effects models to calculate the pooled event-based relative risk ratios (RR) with 95% confidence interval (CI). The Cochran's Q statistic and I2 statistics were first calculated to assess the heterogeneity among the proportions of the included trials. For this study, we collected all events as reported in these trials. We did not consider differences in grade or outcomes. R...

6023 Background: Cediranib is an oral, highly potent and selective inhibitor of VEGF signaling, with activity versus VEGFR-1, -2 and -3. FDG-PET has previously been shown to provide early assessment of the effectiveness of anticancer treatment in solid tumors after chemotherapy. The objectives reported here were to assess the effects of cediranib on 1) tumor metabolic activity using FDG-PET (standardized uptake value, SUVmax) and 2) tumor size (RECIST longest diameter). Methods: Eligible pre-treated patients with metastatic or recurrent HNC or NSCLC received cediranib monotherapy 30 mg/day for 3 weeks, or until disease progression or unacceptable toxicity. Patients showing evidence of response (FDG-PET) or clinical benefit at day 22 could continue study treatment and were assessed on days 43 and 71 by RECIST/FDG-PET. Evaluable patients had baseline and at least one post-baseline measurement available. Results: A total of 19 patients were treated; 17 patients had baseline and day 22 FDG-PET and 18 patients had baseline and at least one post-baseline RECIST assessment. Consistent changes in FDG-PET were observed (Table). At days 22, 43 and 71, a total of 5 (29%), 7 (41%) and 6 (35%) patients had ≥25% decrease in SUVmax (FDG metabolic response), respectively. The combined (HNC/NSCLC) best mean % change in tumor size from baseline for all patients was -25.9%. Best responses of PR and SD were seen in 18.8% and 50% of HNC patients, respectively (Table). The most common adverse events were proteinuria (7 [37%]), fatigue, diarrhea and hypertension (each 6 [32%]). Conclusions: This study provided evidence of antitumor activity with cediranib monotherapy as measured by decreases in FDG uptake, reductions in tumor size and RECIST response rate. Cediranib 30 mg/day was generally well tolerated, with a manageable adverse event profile consistent with previous studies. Further studies are warranted in these tumor types. [Table: see text] [Table: see text]

1022 Background: Pertuzumab binds to the dimerization epitope of the HER2 receptor, inhibits HER dimerization and signal transduction, and induces ADCC. In 2 cohorts of pts (n = 66) with HER2-positive metastatic breast cancer which had progressed during trastuzumab therapy after ≤3 lines of chemotherapy with or without trastuzumab, pertuzumab plus trastuzumab has been shown to be active (CR 7.6%, PR 16.7%, SD ≥6/12 25.8%) (Gelmon et al. ASCO 2008, Abs 1026). To assess the activity of pertuzumab monotherapy in this clinical setting, the protocol was amended to include a 3rd cohort of pts. Methods: Pt selection was not changed except that ≥1 month between the last dose of trastuzumab and study start was required. Pts received pertuzumab monotherapy. If the tumor failed to respond or responded and then progressed, trastuzumab could be added to pertuzumab. 27 pts were to be recruited to ensure that ≥24 were fully evaluable for objective response and stabilization of disease ≥6 months. Standard 21-day schedules of the antibodies were given. Results: 29 pts were recruited. Tolerability was good: the major adverse events were mild diarrhea and rash with no clinical cardiac events. To date, 2 responses have been reported, and several pts have ongoing stabilization of disease. 14 pts have received trastuzumab plus pertuzumab following inadequate response (or response then relapse) on pertuzumab monotherapy. Of these 14, 2, having progressed during trastuzumab, failed to respond to pertuzumab monotherapy but underwent confirmed response when trastuzumab was added to the pertuzumab –possibly the first report of such a phenomenon and providing good evidence of an enhanced effect when the antibodies are combined. Updated results will be presented. Conclusions: Pertuzumab monotherapy is active against HER2-positive breast cancer which has progressed during trastuzumab-based therapy. The combination of the two antibodies appears to be more active than either antibody alone. The combination is also active in patients that had failed both antibodies given separately. In clinical studies, the use of the two antibodies combined is justified. [Table: see text]

e12000 Sorafenib is a potent multikinase inhibitor approved by the FDA and EMEA for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma. As a single agent, sorafenib has been shown to have activity in pts with BC. Here, we review the TIES program, a compilation of currently ongoing investigator-sponsored phase IIb multinational, randomized, double-blind, placebo-controlled studies that aim to determine the optimal sequencing of pharmacologic agents for the treatment of BC. All studies will combine sorafenib with first- and/or second-line chemotherapy and/or hormonal therapy in pts with HER2-negative metastatic or locally advanced BC, enroll 220 pts, stratify pts by visceral vs nonvisceral disease, allow pts with evaluable and measurable disease, and include pts with treated brain metastases. The primary endpoint of all trials will be progression-free survival. Secondary endpoints will be safety, overall survival, objective response rate, duration of response, and time to progression. Some studies will also assess quality of life, pharmacokinetic sampling, and biomarkers. Additional information on four of the trials is shown below (Table). Patient characteristics and accruals will be reported. [Table: see text] No significant financial relationships to disclose.

3514 Background: JNJ-26854165 is a novel first-in-clinic oral Human Double Minute-2 (HDM-2) ubiquitin ligase antagonist. It increases the level of HDM-2 client proteins (e.g. p53) by inhibiting the association of HDM-2-client protein complex with the proteosome. Preclinical studies have demonstrated potent anti-proliferative and apoptosis-inducing activity of JNJ-26854165 in a broad range of p53 wild type and mutant tumor models. Methods: A 3+3 dose escalation study with the primary objectives to determine the adverse event (AE) profile, dose limiting toxicities (DLT) and maximum tolerated dose of JNJ-26854165 is ongoing. Secondary objectives include evaluation of PK and PD activity. Eligible patients have ECOG PS≤2 and adequate hematological, renal and hepatic function. JNJ-26854165 is administered orally once daily on a continuous schedule (21-day cycles). Sequential skin and tumor biopsies are taken, and evaluations for HDM-2, p53 and other pathway related markers are performed, including further molecular analyses for HDM-2 activity. Results: 37 pts have been treated at 9 dose levels (DL), 4–300 mg qd. AEs included nausea, vomiting, fatigue, anorexia, insomnia, electrolyte disturbances, liver function tests and creatinine elevations, and asymptomatic QTc prolongation, mostly grade 1–2. A DLT, grade 3 QTcF prolongation, was observed in one patient at DL 9. The patient was asymptomatic and the QTc prolongation recovered after treatment discontinuation. PK data showed dose-proportionality. After dosing at 300 mg, steady state Cmax and AUC0–24h were 2–3 μg/mL and ≈50 μg.h/mL, respectively, well exceeding the expected effective exposure modeled by preclinical studies. PD data showed engagement of the targeted pathway such as dose-dependent p53 upregulation in skin, upregulation of HDM-2 levels in tumors after treatment, and an increase in plasma MIC-1 levels. No objective responses have been observed so far. Conclusions: JNJ-26854165 was well tolerated at doses beyond the expected effective exposure modeled by preclinical studies. PD activity was observed at the 150–300 mg dose levels. The trial continues with cohort expansion at 300 mg. Updated results will be presented. [Table: see text]

3500 Background: XL147 is a selective inhibitor of Class I PI3K isoforms. In preclinical cancer models XL147 is cytostatic or cytoreductive as monotherapy and enhances the efficacy of targeted agents and chemotherapeutics. This open label, Phase 1 dose escalation study assesses the safety, pharmacokinetics, pharmacodynamics, and efficacy of XL147 in advanced solid tumors. Methods: For each 28 day cycle, patients (pts) receive XL147 on Days 1–21 (21/7) or as a continuous daily dose (CDD). Cycle 1 safety data determine dose-limiting toxicities (DLTs). Tumor response is assessed every 8 weeks. Results: As of December 2008, 39 pts have been treated: 36 on 21/7 across 7 dose levels (30–900 mg) and 3 on CDD at 100 mg. At 900 mg, 2 of 3 pts experienced a DLT of reversible grade 3 rash, and the MTD was established as 600 mg based on 15 pts. Drug-related toxicities included grade 3 skin rash (3 pts), grade 3 arterial thrombosis (1 pt), grade 2 transaminase elevation (1 pt), and grade 1 hyperglycemia (4 pts). XL147 exposure increased with dose from 30–400 mg and was similar from 400–900 mg. XL147 reached steady-state plasma concentrations by Day 15–20. Mean t1/2, z at steady-state ranged from 3.7–6.3 days. Doses ≥400 mg yielded exposures that exceeded the EC90 in xenograft models. A trend suggesting augmented food-induced changes in insulin was evident; however, glucose was minimally affected. XL147 reduced levels of phosphorylated PI3K pathway components in PBMCs, hair, skin, and tumor tissues in an exposure-dependent manner. In 2 pts dosed at the MTD, reductions of ≥70% in PI3K pathway signaling were observed in tumor tissue without compensatory upregulation of MEK/ERK phosphorylation. As of December 2008, 6 pts (3 NSCLC, 1 BCC, 1 NHL, 1 PC) continued on study >6 months including 3 >10 months (NHL, NSCLC, BCC). One pt with hormone refractory PC has sustained a normalization of PSA levels through 5 months. Conclusions: XL147 was generally well tolerated with the MTD for the 21/7 schedule defined as 600 mg. The most common drug-related toxicity was skin rash. Inhibition of PI3K pathway signaling has been demonstrated in tumor and surrogate tissues. Prolonged stable disease has been observed. [Table: see text]

e20527 Background: Elderly breast cancer (BC) patients (pts) are usually excluded from clinical trials. Nevertheless, with the increased use of trastuzumab (T) there is a need to assess and predict T-related cardiotoxicity in this population. Methods: Data were collected from women ≥70 years with BC and serial cardiac monitoring treated with T at our institution since 2005. Cardiovascular risk factors (CRF) were analysed together with left ventricular systolic function (LVEF) assessed at baseline and during T. Results: Thirty pts with early (10) or advanced (20) BC, median age 75.7 years (range 70–87), were identified. WHO performance status was 0–1 in 90% of pts. Median duration of treatment was 45 weeks (range 2–87). Basal LVEF was 63.8% (range 46.3–76). Five of 30 pts (16.6%) experienced asymptomatic cardiotoxicity defined as an absolute drop ≥10% with a final LVEF < 50% (13.3%, 4/30 pts) or any absolute drop >20% (3.3%, 1/30 pts). Four of 30 patients (13.3%) developed symptomatic cardiac heart failure. Median time to LVEF decline was 9 weeks (range 3–87). LVEF recovered to normal values in a median time of 4 weeks (range 3–48) in all but one patient. CRF are shown in Table 1 . Pts with T-related cardiotoxicity presented more often with history of cardiac disease (22.2% versus 9.5%), diabetes (22.2% versus 5%) and BMI>30 (68% versus 45%) as compared to the rest. No relevant difference was seen in terms of hyperlipemia, tobacco or hypertension. Previous or concomitant exposure to anthracyclines was not found as a risk factor either. Conclusions: Despite the limited numbers, this series shows that elderly BC pts treated with T experience reversible cardiac events similarly to those already described in younger pts. However, particular attention may be paid to cardiac history, diabetic and obese pts who appear more likely to develop T-related cardiotoxicity. [Table: see text] No significant financial relationships to disclose.

1015 Background: Lapatinib (L) is an oral, small-molecule inhibitor of EGFR and HER2 with a mechanism of action distinct from that of trastuzumab (T). Preclinical data suggest synergy between L and T. We studied L alone and in combination with T in pts with HER2+ MBC who progressed on T. Methods: Eligible women had received prior anthracycline and taxane therapy, had MBC with measurable lesions or bone-only disease, and had progressed on prior T-containing therapy. Pts were stratified by hormone receptor status and visceral/nonvisceral disease, then randomized to receive either L (1,500 mg QD) or L (1,000 mg QD) plus T (2 mg/kg weekly after 4 mg/kg loading dose). If pts progressed on the L arm, they could cross over to the L+T arm. The primary endpoint was PFS (investigator assessment), and secondary endpoints were clinical benefit rate (CBR) at 24 wks, RR, and OS. Results: 296 pts were randomized. All pts had received prior T; the median number of prior chemotherapy regimens was 6. Combination therapy si...

14508 Background: PI3K mutations are frequent in human cancer and play a role in the malignant phenotype and therapeutic resistance. NVP-BEZ235 is a small molecular mass compound in phase I clinica...

4129 Background: KRAS mutation status predicts sensitivity to anti-epidermal growth factor receptor (EGFR) agents in pts with refractory mCRC. In order to assess the efficacy of cetuximab alone and...

504 Background: The NOAH trial evaluated the addition of trastuzumab (H) to chemotherapy (CT) for pts with HER2-positive LABC. A significant improvement in pCR has been reported (Gianni. ASCO 2007; abs 532). Methods: 228 pts were randomized to receive 3 cycles of doxorubicin (60 mg/m2) and paclitaxel (150 mg/m2) q3w, 4 cycles of paclitaxel (175 mg/m2 q3w) and 3 cycles of CMF (C 600 mg/m2, M 40 mg/m2, F 600 mg/m2 d 1+8 q4w) with or without concomitant H (8 mg/kg loading dose then 6 mg/kg q3w for 1 year) before surgery. 171 (75%) core biopsies obtained before treatment were available for assays of c-Myc (by FISH), PTEN (by IHC) and IGF1R (by IHC) in addition to estrogen receptor (ER) and progesterone receptor (PgR). Results: The 171 pts with available biopsies were representative of the overall NOAH population, although with a lower incidence of ER+ tumors. Negative PgR status was strongly associated with pCR in the H group (51% vs 16% in PgR-positive tumors; p=0.008). Overall, 32 pts had c-Myc amplificatio...

22011 Background: The aim of our study was to investigate pretreatment serum CA-125 concentration as a prognostic factor in pts with EOC. Methods: A retrospective analysis was conducted on 219 pts ...

1538 Background: Women at risk of HBOS are recommended biannual/annual clinical breast examination (CBE), annual mammography (MX) and annual pelvic or transvaginal ultrasound (PTVUS) starting at ag...

19125 Background: Inhibition of the EGFR pathway has become an established strategy in NSCLC patients (pts) treatment. The aim of this study is to assess the value of predictive clinical variables ...

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.

1051 Background: Based on clinical activity of capecitabine(C) and gemcitabine (G) on the treatment of MBC, we performed a multicentric phase II trial of the combination to test its efficacy and safety profile. Methods: Sample size of 72 evaluable MBC patients (pts) previously An-treated (neoadjuvant 8%, adjuvant 69%, advanced 30%). Median age: 59 years (35–76 years). Estrogen Receptor positive: 47 (65%). HER2 overexpression: 16 (22%). Prior hormonal/trastuzumab allowed. Soft tissue/ganglionar/pleural/bone disease: 19 (26%); visceral metastasis: 53(74%). Stratification: previous chemotherapy (CT) for advanced disease (none: group 1; any: group 2). Study treatment: oral bid C 1,660 mg/m2/day (d) (d1–14) + iv G 1,000 mg/m2/d (d1&8). Cycles repeated every 3 weeks. RECIST/NCI-CTC 2.0 criteria. Primary end point: Objective Response Rate. Results: Response Rates and Clinical Benefit (CB) are detailed in the table . Median follow-up 7.2 months (m) (0.2–18.4). Median time to progression 11.2 m: group 1, 12 m (95%CI: 6.4–14.5); group 2, 8.9 m (95%CI: 6.9–14).Total and median administered cycles/pt: 479 and 8. Delayed cycles: 103(21.5%): 27% due to hematological toxicity, 11% due to non-hematological toxicity, 62% due to other causes. C dose reduced in 27 cycles (5.6%), 12 of them due to non- hematological toxicity. G dose reduced in 169 cycles (35%), mostly on day 8, and due to hematological toxicity (80% of reduced cycles). Grade 3–4 neutropenia: 32 pts (56%), 1 case of febrile neutropenia. Grade 3–4 non-hematological toxicities: asthenia 8 pts (14%), hand- foot syndrome 6 pts (10.5%), mucositis 3 pts (5%), diarrhea 2 pts (3.5%). Conclusions: Combination of C+G in the treatment of previously anthracycline-treated MBC is safe and active, with a manageable toxicity profile and a good clinical activity. [Table: see text] No significant financial relationships to disclose.

1004 Background: T and P bind to different epitopes on the extra cellular domain of HER2. Unlike T, P binds to the dimerization domain and blocks homo- and hetero-dimerization of HER2 with other HER kinase family members. Xenograft models support the hypothesis that the complementary mechanisms of action could result in augmented efficacy when T and P are combined. Methods: Two-stage design, criteria to proceed to the 2nd stage were: ≥ 2 partial responses (PR) or 1 PR and 12 stable disease (SDs) or 13 SDs. Eligibility included: measurable, centrally-tested HER2 positive breast cancer; up to 3 lines of prior chemotherapy plus T (including adjuvant chemotherapy plus T); disease progression during T as most recent treatment for metastatic disease; baseline left ventricular ejection fraction (LVEF) ≥ 55% and no decrease of LVEF to below 50% during prior T treatment. Consenting Pts received T i.v. weekly or every 3 weeks at 2 mg/kg or 6 mg/kg respectively (with re-loading dose if required) plus 420mg fixed dose of P i.v. every 3 weeks following loading dose 840mg. Study treatment was initiated within 9 weeks of the last dose of T given as most recent therapy. An independent data safety monitoring board has overseen the 1st stage safety data. Results: Recruitment into 1st stage is complete. The main adverse events were diarrhea (71%), fatigue (46%), nausea/vomiting (38%) and rash (25%). Most AE’s were mild to moderate (there was 1 case of Grade 3 diarrhea) and none was treatment-limiting. There were no clinical cardiac events, and central review revealed no case of fall in LVEF of ≥10% and to ≤50%. Response status: 5 confirmed PR (21%); 12 SD (50%). Responses have been observed in lymph node and liver metastases. Recruitment into the 2nd stage of the trial has commenced. Conclusions: The combination of the P and T is active and well tolerated in patients with pre-treated HER2 positive breast cancer which has progressed during treatment with T. No significant financial relationships to disclose.