Incidence Of AEs Research Articles

Association of adverse events and tumor response in melanoma patients treated with tremelimumab.

e13104 Background: Several analyses of data from trials of anti-CTLA4 mAbs have suggested a relationship between antitumor activity and certain AEs. Such associations are confounded by the fact that responding patients receive more doses of drug and have longer follow- up. An analysis was done using data from 2 pivotal tremelimumab melanoma studies to determine whether certain AEs in the first treatment cycle (90 days) predict response to tremelimumab. This time period was chosen in order to decrease the difference in follow up time between responders and nonresponders. Methods: Tremelimumab was administered at 15 mg/kg Q90days in studies A3671008 and A3671009. Adverse events were reported for 90 days post last dose or until start of new therapy. RECIST responders were determined by independent radiological review for A3671008 and by sponsor using investigator measurements for A3671009. The following AE categories were analyzed: diarrhea/colitis, all grades and grade ≥3; endocrine events, rash, and pruritus. Results: 37 of 325 treated pts in A3671009 and 16 of 246 treated pts in A3671008 achieved response. All responders and 67% of nonresponders remained on study at least 80 days. Most tumor responders received ≥4 doses and were on study for ≥1 year. Most nonresponders received only a single dose. Rash but not pruritus was more frequent in the first cycle in responders compared to nonresponders. Rates of diarrhea and of severe diarrhea in the first cycle were similar in responders and nonresponders. None of the responders reported endocrine events in the first cycle. Conclusions: Endocrine and GI AEs occurring in the first cycle did not predict response. The higher incidence of endocrine and GI events AEs reported on study in pts with tumor response is due to the greater number of doses received and longer time on study. Responders were more likely than nonresponders to report rash, but not pruritus, in the first cycle; however, about half of the responders did not experience rash in the first cycle, so appearance of rash should not be used to decide whether to continue therapy. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer

Eribulin mesylate pharmacokinetics in patients with hepatic impairment.

2582 Background: The nontaxane microtubule dynamics inhibitor, eribulin mesylate (E7389), has a novel mechanism of action and is in development for the treatment of metastatic breast cancer, lung cancer, and other solid tumors. The objective of this study was to evaluate the effect of hepatic impairment on the pharmacokinetics of eribulin. Methods: This phase I, open-label, parallel-group study recruited adult patients with advanced solid tumors that progressed after standard therapy or for which no standard therapy existed. Patients with normal hepatic function (n=6), mild (Child-Pugh A, n=7) or moderate (Child-Pugh B, n=4) hepatic impairment received eribulin mesylate on day 1 at respective intravenous (IV) doses of 1.4, 1.1, and 0.7 mg/m2 respectively. Plasma samples were collected over 168 hr post dose for pharmacokinetic analysis. Safety was also assessed. Results: Hepatic impairment decreased clearance (4.57, 2.75, and 1.96 L/hr for normal, mild and moderate hepatic impairment, respectively) and prolonged elimination half-life (36.1, 41.1, 65.4 L/hr for normal, mild and moderate hepatic impairment). The mean dose- normalized Cmax for eribulin was comparable between patients with normal and mildly impaired hepatic function (72 vs. 84 ng/mL/mg, ratio estimate 1.1 [90% CI 0.8-1.6]), but moderate hepatic impairment increased Cmax 1.5-fold (111 ng/mL/mg, 90% CI 1.0-2.2). Eribulin exposure was increased in patients with mild and moderate hepatic impairment. The mean dose-normalized AUC(0-∞) increased 1.7-fold (420 ng.hr/mL/mg, 90% CI 1.2-2.7) and 2.8-fold (720 ng.hr/mL/mg, 90% CI 1.7-4.5), compared with patients with normal hepatic function (229 ng.hr/mL/mg). Overall, the most common treatment-emergent adverse events (TEAEs) were alopecia (n=7), nausea (n=5) and fatigue (n=4). AEs probably related to treatment included neutropenia (n=3) and peripheral neuropathy (n=1). Most of the former (3 of 4) resolved without dose reduction. The highest incidence of AEs was reported in patients with mild hepatic impairment. No deaths, treatment-related serious AEs, or discontinuations were reported. Conclusions: Eribulin exposure increased with decreasing hepatic function. Eribulin was generally safe and well tolerated. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eisai Eisai

An assessment of adverse effects of vildagliptin versus comparators on the liver, the pancreas, the immune system, the skin and in patients with impaired renal function from a large pooled database of Phase II and III clinical trials

To assess the safety of vildagliptin versus all comparators (ACs) with regard to organs, systems or tissues of particular interest in type 2 diabetes (T2DM) and areas of potential concern with dipeptidyl peptidase-IV (DPP-4) inhibitors. Data were pooled from 38 studies where vildagliptin was given for > or =12 to > 104 weeks in patients with T2DM. Absolute and exposure-adjusted incidence rates and Peto odds ratios (ORs) versus ACs with corresponding 95% confidence intervals (CI) were calculated. There were > 7000 subject-years of exposure (SYE) to vildagliptin 50 mg bid and > 6500 SYE to ACs. For mild hepatic enzyme elevations with and without elevated bilirubin levels, the ORs for vildagliptin 50 mg bid were 1.24 (95% CI: [0.80, 1.93]) and 1.19 (95% CI: [0.29, 4.90]), respectively. The exposure-adjusted incidences of markedly elevated hepatic enzymes and for enzyme elevations with bilirubin > or = 2x ULN with vildagliptin 50 mg bid were < or = those in the ACs group. For hepatic and pancreatitis-related AEs, the ORs for vildagliptin 50 mg bid were 0.87 (95% CI: [0.64, 1.19]) and 0.70 (95% CI: [0.26, 1.88]), respectively, and for any AE in the infections and infestations SOC, this was 1.04 (95% CI: [0.96, 1.13]). The incidences of skin-related AEs were low and the risk with vildagliptin 50 mg bid was not significantly different from ACs [(OR = 1.10 (95% CI: [0.80, 1.51])]. The present meta-analyses indicate that vildagliptin was not associated with increased risk of hepatic events or hepatic enzyme elevations indicative of drug-induced liver injury, pancreatitis, infections or skin-related toxicity.

Efficacy and Safety of Ibuprofen and Acetaminophen in Children and Adults: A Meta-Analysis and Qualitative Review

To evaluate the analgesic and antipyretic efficacy and safety of ibuprofen compared to acetaminophen in children and adults. Literature searches were performed using PubMed/MEDLINE (through August 2009) and EMBASE (through January 2008) and were restricted to the English language. In PubMed/MEDLINE, search terms used were ibuprofen, acetaminophen, paracetamol, clinical trials, and randomized controlled trials. EMBASE search terms included ibuprofen and acetaminophen, restricted to human and clinical trials. All English-language articles identified from the data sources were reviewed. Multiple review articles were studied for any pertinent references and this yielded additional articles. Only articles that directly compared ibuprofen and acetaminophen were eligible for this review. Eighty-five studies that directly compared ibuprofen to acetaminophen were identified; 54 contained analgesic efficacy data, 35 contained antipyretic/temperature reduction data, and 66 contained safety data (some articles contained more than 1 type of data). Qualitative review of the literature revealed that, for the most part, ibuprofen was more efficacious than acetaminophen for the treatment of pain and fever in both pediatric and adult populations, and that these 2 drugs were equally safe. Meta-analyses on the subset of randomized clinical trial articles that reported sufficient quantitative information to calculate either an odds ratio (adverse event [AE]) or standardized mean difference (pain and fever) confirmed the qualitative results for adult (standardized mean difference [SMD] 0.69; 95% CI 0.57 to 0.81) and pediatric (SMD 0.28; 95% CI 0.10 to 0.46) pain at 2 hours postdose and pediatric fever (SMD 0.26; 95% CI 0.10 to 0.41) at 4 hours postdose. Conclusions regarding adult fever/temperature reduction could not be made due to a lack of evaluable data. The combined odds ratio for the proportion of adult subjects experiencing at least 1 AE slightly favored ibuprofen; however, the difference was not statistically significant (1.12; 95% CI 1.00 to 1.25). No significant difference between drugs in AE incidence was found for pediatric patients (0.82; 95% CI 0.60 to 1.12). Ibuprofen is as or more efficacious than acetaminophen for the treatment of pain and fever in adult and pediatric populations and is equally safe.

Baseline anxiety effect on outcome of SSRI treatment in patients with severe depression: escitalopram vs paroxetine

Objective:To investigate if treatment outcome for severely depressed patients depends on their baseline level of anxiety.Research design and methods:Patients with a primary diagnosis of severe major depressive disorder (n = 459) were randomised to 24 weeks of double-blind treatment with escitalopram (20 mg) or paroxetine (40 mg). Post hoc analyses of efficacy in patients with a baseline HAM-A total score ≤20 (n = 171) or >20 (n = 280) were based on analysis of covariance (ANCOVA) (ITT, LOCF).Results:At week 24, the mean change from baseline in MADRS total scores was −24.2 for escitalopram-treated patients (n = 141) and −21.5 for paroxetine-treated patients (n = 139) (p < 0.05) in high baseline anxiety patients and the mean change from baseline in HAM-A total score was −17.4 (escitalopram) and −15.1 (paroxetine) (p < 0.05). When examining the proportion of complete remitters (CGI-S = 1) after 24 weeks of treatment, there was an increasing treatment difference as a function of baseline HAM-A total score in favour of escitalopram (ITT, LOCF). There was no treatment difference in the low baseline anxiety group. Significantly more patients (p < 0.01) withdrew from the paroxetine group (31%) than from the escitalopram group (17%), partly as the result of significantly more withdrawals due to AEs (p < 0.05). Incidence of AEs and withdrawals were not related to baseline anxiety and there were no significant differences in the incidence of individual AEs with escitalopram compared to paroxetine.Limitations:The post hoc nature of these analyses, the absence of placebo control group, and the requirement that patients should be suffering from severe depression, limit the generalisability of the results.Conclusion:Patients with severe depression together with comorbid anxiety symptoms responded significantly better to treatment with escitalopram 20 mg compared with paroxetine 40 mg. Contrary to paroxetine, escitalopram maintained its efficacy with increasing baseline anxiety levels.

P03-346 Effects of placebo-controlled withdrawal after long-term open label treatment with OROS MPH in adults with ADHD

ObjectiveTo explore maintenance of effect with OROS MPH in adults with ADHD.MethodsMulticenter study randomizing adult subjects with ADHD who completed open-label (OL) treatment with OROS MPH (18-90mg/day) for at least 52-week and consented to a 4-week, randomized, double-blind (DB), placebo-controlled (PLC) withdrawal period. Efficacy measures included total CAARS score, CAARS-S:S, GAE, CGI-S and CGI-C. Endpoint analyses were performed using LOCF.Results99/155 patients completed the OL OROS MPH treatment phase, only 45/99 patients consented to double-blind randomization. At DB baseline, mean ± SD TCS was 12.1±5.34 (n=23) in the continued OROS MPH group and 16.5±7.49 (n=22) in the placebo group. CAARS changed from DB baseline to DB endpoint by 4.0±7.61 and 6.5±7.82, respectively (p = 0.2586 between groups). CGI-C scores indicated more worsening of symptoms in the placebo group compared to the continued PR OROS MPH (p = 0.0422). Median (range) GAE scores at endpoint were 2.0 (0-3) and 0.5 (0-3), respectively (p=0.0254). Other efficacy endpoints were numerically in favor of OROS MPH. The randomized withdrawal phase may have been underpowered to show statistical significance between treatment groups for the primary outcome. The incidence of treatment-emergent AEs during the DB phase was comparable between groups.ConclusionsThe results indicate that treatment discontinuation after long-term exposure of adults with ADHD to OROS MPH is associated with worsening of clinical symptoms. Statistical significance for several outcomes was not reached, possibly due to study limitations.

PW01-28 - Asenapine as adjunctive treatment for bipolar mania: a placebo-controlled 12-week study and 40-week extension

ObjectivesAsenapine is indicated in adults for acute treatment of schizophrenia and bipolar I disorder. We describe the efficacy and tolerability of adjunctive asenapine in bipolar patients showing incomplete response to lithium or valproate monotherapy.MethodsIn a 12-week core study, patients were randomized to flexible-dose asenapine (5 or 10 mg BID) or placebo as an adjunct to continued mood stabilizer therapy. Patients completing the core study without protocol violations could enter a 40-week extension. Changes from core study baseline on the Young Mania Rating Scale (YMRS) and Montgomery-Asberg Depression Rating Scale (MADRS) total scores were assessed at week 3 of the core study and at week 52 in the extension. Efficacy in the core study was assessed using ANCOVA with LOCF to impute missing data. The extension was not powered for statistical comparisons; descriptive statistics were employed.ResultsThe intent-to-treat population comprised 318 patients (asenapine, 155; placebo, 163) in the core study and 71 (38; 33) in the extension. Mean±SD changes at week 3 with asenapine and placebo, respectively, were -9.7±10.1 versus -7.7±9.6 (P=0.0257) on YMRS and -2.8±7.2 versus -2.2±6.8 (P=0.3684) on MADRS. Mean±SD changes at week 52 with asenapine and placebo were -17.2±13.7 versus -19.7±11.8 on YMRS and -3.3±9.8 versus -3.9±7.7 on MADRS. The incidence of treatment-emergent AEs with asenapine and placebo was 73% and 69% in the core study, 78% and 69% in the extension.ConclusionsAsenapine was effective as an adjunct to mood stabilizer in bipolar I disorder and was well tolerated.

RIBBON-2: A Randomized, Double-Blind, Placebo-Controlled, Phase III Trial Evaluating the Efficacy and Safety of Bevacizumab In Combination with Chemotherapy for Second-Line Treatment of HER2-Negative Metastatic Breast Cancer.

Abstract Background: Three prior Phase III trials (E2100, AVADO, and RIBBON-1) established the clinical benefit of adding bevacizumab (BV) to various chemotherapies (chemos) as first-line treatment for metastatic breast cancer (MBC). A previous Phase III study (AVF2119g) in patients with predominantly heavily pre-treated MBC, in which BV was added to capecitabine (Cape), resulted in a significant increase in objective response rate (ORR), but did not meet the primary endpoint for progression-free survival (PFS). The current study, RIBBON-2, was designed to evaluate the efficacy and safety of the addition of BV to chemotherapies used as second-line treatment for MBC.Methods: Patients were randomized in a 2:1 ratio to chemo+BV or chemo+placebo (PL). Key eligibility criteria included one prior cytotoxic treatment for MBC, ECOG performance status of 0 to 1, and HER2-negative or unknown status. Prior to randomization, investigators chose one of the following chemo agents: taxane (T; paclitaxel 90 mg/m2/wk for 3 of the 4 weeks; paclitaxel 175 mg/m2, nab-paclitaxel 260 mg/m2, docetaxel 75–100 mg/m2, all given q3wk), gemcitabine (G; 1250 mg/m2 on Days 1 and 8 q3wk), Cape (2000 mg/m2 Days 1–14 q3wk), or vinorelbine (V; 30 mg/m2/wk). BV or PL was administered at 10 mg/kg q2wk or 15 mg/kg q3wk, depending on the chemo regimen. The primary endpoint of the study was investigator-assessed PFS pooled across the chemo cohorts. Key secondary endpoints included overall survival (OS), PFS within individual chemo cohorts, ORR, and safety.Results: 684 patients (T, 304; G, 160; Cape, 144; and V, 76) at 211 sites in 19 countries were randomized between February 2006 and June 2008. Overall, the two study arms were balanced for patient characteristics at baseline. The study met its primary endpoint of PFS pooled across chemo cohorts and also demonstrated a 10% increase in ORR when BV was added to chemo. At the interim analysis for OS, the median durations were 18 mo for chemo+BV and 16.4 mo for chemo+PL (see table).Across all chemo cohorts the incidence of BV-related AEs was consistent with data from previous studies. Hypertension was the only BV-related AE consistently increased in the chemo+BV arm across all chemo cohorts.Conclusions: The addition of BV to chemotherapies used for second-line treatment of MBC led to a significant improvement in PFS. The AE profile of BV in the overall study population and across the chemotherapy cohorts was consistent with that previously observed. Additional analyses, including PFS for the individual chemo cohorts, will be presented. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 42.

Efficacy and Safety of First-Line Bevacizumab (BEV) Combined with Paclitaxel (PAC) According to Age: Subpopulation Analysis of a Large, Multicenter, Non-Interventional Study in Patients (Pts) with HER2-Negative Metastatic Breast Cancer (MBC).

Abstract Background: In three randomized phase III trials (E2100, AVADO, RIBBON-1), the combination of Bev with taxane-based therapy significantly improved PFS and response rate versus taxane alone in HER2-negative MBC. Subpopulation analysis of AVADO suggested that the magnitude of the benefit derived from Bev was similar in older and younger pts (≥65 vs &amp;lt;65 years). To gain further information on the safety and efficacy of first-line Bev–pac in older pts treated in the real-life setting, we conducted a subpopulation analysis of data from an ongoing multicenter non-interventional study initiated after the approval of Bev in Germany. Materials and methods: Pts who had received no prior chemotherapy for their MBC were treated with Bev–pac according to the European indication. Efficacy and safety data were collected for up to 1 year (or until progression, death, or discontinuation of Bev if earlier).Results: Safety and efficacy data are currently available for 307 pts, of whom 102 (33%) are ≥65 years and 56 (18%) are ≥70 years (Table). Mean duration of documented Bev therapy was 7.0 months in pts &amp;lt;65 years and 6.4 months in those ≥65 years. &amp;lt;65 years (n=205)≥65 years (n=102)Mean disease-free interval, years ± SD3.8 ± 3.56.8 ± 5.8Tumor grade, %1212476034929Unknown311Metastatic sites, %Liver4347Lung3537Bone5556CNS21Receptor status, %ER and/or PgR positive6673Triple (ER, PgR, HER2) negative2514ECOG performance status, %040321485521010322(Neo)adjuvant chemotherapy, %7052Taxane and anthracycline239Anthracycline, no taxane3427Taxane, no anthracycline40Other715Missing&amp;lt;11Endocrine therapy for MBC, %2531Grade ≥3 Bev-related AEs of special interest, %Hemorrhage/bleeding1.01.0Hypertension2.9a2.0aThrombosis/embolism2.42.0Arterial thrombotic event0.5a1.0aGastrointestinal perforation1.00Proteinuria00Overall response rate, %6047Stable disease, %2223Not evaluable/unknown816PFS events, n (%)106 (52)51 (50)6-month PFS rate, % (95% CI)70 (63–77)63 (53–74)baNo grade 4b69% (95% CI: 56–84) in pts aged ≥70 yearsConclusions: In this study in pts representing real-life practice, the efficacy and safety profile of Bev–pac supports results from prospective randomized clinical trials of Bev combined with taxane-based therapy. Although differences in baseline characteristics complicate interpretation of this analysis, there appeared to be no increase in the incidence of Bev-related AEs of special interest in pts ≥65 versus &amp;lt;65 years. Efficacy was broadly similar irrespective of age; of note, in the small subgroup of pts ≥70 years, the 6-month PFS rate was very similar to that in pts ≤65 years. These data support findings of subpopulation analyses of older pts treated in the AVADO and MO19391 trials. First-line Bev combined with pac in this elderly pt population offers a highly active and well-tolerated treatment, especially when considering that many of these pts may not be candidates for combination chemotherapy. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6085.

Abstract B57: Safety profile of zoledronic acid in a novel oral formulation

Abstract Background: Orazol™(MER-101) tablets utilize GIPET® to formulate an oral alternative to intravenous zoledronic acid (ZA) IV (Zometa®). Orazol's enteric coating and high bioavailability decreases GI exposure and provides a tablet with an excellent safety profile. Three clinical trials on doses from 10 to 20mg demonstrated that a weekly 20mg tablet delivers systemic ZA doses equivalent to 4mg infusions given every 4 weeks. Therapeutic equivalence of 20mg tablets and the 4mg infusion has been demonstrated in prostate cancer patients with bone metastatic disease based on change from baseline values for biomarkers of bone metabolism, including uNTX and sCTX. Methods: Safety information from three open label studies is presented here. MER-101-01 was a pilot single weekly dose, 3-way crossover study in 13 osteoporotic women. Orazol tablets 10mg and 20mg were administered versus a 1mg IV infusion after an overnight fast (and 4 hours fast post-dose). Absorption was determined by LCMS urine assay over 48 hours post-dose. MER-101-02 was a single-dose, 5-way crossover study in 30 postmenopausal women and examined Orazol 15mg and 20mg tablets versus 1mg IV infusion. Absorption was determined by serum LCMS assay over 36 hours post-dose. Treatments:(a) Orazol 15mg, overnight fast, breakfast 30 minutes later.(b) Orazol 20mg, overnight fast, breakfast 30 minutes later.(c) Orazol 20mg, FDA standardized breakfast.(d) Orazol 20mg, bedtime, following a 4-hour fast.(e) ZA 1mg IV infusion. MER-101-03 was a multi-center, 8 week, Phase II study comparing two regimens of Orazol tablets 20mg to the standard dose of ZA 4mg infusion in male bisphosphonate-naive hormone-refractory prostate cancer patients with bone metastases. The cohorts were:Cohort A: ZA 4mg infusion, Day 0 &amp; 28.Cohort B: Orazol tablets 20mg, Days 0, 7, 14, 21, 28, 35, 42 &amp; 49.Cohort C: Orazol tablets 20mg, Days 0, 1, 2, 3, 28, 35, 42 &amp; 49. Safety assessments included AE monitoring, PE, hematology, urinalysis, and blood chemistry panels. Results: Orazol tablets yielded a very acceptable safety profile. In MER-101-03, which evaluated Orazol tablets directly against the 4mg infusion, the greatest incidence of AEs occurred in patients on the ZA infusion (75%). Half of the patients in this cohort experienced fever following administration, which lasted up to 72 hours post-dose. The incidence of bone pain was twice that in patients on oral Orazol therapy. There was a consistent decrease in mean diastolic blood pressure, and a greater number of abnormal hematology laboratory results for patients on IV than for Orazol. In analyzing MER-101-01 and MER-101-02 together, which compared Orazol tablets to a 1mg Zometa infusion, AEs were evenly distributed across groups. GI related AEs were similar with the Orazol treatments compared to the ZA infusions. Conclusions: Based on data collected thus far, Orazol tablets offer a substantial improvement over IV infusion in bisphosphonate therapy for oncological uses. The results of these studies combined with the excellent safety profile of Orazol tablets 20mg administered weekly support further development as a preferred route of ZA administration. Results to date indicate Orazol is an effective and potentially safer alternative to IV ZA, which may substantially improve patients’ quality of life. Orazol offers a new treatment paradigm for patients with metastatic bone cancer. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B57.

A 25-week, open-label trial investigating rivastigmine transdermal patches with concomitant memantine in mild-to-moderate Alzheimer’s disease: a post hoc analysis

Objective:To investigate the tolerability and efficacy of the rivastigmine transdermal patch in patients with mild-to-moderate Alzheimer’s disease receiving concomitant memantine.Research design and methods:Post hoc analysis of a 25-week, randomized, prospective, open-label, parallel-group study. Patients receiving donepezil were switched to rivastigmine patches (4.6 mg/24 h) immediately or following a 7-day withdrawal for 4 weeks (core phase), before titrating up to 9.5 mg/24 h for a further 20-week extension phase. Prior memantine therapy was continued throughout. Clinical trial registration: clinicaltrials.gov. NCT00428389.Main outcome measures:Tolerability (adverse events [AEs], serious AEs [SAEs] and discontinuations) and efficacy (cognition, global functioning and activities of daily living [ADLs]) were assessed for the rivastigmine transdermal patch, with or without concomitant memantine.Results:Overall, 135 and 126 patients received rivastigmine with and without memantine, respectively. Of these, 122 (90.4%) and 118 (93.7%) patients with and without memantine, respectively, completed the core phase; 120 and 114 patients, respectively, entered the extension phase, and 90 (75.0%) and 86 (75.4%) completed the study. The incidences of AEs (73.3 vs. 67.5%) and SAEs (10.4 vs. 7.1%) were both slightly larger in patients receiving concomitant memantine, but the differences were not statistically significant (95% CIs: −5.2, 16.9 and −3.6, 10.1 for AEs and SEAs, respectively). The incidence of gastrointestinal AEs was low in both groups. Discontinuation due to AEs was higher in patients who received memantine (17.0 vs. 11.9%). Changes in cognitive and global function were similar between groups. ADL scores worsened in both groups; significantly more in those treated with memantine.Conclusion:Use of the rivastigmine transdermal patch in patients on established memantine appears to be well-tolerated, with only modest, non-significant increases in AEs compared with monotherapy, and did not seem to affect cognition or global functioning adversely.

Phase II Dose-Finding Study with TAK-442, An Oral Factor Xa Inhibitor, in Patients Undergoing Elective Knee Arthroplasty.

Abstract 170TAK-442 is an oral, selective, direct competitive inhibitor of activated factor X (fXa). This phase 2, multicenter, randomized, parallel-group study compared a range of TAK-442 doses with enoxaparin for thromboprophylaxis after elective unilateral total knee arthroplasty. After surgery, males and females 18 years of age or older were randomly assigned to 1 of 7 treatment groups: TAK-442 at doses of 40 or 80 mg p.o. once daily (QD) or 10, 20, 40, or 80 mg p.o. twice daily (BID), or enoxaparin 30 mg s.c. BID (n=150 per group). Enoxaparin was given unblinded, whereas TAK-442 given double-blinded with regard to dose and regimen. The first dose of TAK-442 was administered 6-8 hours postoperatively and after hemostasis was established, while the first dose of enoxaparin was given 12-24 hours after surgery according to North American guidelines; TAK-442 and enoxaparin were given for 10 days and patients were followed for 30 days after the last dose of study drug. Bilateral ascending venography was performed after the last dose of study drug to screen for deep vein thrombosis (DVT). The primary efficacy endpoint was the composite of all-cause mortality, symptomatic and asymptomatic DVT, and pulmonary embolism (PE). The primary safety endpoint was major bleeding, based on a pre-specified bleeding scale. Independent, blinded committees adjudicated all suspected efficacy outcomes and bleeding events. Of the 1038 patients who received study drug and were included in the full analysis set (FAS) and safety population, 949 completed the study; 730 patients had evaluable venograms. Following the recommendation of the Data Safety Monitoring Board, the TAK-442 10 mg and 20 mg BID groups were discontinued prematurely because of lack of efficacy with respect to asymptomatic DVT. The incidences of the primary efficacy endpoint and its components in the population with evaluable endpoints, and of major bleeding in the safety population, are shown in the table. [Display omitted] Patients in the FAS exhibited a similar trend in efficacy, with incidences of the composite primary endpoint of 28.8%, 25.8%, 16.7%, 14.8%, 18.8%, and 10.6%, respectively, across the TAK-442 doses, and 14.9% for enoxaparin. The minimum effective dose of TAK-442 was determined to be 40 mg QD, while the maximum dose of 80 mg BID tended to be more effective than enoxaparin in this study. The frequency of major and clinically significant non-major (CSNM) bleeding was not dose-dependent or different from that seen with enoxaparin. Similarly, the frequency of liver function test abnormalities was not dose-dependent or different from that seen with enoxaparin. Treatment-emergent AEs leading to study drug discontinuation occurred in 5.5% of the TAK-442 subjects and 7.5% of the enoxaparin subjects. In addition, the overall incidence of AEs or SAEs in the TAK-442 treatment groups was not dose-dependent or greatly different from that seen with enoxaparin 30 mg BID. These data suggest that, at total daily doses of 40 to 160 mg, the efficacy of TAK-442 is similar to that of enoxaparin 30 mg BID in patients undergoing total knee replacement. The low incidence of major and CSNM bleeding suggests that TAK-442 has a favorable benefit to risk profile in this population. Disclosures:Weitz:Daiichi-Sankyo: Consultancy; Bayer: Consultancy; BMS: Consultancy; Pfizer: Consultancy; Boehringer-Ingelheim: Consultancy; Takeda Global Research & Development, Inc.: Consultancy; Astra-Zeneca: Consultancy; The Medicines Company: Consultancy; Merck: Consultancy. Cao:Takeda Global Research & Development, Inc.: Employment. Eriksson:Takeda Global Research & Development, Inc.: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boehringer Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Fisher:Bristol Myers Squibb: Research Funding; Takeda Global Research & Development, Inc.: Honoraria; Bayer: Consultancy, Honoraria, Research Funding; sanofi-aventis: Honoraria, Research Funding, Speakers Bureau; Boeringer-Ingelhiem: Consultancy, Speakers Bureau. Kupfer:Takeda Global Research & Development, Inc.: Employment. Raskob:Takeda Global Research & Development, Inc.: Consultancy; Bayer: Consultancy; BMS: Consultancy; Boehringer –Ingelheim: Consultancy; Daiichi-Sankyo: Consultancy; Johnson and Johnson: Consultancy; Pfizer: Consultancy; sanofi-aventis: Consultancy. Spaeder:Takeda Global Research & Development, Inc.: Employment, Equity Ownership. Turpie:Takeda Global Research & Development, Inc.: Consultancy; Astellas: Consultancy; Portola: Consultancy; Bayer: Consultancy; Johnson & Johnson: Consultancy.

Efficacy and Safety of Deferasirox (Exjade®) in β-Thalassemia Patients with Myocardial Siderosis: 2-Year Results From the EPIC Cardiac Sub-Study.

Abstract 4062Poster Board III-997 BackgroundOver 70% of deaths in regularly transfused patients with β-thalassemia major (TM) are related to iron-induced cardiomyopathy. Deferasirox (Exjade®), in a sub-study of the 1-year multicenter prospective EPIC trial, demonstrated efficacy in reducing myocardial iron in TM patients with mild, moderate and severe cardiac siderosis, as evidenced by a statistically significant improvement in myocardial T2*. We herein report the extension phase results from the same study in patients who have received up to 2 years of deferasirox therapy. MethodsPatients aged ≥10 years with myocardial T2* >5–<20 ms (indicating cardiac siderosis) by cardiovascular magnetic resonance (CMR), left ventricular ejection fraction (LVEF) ≥56%, serum ferritin >2500 ng/mL, MR (R2) LIC >10 mg Fe/g dry weight (dw), and a lifetime minimum of 50 transfused blood units were included in the cardiac sub-study. Deferasirox was initiated at 30 mg/kg/day and increased to 40 mg/kg/day by the time patients had entered the 1-year extension. Dose decreases were allowed for safety reasons. The primary endpoint was change in myocardial T2* from baseline to 2 years. ResultsOut of 100 patients who entered the 1-year extension phase, 85 completed (85%); 24-month CMR data are available for 81 patients. Mean age was 20.6 ±7.3 years. Baseline cardiac T2* was <10 ms (severe cardiac siderosis) in 39 patients (39%) and 10–20 ms (mild-to-moderate cardiac siderosis) in 61 (61%). 67.0% had received prior deferoxamine (DFO) and 33.0% prior DFO/deferiprone combination therapy. Mean actual deferasirox dose increased from 33.1 ±3.7 mg/kg/day in the core 1-year phase to 36.1 ±7.4 mg/kg/day during the extension. Continued improvement in myocardial T2* was observed in the extension phase so that after 2 years of deferasirox treatment, T2* had significantly increased from a baseline geometric mean of 11.2 to 15.3 ms (P<0.001). Significant increases from 7.3 to 9.3 ms (P<0.001) and from 14.6 to 19.9 ms (P<0.001) were respectively noted in patients with baseline T2* <10 and 10–20 ms (Figure). LVEF remained stable in both subgroups throughout the 2-year follow up period. Both mean LIC and median serum ferritin were significantly reduced from baseline by 10.7 ± 12.8 mg Fe/g dw and 2343 ng/mL (range –12795 to 25127), respectively (P<0.001; based on last-observation-carried-forward analysis). [Display omitted] Reasons for discontinuation were: unsatisfactory therapeutic effect (n=8), consent withdrawal (n=3), protocol violation (n=2), lost to follow up (n=1) and abnormal laboratory value (increased urinary protein/creatinine ratio) leading to consent withdrawal (n=1); no deaths were reported. Incidence of investigator-assessed drug-related AEs (≥5%) decreased overall from the core phase to the extension: increased blood creatinine (n=21 [21.0%] vs n=18 [18.0%]), rash (n=15 [15.0%] vs n=0), increased alanine aminotransferase (ALT) (n=6 [6.0%] vs n=4 [4.0%]) and increased aspartate aminotransferase (n=4 [4.0%] vs n=3 [3.0%]). There were no drug-related serious AEs over 2 years. In total, 4 patients (4.0%) had increased serum creatinine >33% above baseline and the upper limit of normal (ULN) on two consecutive visits; 3 patients (3.0%) during the core and 1 (1.0%) during the extension. 4 (4.0%) patients had increased ALT >10xULN on two consecutive visits; 2 patients (2.0%) during the core and 2 (2.0%) during the extension; levels were already >ULN at baseline in these patients. ConclusionsThis is the first large prospective study to report 2-year data on cardiac iron removal for any iron chelator. Results show that continued therapy with deferasirox for up to 2 years at doses 30–40 mg/kg/day was effective in removing iron from the heart in TM patients with mild, moderate and severe cardiac siderosis. Myocardial T2* continued to improve in year 2 and the statistically significant improvement from baseline was associated with maintenance of normal cardiac function and a concomitant decrease in hepatic and total body iron burden. Overall, deferasirox was well tolerated. Disclosures:Pennell:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Apopharma: Consultancy, Honoraria; Cardiovascular Imaging Solutions: Equity Ownership; Siemens: Research Funding. Off Label Use: THE SPECIFIC USE OF CHELATION FOR CARDIAC SIDEROSIS IS OFF-LABEL. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vifor International: Membership on an entity's Board of Directors or advisory committees. Cappellini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees. Chan:Novartis: Honoraria, Research Funding. Aydinok:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ibrahim:Novartis: Research Funding. Li:Novartis: Consultancy, Speakers Bureau. Viprakasit:Thai Government : Employment; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Government Pharmaceutical Organization of Thailand: Honoraria, Research Funding. Kattamis:Novartis: Consultancy, Honoraria, Speakers Bureau. Smith:Novartis Pharma AG: Consultancy, Employment at Royal Brompton Hospital funded by Novartis Pharma AG. Habr:Novartis Pharmaceuticals: Employment. Domokos:Novartis Pharma AG: Employment. Roubert:Novartis Pharma AG: Employment. Taher:Novartis: Honoraria, Research Funding.

Neutropenia Is a Predictable and Early Event in Affected Patients with Relapsed/Refractory Multiple Myeloma Treated with Lenalidomide in Combination with Dexamethasone.

Abstract 2879Poster Board II-855 Background:Lenalidomide (len) is an immunomodulatory compound with established clinical efficacy and safety in patients with multiple myeloma (MM). Two pivotal phase III trials in patients with relapsed/refractory MM evaluating lenalidomide + dexamethasone (len + dex) vs placebo + dex (MM-009 and MM-010) demonstrated that len + dex is well tolerated with significant improvements in response and overall survival in comparison to placebo + dex (Weber et al, NEJM 2007; Dimopoulos et al, NEJM 2007). Despite a favorable safety profile, neutropenia is one of the most common hematologic adverse events in patients receiving len + dex. Patients who experience neutropenia may require dose adjustments or discontinuation of len + dex therapy. The aim of this study was to understand the incidence, onset, and duration of neutropenia in patients with relapsed/refractory MM receiving long-term administration of len + dex. Methods:Pooled data for patients treated with len + dex from the two phase III studies (MM-009/010) with a median follow-up of 48 months in all patients surviving as of the data cutoff of July 2008, were analyzed for all neutropenia reported as adverse events (neutropenic AE), including all related terms. The change in incidence and severity of neutropenic AE over time was determined by capturing the highest grade of event reported for each patient within each month. Both the severity (grades 1-4) and duration (days) of neutropenic AE were also determined for patients within each month. To evaluate the change in the rate of neutropenic AE for all patients by month, monthly rates were modeled using Poisson regression with a factor for month and the log of the total number of patients included as an offset parameter. Results:Of 353 patients treated with len + dex, 164 (46%) experienced a neutropenic AE of any grade at some point during the course of the study. A grade 3 or 4 event occurred in 137 (39%) patients. Of the patients who experienced neutropenic AE of any grade, 97 (59%) received G-CSF at some point in the study compared to 8 (4%) of the patients without neutropenic AE. Sixty percent of patients who experienced a neutropenic AE, experienced more than 1 event. Overall, neutropenic AE occurred early, with 52% and 76% of patients experiencing their most severe event within 6 and 12 months of therapy, respectively (Figure). Only 24% of patients who experienced neutropenia experienced their highest grade of event after 12 months of therapy. The median duration of neutropenic AE overall was 10 (25th percentile 8; 75th percentile 29) days. The majority of severe neutropenic AE were grade 3, with very few patients experiencing a grade 4 event. Of the 353 patients treated with len + dex, only 11 (3.1%) patients had febrile neutropenia (12 events). Seven of the patients had their first febrile neutropenia within the first 6 months and 4 patients after 12 months. Twelve patients (3.3%) had their study drug discontinued due to a neutropenic event. Overall, the incidence, severity, and the duration of any neutropenic events did not significantly change over time. [Display omitted] Conclusions:Overall, the first neutropenic AE in patients receiving len + dex occurs early, with more than 50% of patients experiencing their highest grade of event within 6 months of initiation of therapy and only 3.1% of patients treated with len + dex developed febrile neutropenia. These data support the predictable safety profile of len + dex, thereby supporting the long-term use of len + dex in patients with relapsed/refractory MM, and demonstrating the predictable safety profile of this combination therapy. Disclosures:Lonial:Gloucester: Research Funding; Novartis: Consultancy; BMS: Consultancy; Millenium: Consultancy, Research Funding; Celgene: Consultancy. Baz:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Swern:Celgene: Employment. Weber:Celgene: Honoraria, Research Funding. Dimopoulos:Celgene: Honoraria.

Aclidinium bromide provides long-acting bronchodilation in patients with COPD

Aclidinium bromide is a novel, long-acting, muscarinic antagonist in phase III development for the maintenance treatment of COPD. This phase IIb study investigated the efficacy and safety of aclidinium for the treatment of moderate to severe COPD to establish the optimal dose for phase III studies. A total of 464 patients with moderate to severe stable COPD were randomised to double-blind, once-daily treatment with aclidinium (25, 50, 100, 200, or 400 μg), placebo, or open-label tiotropium (18 μg) for 4 weeks. Spirometric measurements were performed at 22–24 h after the first dose and then at weekly intervals, and from 0.5 to 6 h post-dose on day 1 and day 29. Compared with placebo, aclidinium 200 μg and 400 μg significantly increased trough FEV 1 on day 29 versus baseline. During the first 6 h post-dose, the bronchodilatory effect of aclidinium (all doses) on day 1 was comparable to that on day 29. Time to peak FEV 1 was 3 h for aclidinium 100–400 μg. Aclidinium was well tolerated, with no dose-dependent effect on ECG, laboratory parameters, or adverse events. The incidence of AEs was generally comparable to placebo. Aclidinium produced sustained bronchodilation over 24 h and was well tolerated during this short-term study. Based on these data, aclidinium 200 μg was selected as the investigational dose for future clinical trials in COPD.

An open, randomized, multicentre, phase III trial comparing the efficacy of two tamoxifen (T) schedules in preventing gynecomastia (gy) induced by bicalutamide monotherapy (BM) in prostate cancer patients (pca pts)

e16080 Background: BM is a valuable option for pca pts who wish to avoid the consequences of androgen deprivation and to mantain sexually active.BM is commonly well tolerated:however gy and mastalgia virtually develop in all pts and represent a major cause of treatment discontinuation. We had previously demonstrated that T is safe and effective in preventing breast events induced by BM without affecting B tumor activity (Boccardo, J Clin Oncol. 2005;23:808). However possible interferences between B and T,especially after prolonged administration, remain a matter of concern.In order to reduce the exposure to T,we considered the putative advantages of a weekly administration based on T effects being dose -dependent and on drug long half-life. Methods: This was a non inferiority trial. 80 pts with localized, locally advanced or biochemically recurrent pca were randomly assigned to receive daily B (150 mg) plus T 20 (mg) continuously (d group: n = 41) or same but with T at 20 mg/weekly after the first 8 weeks (wk group: n = 39). Gy (primary endpoint), breast pain (bp), serum PSA levels and sexual functioning scores were evaluated. Results: At a median F.U. of 24.2 mos (95% CI: 23.7 -24.6) gy developed in 31.7% of pts in d group and in 74.4% of pts in wk group (p &lt; 0.000). Bp occurred in 12.2% and 46.1% of pts respectively (p = 0.008) and it was more severe in patients switched to weekly T. The incidence of Aes was comparable (d group:58.8%;wk goup: 56.4%). However most events were mild and easily manageable. There were no major differences among treat. schedules relative to sexual functioning scores, PSA behaviour and disease progression. Conclusions: This study failed to demonstrate that it might be possible to maintain comparable prophylactic effect of T by switching from a daily to a weekly schedule and confirms that T at the daily dose of 20mg is safe and effective in preventing the incidence and severity of BM induced breast events. No significant financial relationships to disclose.

A phase II multicenter study of CNTO 328, an anti-IL-6 monoclonal antibody, in patients (pts) with relapsed or refractory multiple myeloma (MM)

8527 Background: Relapsed/refractory MM constitutes a specific and unmet medical need with poor overall response and survival. Interleukin-6 (IL-6) plays an important role in MM cell proliferation, survival, and corticosteroid resistance and previous studies have shown clinical benefit from anti-IL-6 therapy. We therefore evaluated the combination of CNTO328, a chimeric monoclonal antibody with high affinity for human IL-6, and dexamethasone (dex) in pts with relapsed/refractory MM. Methods: Pts were treated with 6 mg/kg CNTO328 IV Q2 weeks. Oral dex (40mg) was given once daily, days 1–4, 9–12, and 17–20 for a max of 4 cycles; and on days 1–4 for subsequent cycles. Inclusion criteria were &gt; 2 prior lines of systemic therapy, creatinine clearance &gt;20 ml/min, platelets &gt;50,000/mm3, and neutrophils &gt;1000/mm3. Primary endpoint was overall response with secondary endpoints of time to progression, incidence of AEs and SAEs. Results: Thirty-nine pts received at least 1 infusion of CNTO328 in combination with dex - median age 66 yrs (range 43–89), median disease duration 4.2 yrs (1–13), median lines of prior therapy 5 (2–9) including bortezomib (100%), IMIDs (87%), and ASCT (59%). The median duration of therapy was 3.3 months (0.5–21+). Of the 36 pts who were evaluable, the overall response rate (CR+PR+MR) using EBMT criteria was 31% (7PR, 4MR). An additional 4 uMR and 4 SD lasting ≥3 months have been reported. PRs were durable; 6 out of 7 pts had responses ranging from 3 months to up to more than 1 year (with 1 still ongoing for more than 1 year). Duration of MRs ranged from 2–5 months. Responses were seen in pts relapsing after and refractory to at least one other prior treatment including bortezomib, IMIDs, or steroids. Median time to disease progression (PD) was 3.7 months (0.3–18+). Main reasons for treatment discontinuation were PD (24) and AEs (6). Hematologic toxicities Grade ≥ 3 were common though not dose-limiting. Three pts had Grade ≥ 3 infections considered reasonably related to CNTO328. Conclusions: CNTO 328 in combination with dex shows promising preliminary activity in this heavily pretreated patient population with an acceptable safety profile. Further investigation is ongoing. No significant financial relationships to disclose.

Phase II study comparing volociximab (an antiangiogenic antibody) and pegylated liposomal doxorubicin (PLD) with PLD alone in recurrent ovarian or primary peritoneal cancer

5560 Background: Volociximab (V), a chimeric monoclonal antibody with direct antitumor effects, blocks α5β1 binding to fibronectin and induces apoptosis in proliferating endothelial cells. A Phase I/II study was performed to evaluate PLD with/without V in patients (pts) with recurrent ovarian or primary peritoneal cancer that relapsed after platinum/taxane-based chemotherapy (maximum 2 prior lines). Methods: A 3-arm adaptive randomization design compared efficacy and safety of PLD (40 mg/m2 q4wk) + V (15 mg/kg q2wk or qwk) vs. PLD alone. Pts were stratified by platinum sensitivity and received treatment until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Pharmacokinetic (PK) and pharmacodynamic effects were also evaluated. Results: There were 6 iterations of adaptive randomization based on accumulating PFS data. 127 pts were randomized: 66 in Group A (PLD), 34 in Group B (PLD+V [q2wk]), and 27 in Group C (PLD+V [qwk]). The incidence of AEs was balanced across treatment groups. The most common Grade 3/4 AEs (≥5% in any group) were abdominal pain, intestinal obstruction, ascites, fatigue, hypoalbuminemia, and cytopenias. Based on preclinical data, therapeutic levels of V were maintained during treatment, and V did not appear to alter the PK of PLD. Response rates were comparable across groups. There were no CRs; PRs were 16%, 18%, and 19%. The median PFS estimates were 193, 164, and 221 days. Conclusions: The safety profile of V+PLD appeared similar to PLD alone. Preliminary analysis of PFS suggested that there was a low probability of detecting a statistically significant difference in favor of V+PLD, so the study was closed to enrollment. Analyses correlating PFS with platinum sensitivity and α5β1 tumor expression are ongoing. [Table: see text]

Hepatobiliary (HB) safety of eltrombopag administered after carboplatin+paclitaxel (Carb+Pac) in patients (pts) with solid tumors

e20667 Background: Eltrombopag is an oral, small molecule, non-peptide, TPO-receptor agonist studied for the treatment of thrombocytopenia (TCP) due to various causes, including chemotherapy (CT)-induced TCP and is approved for the treatment of chronic ITP in the US. Since eltrombopag is excreted primarily through the liver and liver function is an important safety parameter, HB lab values and AEs were analyzed in a double-blind, placebo (pbo)-controlled, multicenter ph II study. Methods: The safety of eltrombopag was evaluated in adults with advanced solid tumors (mainly NSCLC and ovarian). Pts received up to 8 cycles of Carb (AUC 5–6 IV) + Pac (175–225 mg/m2 IV), both administered on day 1 q 21 days. 183 pts were randomized to eltrombopag 50, 75, 100mg, or pbo (1:1:1:1). Eltrombopag or pbo were taken from Day 2 - 11 in each cycle of CT. Results: Baseline characteristics, prior medical conditions and number of CT cycles during the study were similar between the treatment groups. At baseline, one pt reported liver metastases (75mg group). Similar numbers of pts had HB lab abnormalities in all groups ( table ). Additionally, HB AEs (34 AEs) occurred in 15 pts across all treatment groups ( table ). Conclusions: In this study, eltrombopag did not increase the incidence of HB AEs or HB lab abnormalities compared to pbo. [Table: see text] [Table: see text]

Safety and efficacy of first-line bevacizumab (B) plus chemotherapy (CT) for locally recurrent or metastatic breast cancer (LR/mBC): Analysis of MO19391 according to CT

1033 Background: Combination of B with first-line paclitaxel (TP) or docetaxel (TD) significantly improves PFS vs taxane alone in pts with LR/mBC. The open-label, multicenter MO19391 trial further assessed safety and efficacy of first-line B plus a taxane in &gt;2,000 pts in routine clinical practice. Methods: Eligible pts had HER2- negative LR/mBC (or HER2-positive LR/mBC progressing after trastuzumab-containing therapy), ECOG PS 0–2, no prior CT for LR/mBC and no evidence of CNS metastases. Pts received B 10mg/kg q2w or 15mg/kg q3w plus the physician's choice of taxane (TP or TD alone or with another CT) or other non-anthracycline CT according to physician's standard of care. Treatment was continued until disease progression, unacceptable toxicity, or refusal. The primary endpoint was safety (NCI CTCAE v3.0); secondary endpoints included TTP, OS, and safety in pts developing CNS metastases. Results: From Sept 2006 to June 2008, 2,027 pts from 37 countries were enrolled. Median follow-up is 7.4 months. CT included a taxane (alone or with CT) in ∼75% of pts. Non-taxane agents included capecitabine (X) and vinorelbine (V). In the overall population, median age was 54 years (range 21–93), 70% were ER and/or PgR positive, and 32% had disease-free interval (DFI) ≤24 months. Baseline characteristics were broadly similar across subgroups. However, the X monotherapy subgroup included fewer pts with &gt;3 metastatic lesions and more with a DFI ≤24 months and/or triple-negative disease compared with other subgroups. Safety and efficacy results grouped by CT are shown below. OS data are still immature (85% of pts alive at this analysis). Conclusions: In this large phase IV study, safety and efficacy of B plus TP or TD was similar to results of E2100 and AVADO. Variations in toxicities were consistent with the known profiles of each CT and no new safety signals for B were observed. The lowest incidences of serious Aes were seen with B plus TP or X. TTP was shorter with X and non-taxane combinations. Such findings are potentially attributable to small pt numbers and differences in baseline characteristics. These results show that B can be safely and effectively combined with a wide range of commonly used CT regimens as first-line therapy for mBC. [Table: see text] [Table: see text]