Abstract Background A Phase III trial (Study 301; NCT00337103) in MBC comparing eribulin (E) with capecitabine (C) showed a trend for improved overall survival (OS) (hazard ratio [HR] 0.88; 95% CI 0.77, 1.00; P = 0.056) but not progression-free survival (PFS) (HR 1.08; 95% CI 0.93, 1.25; P = 0.30) with E. In order to investigate this apparent discordance, post-hoc analyses assessed the effect of PPT and events defining disease progression on OS. Methods Pts with locally advanced or MBC who had received an anthracycline and a taxane (≤2 prior chemotherapy regimens for advanced disease), were randomized to E (554) or C (548). Co-primary endpoints were OS and PFS. The impact of PPT on OS was assessed by analysis of exploratory PPT subgroups. Analyses of OS sensitivity censoring at time of PPT, and OS adjusted by PPT as a time-dependent covariate in a Cox regression model, were performed. The relationship between OS and progression events (appearance of a “new” lesion or metastasis [NM]; increase in size of pre-existing lesions [IPEL]; or other [death, clinical progression, or censored]) was investigated using Cox regression. Results PPT was received by 70% and 62% of E and C pts, respectively. For E pts, there were no significant OS differences by PPT (Table 1). Excluding 56 pts (22 E, 34 C) who received anti-HER2 therapy as PPT from the intent-to-treat OS analysis, OS was longer with E (HR 0.86; 95% CI 0.76, 0.99; nominal P = 0.03). OS sensitivity analysis censoring at time of PPT was consistent with the overall study results (HR 0.82; 95% CI 0.65, 1.03). Assessment of the overall effect of PPT, adjusting by PPT as a time-dependent covariate in a Cox regression model, showed that OS was longer with E (HR 0.85; 95% CI 0.75, 0.97; nominal P = 0.02). Progression due to NM or IPEL occurred in 271 and 147 of E pts, and 285 and 129 of C pts, respectively. Median OS was similar between arms in pts with IPEL and longer with E vs C in pts with NM (Table 2). Pts who progressed due to NM were at higher risk of death (HR 2.12; 95% CI 1.84, 2.43; nominal P<0.01). Conclusions Treatment with C or any other PPT after progression on E did not account for the trend in OS benefit with E observed in the primary analysis. Pts who progressed with NM had a worse prognosis than those with IPEL. The appearance of NM was highly correlated with OS, and the apparent discordance between PFS and OS seems to be related to these different progression events. Tab 1: OS by PPT after EPPTAll ptsC as 1stOther than C as 1stC at any timeOther than C at any timeNoneN554221169275115164Median OS, months (95% CI)15.9 (15.2, 17.6)18.3 (15.8, 20.9)19.9 (17.6, 24.0)19.6 (17.6, 21.5)18.0 (15.4, 22.7)7.4 (6.2, 9.1) Tab 2: OS by progression event Progression event NMIPELOther ECECECN271285147129136134Median OS, months (95% CI)15.5 (14.2, 17.5)12.9 (11.3, 14.5)17.4 (14.4, 19.7)17.4 (15.3, 20.9)16.7 (14.8, 24.2)15.5 (11.7, 18.3)HR (95% CI)0.81 (0.68, 0.97)1.13 (0.87, 1.46)0.78 (0.59, 1.03)Nominal P -value0.020.350.08Time to NM or death, months (95% CI)5.8 (5.2, 6.5)5.2 (4.3, 5.9)NANAHR (95% CI)0.90 (0.77, 1.05)NANANominal P-value0.17NANA Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-13-03.

Abstract Background: The Phase III trial (NCT00337103) compared eribulin (E) with capecitabine (C) in patients (pts) with metastatic breast cancer (MBC) in the 1st-, 2nd-, and 3rd-line setting. Median overall survival (OS) was 15.9 and 14.5 months (HR 0.88; 95% CI 0.77, 1.00; P = 0.056) and median progression-free survival (PFS) was 4.1 and 4.2 months (HR 1.08; 95% CI 0.93, 1.25; P = 0.30) for E and C, respectively. This analysis compares toxicity and efficacy of E and C in relation to age. Material and methods: In this post-hoc exploratory analysis, the effect of age on the incidence of adverse events (AEs), OS, PFS, and objective response rate (ORR) with E and C were analyzed for two age groups: ≤65 years (E, n = 468; C, n = 491) and >65 years (E, n = 86; C, n = 57). For OS and PFS, analyses were stratified by HER2 and geographic region. Results: With increasing age, the proportion of pts with worse performance status (PS ≥1: 54.5% vs 69.2% for ≤65 and >65 years, respectively), ER+ (47.4% vs 57.3%), and PgR+ MBC (41.3% vs 45.5%) increased, and the proportion with triple-negative MBC decreased (26.6% vs 20.3%). With both treatments, AEs were reported in a higher proportion of pts in the older age group, this becoming more apparent for grade 3+ AEs (E: 64.6% vs 70.2%, and C: 45.0% vs 54.4% for ≤65 and >65 respectively). With E, there was a trend for increased incidence of grade 3/4 neutropenia (45.0% vs 50.0%) and leukopenia (13.7% vs 22.6%) but, in contrast, decreased peripheral sensory neuropathy (3.9% vs 1.2%) with increasing age. For C, there was a trend for increased palmar-plantar erythrodysethesia syndrome (total: 44.4% vs 50.9%; grade 3/4: 14.1% vs 17.5%), and grade 3/4 fatigue (1.8% vs 7.0%) and diarrhea (4.7% vs 10.5%) with increasing age; emesis and nausea were similar for both age groups. Dose adjustments due to AEs with E were slightly higher in the older age group: withdrawals 7.4% vs 10.7%; dose reductions 31.1% vs 36.9%; and dose delays 30.9% vs 36.9%. With C, there was a trend for an increased incidence of withdrawals (9.2% vs 21.1%) and dose delays (34.2% vs 49.1%) due to AEs with increasing age: the incidence of dose reductions was slightly higher in the older age group (31.3% vs 36.8%). In an unadjusted analysis, a trend for improved OS with E vs C was observed in both subgroups (≤65 years: median 15.8 vs 14.5 months; HR 0.90; 95% CI 0.78, 1.04; P = 0.16, and >65 years: median 18.4 vs 14.1 months; HR 0.74; 95% CI 0.50, 1.12; P = 0.16). PFS and ORR for E and C were: median PFS: E, 4.0 and 5.4 months; C, 4.2 and 5.9 months; ORR: E, 10.9% and 11.6%; C, 11.6% and 10.5%, in the ≤65 and >65 groups respectively. Conclusions: This exploratory and unadjusted analysis suggests a trend for improved OS with E in both younger and older pts with MBC. With both treatments there was a suggestion that AEs were reported in a higher proportion of pts in the older age group, this becoming more apparent for grade 3+ events. Specifically, these data suggest an increased incidence of grade 3/4 diarrhea, dose delays, and study withdrawal due to AEs in pts treated with C, and potentially suggest that with E there may be less difference between the AE profile in younger vs older pts than with C. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-13-04.

Poster Retreat vom ASCO 2013. Abstract: Zielsetzung: Eine Phase III-Studie zum Vergleich Eribulin (E) gegen Capecitabin (C) bei Patientinnen mit lokal fortgeschrittenem oder metastasiertem Brustkrebs (mBC) konnte keine statistisch signifikante Überlegenheit hinsichtlich PFS oder OS zeigen. Die Verträglichkeitsprofile entsprachen bekannten Nebenwirkungen. Hier werden die Lebensqualitätsdaten (QoL) vorgestellt. Materialien und Methoden: Patientinnen erhielten entweder 1,23 mg E/m2 an Tag 1 und 8 oder C 1,25 g/m2 2x täglich p.o. an Tag 1 – 14 in einem 21 Tage Zyklus. Patientinnen mussten vorherige Behandlung mit Anthrazyklin oder Taxan erhalten haben und erhielten die Studienmedikamente als Erst-, Zweit-, oder Drittlinientherapie für fortgeschrittene Erkrankung. Lebensqualität wurde als sekundärer Endpunkt mittels EORTC QLQ-C30 und QLQ-BR23 Fragebögen bei Studienbeginn, nach 6 Wochen, 3, 6, 12, 18 und 24 Monaten nach Behandlungsbeginn (oder bis Progression/Therapiewechsel) sowie bei ungeplanten Studienvisiten bestimmt. Longitudinale Analysen wurden anhand von gewichteten allgemeinen Schätzfunktionen durchgeführt, wobei für nicht-zufällige Abgänge durch Lebensverlust innerhalb von 12 Monaten adjustiert wurde. Covariate Faktoren waren die Zeit (Studienvisite), Region und Lebensqualität bei Studienbeginn. Primärer Endpunkt: Veränderung versus Baseline des Global Health Status (GHS/QoL insgesamt); explorativ: Änderung versus Studienbeginn für einzelne Funktionsbereiche und Parameter/Symptome. Ergebnisse: 1102 randomisierte Patientinnen (E 554; C 548) mit niedrigen GHS/QoL Scores (E 56,3; C 54,7 [100 = beste QoL zeigten unter E signifikant stärkere Besserung von GSH/QoL und kognitiver Funktion (E vs. C 6,5 [p = 0,048] bzw. 15,3 [p < 0,001]. C zeigte für emotionale Funktionalität signifikant stärkere Besserung (C vs. E 3,3 [p = 0,033]). Die Stärke von Schmerzen zu Studienbeginn und Abnahme unter Therapie war vergleichbar für E und C. Patienten berichteten unter E von weniger Anzeichen/Symptomen wie Übelkeit und Erbrechen (-1,9; p = 0,043) und Diarrhö (-3,7; p = 0,001). Unter C wurden weniger systemische unerwünschte Wirkungen (5,2; p < 0,001) und Probleme mit Haarverlust berichtet (9,3; p = 0,023). Zusammenfassung: GHS/QoL Scores verbesserten sich stärker bei Patienten unter E als C. Eribulin zeigte Vorteile hinsichtlich gastrointestinaler Effekte, C zeigte Vorteile hinsichtlich Haarverlust.

Poster Retreat vom ASCO 2013: Abstract: Zielsetzung: Diese Phase III-Studie zum Vergleich von Eribulin und Capecitabin zeigte für Eribulin einen nicht-signifikanten Trend zu einem verbesserten Gesamtüberleben (OS; hazard ratio [HR] 0,88 [95% Confidence Intervall (CI) 0,77 – 1,00]; p = 0,056) aber nicht für Progressionsfreies Überleben (PFS; HR 1,08 [95% CI 0,93 – 1,25]; p = 0,31). Bereits gezeigte vordefinierte explorative Subgruppen-Analysen legten nahe, dass Patientinnen mit triple-negativem, Östrogenrezeptor-negativem oder HER2-negativem Brustkrebs unter Eribulin einen größeren Benefit hinsichtlich OS im Vergleich zu Capecitabin haben. Hier werden weitere geplante explorative Analysen zu OS und PFS gezeigt. Materialien und Methoden: An dieser Studie teilnehmende Patientinnen (Eribulin: n = 554; Capecitabin n = 548) mit lokal fortgeschrittenem oder metastasiertem Brustkrebs erhielten ≤3 vorherige Chemotherapie-Regime (≤2 in der fortgeschrittenen Situation), darunter ein Anthrazyklin und ein Taxan. Patienten wurden im Verhältnis 1: 1 auf 1,23 mg/m2 Eribulin an Tag 1 und 8 oder 1,25 mg/m2 Capecitabin 2x täglich p.o. an Tag 1 – 14, jeweils als 21-Tage Zyklus, randomisiert (stratifiziert nach geographischer Region und HER2-Status). Weitere geplante explorative Subgruppen-Analysen umfassten: Alter, Rezeptorstatus, Anzahl und Setting vorheriger Chemotherapie Regime, Lokalisation der Metastasen, Anzahl befallener Organe und Zeit bis zur Progression nach der letzten Chemotherapie. Ergebnisse: Weitere Analysen zum Gesamtüberleben zeigen, dass Patienten unter Eribulin mit ausschließlich nicht-viszeraler Erkrankung (HR 0,51; 95% CI 0,33 – 0,80), mit > 2 befallenen Organen (HR 0,75; 95% CI 0,62 – 0,90) und Progression nach > 6 Monate nach letzter Chemotherapie (HR 0,70; 95% CI 0,52 – 0,95) oder Therapie mit einem Anthrazyklin und einem Taxan in der metastasierten Situation (HR 0,84; 95% CI 0,72 – 0,98) stärker von einer Eribulin-Behandlung als von Capecitabin profitieren könnten. Hinsichtlich OS wurde in keiner der untersuchten Subgruppen ein Vorteil für Capecitabin gesehen. Weitere Daten zu PFS und OS bei anderen vordefinierten Subgruppen werden noch gezeigt. Zusammenfassung: Zusätzlich zu Patientinnen mit triple-, Östrogenrezeptor- oder HER2-negativer Erkrankung weisen weitere geplante explorative Analysen darauf hin, dass auch andere Patientengruppen spezifisch von einer Eribulin-Behandlung profitieren könnten; weitere Studien sind notwendig, um diese Hypothese zu überprüfen.

Background: Management of advanced breast cancer frequently includes palliative radiation therapy (RT) and many chemotherapy agents are radiation-sensitizers. We assessed whether the safety profile of eribulin differed between metastatic breast cancer (MBC) patients receiving eribulin alone and those who also received palliative RT. Methods: Two previous phase 2 and 3 eribulin trials (Studies 211 and 305, respectively) enrolled a total of 794 patients with locally recurrent or MBC who had received 2–5 prior chemotherapy regimens. In both trials eribulin mesylate (1.4 mg/m 2 ) was given on Days 1 and 8 of a 21-day cycle and intercurrent palliative RT was permitted. In this post-hoc analysis, patient-level data were pooled for a descriptive comparison of adverse events (AEs) between the patients who received RT during their study treatment and those who did not. RT delivered within 3 weeks of initiation of eribulin or RT encompassing >30% of marrow was excluded. If palliative RT was utilized on study, the protocol requirements were as follows: indications included bone pain, bronchial obstruction, ulcerating skin lesions; the total field for palliative RT was not to involve >10% of total bone marrow; and the irradiated lesion was not to be used for tumor response assessment. During palliative RT, eribulin treatment was to be delayed and then resumed when the patient had recovered from any RT-associated toxicities. Results: Of the 794 patients (291 patients in Study 211 and 503 in Study 305) who received eribulin, 44 (5.5%) received palliative RT. The majority (26/44, 60%) received ≥10 cGys. Baseline demographics were similar between the RT (n = 44) and no RT (n = 750) subgroups, as was the use of concomitant medications. Six of 44 patients (14%) continued eribulin treatment during the palliative RT, contrary to protocol recommendation. The AE profiles over the course of the study were similar between subgroups. The most common events reported in both subgroups (RT vs no RT) were neutropenia (50% vs 55%), alopecia (48% vs 51%), nausea (43% vs 40%), fatigue (39% vs 32%), and asthenia (27% vs 32%). There were no significant differences in Grade 3/4 treatment-emergent AEs, or other AEs (total AEs: 56.8% vs 58.9%). Potential localized events that were more frequent in the RT subgroup were bone pain (27% vs 15%), back pain (27% vs 10%), and musculoskeletal pain (14% vs 8%); many represent potential indications for RT. Half (22/44) of patients started RT 30 days after the start of eribulin treatment. Palliative RT was short in duration; 33 (75%) patients received ≤7 days, and 11 (25%) patients received 8–20 days. Six of the 44 irradiated patients (14%) had a skin-related toxicity, but most were alopecia (7/8 events) and all were associated with eribulin. Conclusions: This post-hoc subgroup analysis suggests palliative RT while receiving eribulin treatment does not appear to have an effect on the AE profile of eribulin. Further studies to define the optimal use of radiotherapy with eribulin are warranted. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-11-14.

Abstract Background: Eribulin is a non-taxane microtubule dynamics inhibitor. In a previous Phase III trial, eribulin demonstrated a statistically significant improvement in overall survival (OS) versus current treatments and a manageable toxicity profile, in heavily pre-treated patients (pts) with metastatic breast cancer (MBC). Here we report results from a Phase III trial of eribulin compared with capecitabine in earlier-line pts with MBC (NCT00337103). Patients and methods: Pts were randomized 1:1 to eribulin mesylate 1.4 mg/m2 given on Days 1 and 8 of a 21 day cycle or capecitabine 2.5 g/m2/day administered orally BID on Days 1 to 14 of a 21 day cycle. Eligible pts had received prior therapy including an anthracycline and taxane, and were receiving study drug as 1st, 2nd, or 3rd line therapy for advanced disease. The co-primary endpoints of this study were OS and progression free survival (PFS): pre-specified statistical significance at final analysis for eribulin versus capecitabine were p ≤ 0.0372 for OS and p < 0.01 for PFS. Secondary endpoints included objective response rate (ORR), quality of life (QoL) measured using the EORTC questionnaire, duration of response, 1-, 2- and 3-year survival, and safety. The study was stratified for geographic region and HER2 status. Results: Of 1102 pts, 554 were randomized to eribulin and 548 capecitabine (375 and 380 pts were HER2[−], respectively). The median age was 54.0 years (range 24–80). Pts received study treatment as their 1st (27.2%), 2nd (57.4%) or 3rd-line (14.7%) chemotherapeutic regimen in the setting of metastatic disease. The median number of treatment cycles was 6 for eribulin and 5 for capecitabine. Median OS was 15.9 and 14.5 months (hazard ratio [HR] 0.879; 95% confidence intervals [CI] 0.770–1.003; p = 0.056), and PFS (independent review) was 4.1 and 4.2 months (HR 1.079; 95% CI 0.932–1.250; p = 0.305) for eribulin and capecitabine, respectively. ORR (independent review) were 11.0% (95% CI 8.5–13.9) and 11.5% (95% CI 8.9–14.5; p = 0.849), respectively. OS for HER2(−) pts was 15.9 months for eribulin and 13.5 months for capecitabine (HR 0.838; 95% CI 0.715–0.983; p = 0.030). AEs were consistent with the known side-effect profiles of both drugs. The most common AEs for eribulin and capecitabine (>20% all grades) were neutropenia (54.2% vs 15.9%), hand-foot syndrome (0.2% vs 45.1%) alopecia (34.6% vs 4.0%), leukopenia (31.4% vs 10.4%), diarrhea (14.3% vs 28.8%), and nausea (22.2% vs 24.4%), respectively. Conclusion: In this Phase III trial, eribulin demonstrated a trend favoring improved OS, compared with capecitabine, although this improvement does not meet the pre-defined criteria for statistical significance. This study confirms eribulin as an active drug in pts with MBC, and exploratory analyses suggest possible benefits of eribulin in specific subsets of pts, sufficient to warrant further study. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S6-6.

The objectives of this phase I study were to assess the safety and tolerability of E7080 in patients with advanced, refractory solid tumours; to determine the maximum tolerated dose (MTD) and pharmacokinetics profile of E7080; and to explore preliminary evidence of its anti-tumour efficacy.E7080 was administered orally in escalating doses on a once-daily continuous schedule in 28-day cycles to eligible patients. Samples for pharmacokinetic analyses were collected on days 1, 8, 15 and 22 of cycle 1 and day 1 of cycle 2. Anti-tumour efficacy was assessed every two cycles.Eighty-two patients received E7080 in dose cohorts from 0.2 to 32 mg. Dose-limiting toxicities were grade 3 proteinuria (two patients) at 32 mg, and the MTD was defined as 25 mg. The most frequently observed cumulative toxicities (all grades) were hypertension (40% of patients), diarrhoea (45%), nausea (37%), stomatitis (32%) and vomiting (23%). Seven patients (9%) had a partial response and 38 patients (46%) had stable disease as best response. E7080 has dose-linear kinetics with no drug accumulation after 4 weeks' administration.E7080 is well tolerated at doses up to 25 mg per day. Encouraging anti-tumour efficacy was observed in patients with melanoma and renal cell carcinoma.

ABSTRACT Background TURANDOT is the first prospective trial to compare BEV combined with either paclitaxel (PAC) or capecitabine (CAP). We report the planned interim analysis (IA) of efficacy. Methods Patients with HER2-negative mBC who had received no prior chemotherapy for mBC were randomised to receive either BEV–PAC (BEV 10 mg/kg d1 & 15 + PAC 90 mg/m d1, 8 & 15 q4w) or BEV–CAP (BEV 15 mg/kg d1 + CAP 1000 mg/m bid d1–14 q3w) until disease progression or unacceptable toxicity. The primary objective is to demonstrate non-inferior overall survival (OS) with BEV–CAP vs BEV–PAC. Interim and final OS analyses were planned after 175 and 389 deaths, respectively, in the per-protocol (PP) population to reject the null hypothesis of inferiority (hazard ratio [HR] ≥1.33) with 80% power and overall α = 0.025. Secondary endpoints include response rate (RR), progression-free survival (PFS), safety and quality of life. Results Median follow-up was 19 months at data cut-off for this IA (1 Sep 2011). Baseline characteristics were generally similar in the 2 treatment arms. BEV-PAC (n = 285) BEV–CAP (n = 279) Median age, years 59 59 Visceral metastases, % 65 73 Prior (neo)adjuvant taxane, % 20 18 OS a Events, % 33 35 1-year OS rate, % b 81 79 HR (97.5% RCI c ) for non-inferiority 1.04 (-∞ to 1.69) p = 0.0593 d RR Overall, % 44 27 CMH test (superiority) p  PFS Events, % 62 77 Median, months 11.0 8.1 HR (95% CI) 1.36 (1.09 to 1.68) Log-rank (superiority) p = 0.0052 RCI = repeated confidence interval a PP population (n = 533) b Kaplan–Meier estimate c Using O'Brien–Fleming boundaries d Non-inferiority not shown as p > 0.00105 (α at IA) AEs were consistent with the known safety profiles of BEV, PAC and CAP. The most common grade ≥3 AEs were neutropenia (18%), peripheral neuropathy (14%) and leucopenia (7%) with BEV–PAC and hand-foot syndrome (16%), hypertension (6%) and diarrhoea (5%) with BEV–CAP. Conclusion In this planned IA, the non-inferiority criterion has not been met but OS results do not indicate relevant differences. Final results are expected in 2014. PFS and RR were better with BEV–PAC and very similar to previous data for BEV–PAC (E2100) and BEV–CAP (RIBBON-1). Disclosure R. Greil: RG has received research support and honoraria from Roche. S. Beslija: SB has received research support and honoraria from Roche. D. Messinger: Employee of IST GmbH, CRO which is providing various services and consultancies for Hoffmann-La Roche and CECOG. T. Brodowicz: TB has received honoraria from Roche. All other authors have declared no conflicts of interest.

2552 Background: Eribulin mesylate is a microtubule dynamics inhibitor approved by FDA for patients (pts) with metastatic breast cancer after treatment with at least two prior chemotherapeutic regimens. This Phase Ib, open-label dose-escalation study determined the maximum tolerated dose (MTD) of eribulin in combination with capecitabine. Methods: Pts with advanced solid malignancies refractory to standard therapies, adequate organ function and ECOG performance status ≤2 received eribulin mesylate (2–5-min IV) by Schedule 1 (1.2, 1.6 or 2.0 mg/m2 on Day 1) or Schedule 2 (0.7, 1.1 or 1.4 mg/m2 on Days 1 and 8), in combination with twice-daily oral capecitabine 1000 mg/m2 Days 1-14 every 21 days. The MTD was defined as the highest dose in each schedule where ≤1/6 pts experienced dose-limiting toxicity (DLT). Safety and pharmacokinetics (PK) were assessed. Results: Of the 34 pts recruited, 19 (53% male; median age 62 years; 42% ECOG 0, 58% ECOG 1) and 15 (33% male; median age 61 years; 33% ECOG 0, 60% ECOG 1, 7% ECOG 2) were enrolled in Schedules 1 and 2, respectively. Most common tumor types were large intestine (20.6%), lung/bronchus (17.7%) and breast (14.7%). DLTs are shown in the table; there were no unexpected toxicities with the combination. The MTD for eribulin mesylate was 1.6 and 1.4 mg/m2 for Schedules 1 and 2, respectively, in combination with capecitabine 1000 mg/m2 twice-daily. Eribulin PK were dose proportional and independent of schedule or capecitabine co-administration. Combination with eribulin had no effect on the disposition of capecitabine and its metabolites. Although sample size was small, preliminary signs of efficacy were observed. Conclusions: The combination of eribulin and capecitabine was well tolerated with no unexpected safety findings. Schedule 2 MTD (1.4 mg/m2 Days 1 and 8) delivered a higher dose intensity of eribulin than Schedule 1 and was selected for evaluation in an ongoing Phase II breast cancer study. [Table: see text]

The aim of this study was to determine the plasma pharmacokinetics of eribulin mesylate in patients with solid tumors with mild and moderate hepatic impairment.

1060 Background: Metastatic breast cancer (mBC) is common in older patients (pts) with treatment often complicated by comorbidities-resulting in increased toxicity from chemotherapy and sub-optimal therapy if treatment is inappropriately modified. The phase III EMBRACE trial showed significant improvement on overall survival (OS) for eribulin mesylate monotherapy compared to common chemotherapy agents used in the 3rd-line mBC setting. We sought to compare the benefits and toxicities of eribulin in older and younger pts. Methods: In this exploratory analysis, OS, progression-free survival (PFS), overall response rate (OR; PR+CR), clinical benefit rate (CBR; PR+CR+SD for >6 mos) and toxicity of eribulin-treated pts were compared in 4 age cohorts. Age was fitted as a categorical covariate in a cox proportional hazard model for OS and PFS, and as an interaction term for the Cochran-Mantel-Haenszel test to assess ORR and CBR. Analyses were stratified by geographic region, HER2/neu status, and prior capecitabine use. A further sensitivity analysis of OS fitted age as a continuous covariate with similar stratification to the primary analysis. Results: A total of 508 pts received eribulin in the EMBRACE trial-mean age (SD), 54.8 (10.3); range 28−85. Median OS trended inversely with age; however, this effect was non-significant when fitted as a categorical (Log Rank Test, p=0.40) or continuous covariate (p=0.10). Examination of secondary endpoints yielded a similar, non-significant trend-PFS (p=0.36), ORR (p=0.25), and CBR (p=0.96). The rate of grade 3/4 adverse events did not differ significantly across the age groups-neutropenia, 36.9%;50.3%; febrile neutropenia, 3.9%;5.0%; and neuropathy, 0.6%,4.5%. Treatment withdrawal rates did not differ between age groups. Conclusions: This analysis, while in a limited number of older pts, suggests survival outcomes with eribulin are independent of age; importantly, toxicity appears no greater in older pts. Age alone should not preclude the consideration of eribulin for older pts. ITT population REP population Age at recruitment N OS (mos) PFS (mos) N ORR CBR <50 161 11.8 3.5 146 14.4 21.9 50-59 174 13.6 3.7 157 14.7 24.2 60-69 129 13.8 3.8 123 8.1 22.0 >70 44 14.2 4.2 42 7.1 21.4 Abbreviations: REP, response evaluable population.

This paper presents specific and sensitive high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC–MS/MS) assays for the quantification of the novel anticancer agent eribulin in human plasma, whole blood, urine and faeces. These assays, developed to support clinical pharmacological studies with the drug, quantify eribulin concentration ranges of 0.2–100ng/mL for plasma, 0.5–100ng/mL for whole blood and urine and 0.1–25μg/g for faeces, using sample volumes of 500μL or 250μg (faeces). Samples were prepared with liquid–liquid extraction, separated on a C18 column with gradient elution and analysed with a triple quadrupole MS, in positive ion mode. A structural analogue of eribulin was used as internal standard for the quantification. The assays were linear with correlation coefficients (r2) of 0.99 and better, whereby the deviation from nominal concentrations ranged from −8.2 to 8.9% with CV values of maximally 14.2%. Stability assessments demonstrated that eribulin is stable at −20°C in plasma, whole blood, urine and faeces for at least 38, 4, 10.5 and 5months, respectively. In conclusion, the validation results show that the assays are specific and accurate and can therefore adequately be applied to support clinical studies of eribulin.

Aim Eribulin mesylate is a non‐taxane microtubule dynamics inhibitor that was recently approved for treatment of metastatic breast cancer. The aim of this study was to determine the effect of rifampicin, a CYP3A4 inducer, on the plasma pharmacokinetics of eribulin in patients with solid tumours. Methods An open‐label, non‐randomized phase I study was carried out. Patients received intravenous 1.4 mg m −2 eribulin mesylate on days 1 and 15 and oral rifampicin 600 mg on days 9 to 20 of a 28 day cycle. Pharmacokinetic sampling for determination of eribulin plasma concentrations was performed up to 144 h following administration. AUC (0,∞) and C max for eribulin exposure without or with co‐administration of rifampicin were subjected to an analysis of variance ( anova ) and corresponding 90% confidence intervals ( CI ) were calculated. Subsequently, patients were allowed to continue eribulin mesylate treatment with 1.4 mg m −2 eribulin mesylate on days 1 and 8 of a 21 day cycle. Also the adverse event profile and anti‐tumour activity were assessed. Results Fourteen patients were included and 11 patients were evaluable for pharmacokinetic analysis. Co‐administration of rifampicin had no effect on single dose exposure to eribulin (geometric least square means ratio: AUC (0,∞) = 1.10, 90% CI 0.91, 1.34 and C max = 0.97, 90% 0.81, 1.17). The most common treatment‐related grade ≥3 adverse events were grade 3 neutropenia (4/14, 29%), leucopenia and fatigue (both 3/14, 21%). Conclusions These results indicate that eribulin mesylate may be safely co‐administered with compounds that are CYP3A4 inducers.