2505 Background: E6201 is a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK)-1 and MEK kinase-1, with anticancer activity in preclinical models. Methods: This phase I, open-label study evaluated E6201 MTD in advanced solid tumors. Inclusion criteria were ECOG PS ≤1 and adequate bone marrow, renal, and liver function. Sequential cohorts of 3-6 subjects were given E6201 30-min IV infusion on Days 1, 8, and 15 of a 28-day cycle starting at 20 mg/m2 and increasing in 100% increments up to 320 mg/m2 until 2 Grade 2 toxicities or 1 DLT was observed. Doses were then increased by ≤50% up to 720 mg/m2 or until the MTD was determined. Blood samples were collected on days 1 and 15 for PK analysis. PD assessment included evaluation of CTC, serum IL-6 and IL-8 levels, and effects on proliferation and signal transduction pathway in skin and tumor biopsies. Results: 25 subjects (median age 66.6 [range 44-87] yr) received E6201 doses from 20 to 40, 80, 160, 320, and 480 mg/m2. At 480 mg/m2, 2 subjects had DLTs (QTc prolongation [Grade 3] and confusional state [Grade 4]). E6201 was reduced to 400 mg/m2, at which 1 subject had CNS toxicity (dizziness). Therefore, the 320 mg/m2 cohort was expanded to 3 additional subjects (total 6); 1 subject had 1 DLT (Grade 2 QTc prolongation) and Grade 2 CNS toxicities (dizziness, dysarthria, ataxia), confirming 320 mg/m2 as the MTD. Most-frequent AEs across doses were nausea (16%), constipation, dizziness, peripheral edema, and vomiting (all 12%, all Grade 1/2). E6201 was rapidly eliminated (mean t3/4=2.47- 5.60 hr). Exposure to E6201 was dose related and comparable on days 1 and 15. A trend for decreasing IL-6 and IL-8 levels was observed without clear dose dependency or duration of effect. Surrogate tissue (skin) biopsies were not informative. One subject with metastatic ocular melanoma had stable disease (>10 months) (B-Raf wild-type) and another, with B-Raf mutant papillary thyroid cancer, a partial remission. Conclusions: The E6201 MTD of 320 mg/m2 IV once weekly for 3 out of a 4-week cycle was well tolerated in patients with advanced solid tumors. An expansion phase at MTD will continue to assess efficacy and determine the optimal schedule using biomarker-driven endpoints and tumor response. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eisai Eisai
CRA1004^ Background: Eribulin mesylate (E7389; E) is a nontaxane microtubule dynamics inhibitor with a novel mode of action. This study is the first to compare overall survival (OS) with this new chemotherapeutic (CT) agent to real-life choices in heavily pretreated patients (pts) with metastatic breast cancer (MBC). Methods: Women with locally recurrent or MBC were enrolled in this phase III open-label, randomized, multicenter study. Pts had received 2-5 prior CT (≥2 for advanced disease), including an anthracycline and a taxane, unless contraindicated. Pts were randomized 2:1 to E 1.4 mg/m 2 2-5 min IV bolus on days 1 and 8 of a 21-day cycle or treatment of physician's choice (TPC). TPC was any monotherapy (cytotoxic, hormonal, biologic) or supportive care only. The primary endpoint was OS; secondary endpoints were objective response rate (ORR), and progression-free survival (PFS) by independent review, and duration of response (DOR). Safety and tolerability were assessed. Data are from the final analysis after 422 deaths. Results: 762 pts were treated (508 E, 254 TPC). Median age was 55.2 (range 27-85), 16% were HER2-positive, 19% triple-negative, 73% received prior capecitabine, median no. of prior CT was 4. Median OS was 13.1 months (mo) for E vs. 10.7 mo for TPC, p=0.04 (primary analysis, stratified log rank test; HR 0.81; 95% CI 0.66, 0.99). Median PFS was 3.7 mo for E and 2.3 mo for TPC p=0.09 (HR 0.85; 95% CI 0.70, 1.03). ORR was 12% (0.4% complete response [CR], 11.5% partial response [PR]) for E and 5% (0 CR; 5% PR) for TPC, p=0.005. Median DOR was 4.1 mo for E (56 responders) vs. 6.7 mo for TPC (11 responders). Grade [G] 3/4 treatment-related adverse events (AEs) of interest for E were asthenia/fatigue (7.6%), neutropenia (44%), peripheral neuropathy (8.4%). 10% of pts experienced treatment-related serious AEs (12% E, 7% TPC). Conclusions: The study met its primary endpoint with a significant improvement in OS by a median of 2.5 mo with E vs. TPC. E demonstrated a manageable tolerability profile, acceptable for a CT agent used as monotherapy in this late-line setting. [Table: see text] In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519-521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2010 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest .
Abstract Background: Eribulin mesylate (E7389) is a nontaxane microtubule dynamics inhibitor. We conducted a randomized, controlled, open-label, phase III study to compare the efficacy and safety of eribulin vs. TPC in heavily pretreated subjects with locally recurrent or metastatic breast cancer. This report focuses on outcomes for participants enrolled in North America, Western Europe, and Australia (Region 1). Methods: Eligible subjects had locally recurrent or metastatic breast cancer and had received 2-5 prior chemotherapy regimens, including an anthracycline and a taxane, with ≥2 of the regimens given for locally recurrent or metastatic disease. Subjects were stratified by geographic region, HER2/neu status, and prior capecitabine treatment. They were randomized 2:1 to receive eribulin 1.4 mg/m2 intravenously over 2-5 minutes on Days 1 and 8 every 21 days or an approved TPC. The primary endpoint was overall survival (OS); progression-free survival (PFS) was a secondary endpoint. Results: A total of 762 subjects in 135 centers worldwide were enrolled. Subjects had a median age of 55 years, 92% were white, 76% were postmenopausal, and 81% had taxane-refractory disease. The median time since original diagnosis was 6.7 years. The majority of subjects (488 [64%]) were from Region 1, of whom 325 received eribulin and 163 received TPC. The most common treatments received by subjects from Region 1 in the TPC arm were vinorelbine (28%), gemcitabine (17%), capecitabine (13%), taxanes (20%), and anthracyclines (12%). 9% of subjects in this region received other therapies. Among the intent-to-treat population in Region 1, median OS was significantly prolonged with eribulin (13.3 months) vs. TPC (10.2 months) (HR: 0.724; 95% CI: 0.568-0.924; p=0.009). Median PFS was also prolonged with eribulin (3.3 months) vs. TPC (2.2 months; HR: 0.843; 95% CI: 0.666-1.066; p=0.153) in this population, as assessed by independent reviewers. Conclusion: OS was significantly prolonged in eribulin-treated patients participating in the EMBRACE trial in the North America, Western Europe, and Australia region. When assessed by independent review, PFS was also prolonged with eribulin, although this difference did not reach statistical significance for this geographic region. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-13-02.
Abstract Background: Eribulin mesylate (E7389) is a non-taxane microtubule dynamics inhibitor with a novel mode of action. EMBRACE was the first trial to compare overall survival (OS) of this new chemotherapeutic agent to real-life treatment choices (treatment of physician's choice; TPC) in heavily pretreated subjects with advanced breast cancer. TPC was any monotherapy (cytotoxic, hormonal, biologic) or supportive care only. It was previously reported that the study met its primary endpoint with a significant improvement in OS by a median of 2.5 months with eribulin vs. TPC. That primary analysis was based on 422 of 762 events that occurred by May 12, 2009; here we present an updated survival analysis requested by the FDA of the pivotal Phase 3 study through March 3, 2010. Methods: This report is an updated survival analysis based on 589 of 762 (77.3%) events that occurred by March 3, 2010. Data were censored for subjects who were still alive, lost to follow-up, or withdrew consent on or before the date of data cut-off (March 3, 2010). A treatment arm comparison of OS was performed (with geographic region, HER2/neu status and prior capecitabine use as stratification factors for randomization) using a stratified log-rank test. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated to assess the magnitude of the treatment benefit. Results: Seven hundred sixty two women were randomized in the study; 508 to the eribulin arm and 254 to the TPC arm. 386 (76.0%) events occurred in the eribulin-treated arm while 203 (79.9%) events were recorded in the TPC-treated group. Nine (1. 8%) eribulin and 5 (2.0%) TPC patients were lost to follow-up or withdrew consent. OS was significantly longer in the eribulin treatment arm as compared with the TPC treated arm. (p=0.014; HR 0.805; 95% CI 0.677, 0.958). Median OS was 403 days (13.2 months) compared with 321 days (10.5 months) for TPC. A sensitivity analysis in the following 3 populations showed that the HR was similar to the primary (intent to treat) analysis and the treatment difference was statistically different: population of subjects treated (p = 0.016; HR 0.806; 95% CI 0.676, 0.960), at the cut-off of 572 (75%) deaths (p=0.008; HR 0.787; 95% CI 0.660, 0.939) and with no stratification terms (p=0.024; HR 0.822; 95% CI 0.694, 0.975). Based on the Kaplan-Meier analysis, eribulin-treated subjects had a 1-yr and 2-yr survival rate estimate of 54.5 and 21.9% compared with 42.8 and 19.2% for TPC, respectively. Conclusions: The OS advantage associated with eribulin treatment reported in the primary analysis was maintained throughout the observation period. The results of this OS-updated analysis support the initial OS analysis of the pivotal trial EMBRACE, demonstrating the superiority of eribulin over TPC in heavily pretreated women with advanced breast cancer. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-14-18.
Abstract Background: The randomized, controlled, open-label, phase III EMBRACE study compared the efficacy and safety of eribulin mesylate (E7389) vs. treatment of the physician's choice (TPC) in heavily pretreated subjects with late-stage breast cancer. The study met its primary endpoint by showing that eribulin significantly prolonged OS vs. TPC (HR: 0.809; 95% CI: 0.660-0.991; p=0.041). This exploratory subgroup analysis aimed to determine the influence of the number of prior regimens on OS among eribulin-treated subjects. Methods: Eligible subjects had locally recurrent or metastatic breast cancer and had received 2-5 prior chemotherapy regimens, including an anthracycline and a taxane, with ≥2 of the regimens given for locally recurrent or metastatic disease. Subjects had to show progression on or within 6 months of the last chemotherapy regimen. Subjects were stratified by geographic region, HER2/neu status, and prior capecitabine treatment and then randomized 2:1 to receive eribulin 1.4 mg/m2 intravenously over 2-5 minutes on Days 1 and 8 every 21 days or an approved TPC. Results: A total of 762 subjects in 135 centers worldwide were randomized to receive either eribulin (n=508) or TPC (n=254). Subjects had a median age of 55 years, 92% were white, 76% were postmenopausal, and 81 % had taxane-refractory disease. Overall, 47% and 53% of subjects had received ≥3 and >3 prior chemotherapy regimens in total, respectively. Seventy-five percent and 25% of subjects received ≥3 and >3 prior chemotherapy regimens in total for locally recurrent or metastatic disease, respectively. Subgroup analysis identified consistently longer median OS with eribulin vs. TPC in subjects who received ≥3 prior chemotherapy regimens, both in total and specifically for locally recurrent or metastatic disease (Table). Lesser improvements in OS with eribulin vs. TPC were observed in subjects who received >3 prior chemotherapy regimens. The study was not powered to show statistical significance for this subgroup analysis. Conclusion: In this retrospective subgroup analysis, the OS benefit with eribulin appears greater for subjects with locally recurrent or metastatic breast cancer who received fewer previous therapies. Additional studies are underway to confirm these findings in less heavily pretreated patients. Table. Overall survival by treatment history vs. TPC Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-13-01.
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