In a preclinical study, scientists investigated whether ß-tubulin isotype composition of tumor cells affects their sensitivity to 2 natural product-based antitubulin agents, E7389 and E7974. Antiproliferative effects of E7389, E7974, paclitaxel, and vinblastine against a panel of human breast cancer cell lines were determined by methylene blue-based or MTT-based cell growth inhibition assays. Cell lines were tested for evidence of PgP expression by monitoring effects of the PgP blocker verapamil on paclitaxel sensitivity. Using quantitative PCR with specific primers, expression levels of the 7 human ß-tubulin isotypes were determined (I, II, III, IVa, IVb, V, and VI). No evidence for PgP expression was found in any of the cell lines tested. In growth inhibition studies, interdrug correlations were seen between sensitivities to the 3 microtubule polymerization inhibitors E7974, E7389, and vinblastine, but not between the microtubule stabilizer paclitaxel and the other agents. All 7 ß-tubulin isotypes were detected at different levels in each cell line, with isotypes I and IVb showing the least variation, while isotypes II, III, and IVa showed greatest variability between cell lines. A significant correlation was demonstrated between ßIII tubulin expression levels and sensitivity to both E7389 and E7974. These findings in cancer cell lines suggest that tumors expressing higher levels of ßIII tubulin isotype may be more responsive to treatment with E7389 and E7974. If confirmed clinically, such preclinical insights may lay the foundation for selection of patient populations with enhanced sensitivities to these 2 natural product-based antitubulin agents (Agoulnik S, etal, ASCO05, Abs. 2012).

In a preclinical study, scientists at multiple centers in CA used the nsclc cell lines A549 (wild-type p53, wild-tye RB), and Calu-1 (p53-null, wild-type RB), and examined biological and molecular responses to E7389 from 10 pM to 2.0 nM. Growth inhibition was measured by colony formation assay, and cell-cycle and apoptotic proteins were evaluated by Western blotting. IC50 of 24 hour treatments with E7389 include A549, 630 pM; Calu-1, 440 pM. At this timepoint, mitotic arrest was observed, and dose-dependent induction of p27 and phosphorylation of Bcl2 were seen in both cell lines. In the clinical trial, plasma levels of E7389 measured 24 hours after a bolus dose exceeded 750 pM at the first dose level tested (0.125 mg/m²). At the current dose level, E7389 plasma concentrations remain above 1500 pM for up to 72 hours. E7389 shows p53-independent anticancer activity versus nsclc cells in the 0.5 pM range, consistent with levels clinically achievable. Anticancer activity is associated with M-phase arrest, induction of the Cdk inhibitor p27, and phosphorylation of Bcl2. E7389 warrants further study as a potential therapeutic for nsclc, because of this potent p53-independent activity (Kimura T, etal, ASCO03, Abs. 2804).

A preclinical study was conducted on Beagle dogs and Fischer 344 rats to determine its toxicity and reversibility. Beagle dogs were administered doses of E7389 IV over 1 hour on days 1, 5, and 9. Fischer 344 rats were administered doses of E7389 IV bolus injection on days 1, 5, and 9. Hematological effects in dogs were decreases in white blood cells and neutrophils. On days 12 to 19, white and red blood cell parameters were affected. Rats displayed histopathological lesions. Other side effects in rats include bone marrow atrophy, thymic atrophy, and testicular degeneration, and skeletal muscle degeneration. By day 35, all rats made a full recovery except for testicular degeneration. Dogs displayed reversible lymphoid atrophy and splenic lymphoid depletion (Tosca P, etal, AACR02, Abs. 5422).

A preclinical study of E7389 was conducted to evaluate its ability to induce apoptosis after prolonged mitotic block. U937 human histiocytic lymphoma cells displayed arrest at the G2/M phase at 4 to 12 hours after exposure to 100 nM E7389. Hypodiploid cells were observed after 12 hours, indicating the induction of apoptosis in these cells following extended mitotic block. Other apoptosis indications were observed including phosphorylation of Bcl-2, cleavage of PARP, release of cytochrome C from mitochondria, and proteolytic activation of caspase 3. In human LNCaP prostate cancer cells, E7389-induced apoptosis occurred in suspension and monolayer culture conditions. Results show that E7389 induces prolonged mitotic block that leads to apoptosis (Kuznetsov G, etal, AACR02, Abs. 1318).

A preclinical PK study of E7389 was conducted in rats and dogs. Rats were administered E3789 IV. This agent displayed tri-exponential plasma distribution with alpha and beta half-lives of 0.03 hour and 0.36 hour, respectively, followed by a gamma half-life of 11.4 hour. These animals had a steady state distribution of 109.7 L/m², which is suggestive of extensive tissue distribution. Oral bioavailability was 18% when administered in combination with cyclosporine. Dogs were administered IV doses of E7389 over 1 hour. Volume of distribution was determined to be 38.2 and 82 L/m². AUC and Cmax dose and plasma profiles were best fit to a two-compartment model. In a multiple dose toxicity and PK study, dogs were administered E7389 over 1 hour every 4 days x 3. End of infusion levels for this agent were proportional to dose. Only postinfusion levels were observed, ranging from 5.85-7.18 nM. Clearance and Vdss ranged from 71-132 mL/m²/kg and 85-187 L/m², respectively. Results show that E7389 in rats and dogs has rapid and extensive tissue distribution with an extended terminal half-life (Rhie JK, etal, AACR02, Abs. 1066).

In vitro, ER-086526 inhibited growth in a number of human cancer cell lines. In MDA-MB-435 breast cancer, COLO 205 colon cancer, LOX melanoma, and NIH: OVCAR-3 ovarian cancer xenografts, ER-086526 inhibited growth at a dose range of 0.1-1 mg/kg. This agent also arrested cells at the G2/M phase and disrupted mitotic spindles (Towle MJ, etal, Cancer Res, Feb 2001;61(3):1013-21; http://www.ncbi.nlm.nih.gov/pubmed/11221827 ).

metastatic breast cancer previously treated with at least 2 chemotherapy regimens including an anthracycline and a taxane either in the adjuvant or metastatic setting.

In January 2011, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA), gave a positive opinion for the use of Halaven as a monotherapy for the treatment of patients with locally advanced or metastatic breast cancer that progressed after at least two chemotherapeutic regimens for advanced disease. Prior therapy should have included an anthracycline and a taxane unless patients were not suitable for these treatments. The CHMP submission was supported by results from the global phase III EMBRACE (Eisai Metastatic BReast cancer study Assessing treatment of physician's Choice versus Eribulin E7389) clinical trial(protocol ID: E7389-G000-305; NCT00388726; http://clinicaltrials.gov/ct2/results?term=NCT00388726 ), which demonstrated an OS benefit of 2.7 months in patients treated with eribulin compared with standard chemotherapy (13.2 months versus 10.5 months) for a hazard ratio of 0.805 (p=0.014).

In November 2010, the FDA approved Eisai’s Halaven (eribulin mesylate) Injection for the treatment of patients with metastatic breast cancer previously treated with at least two chemotherapeutic regimens including an anthracycline and a taxane either in the adjuvant or metastatic setting. The FDA approval of Halaven is based on results from the EMBRACE (Eisai Metastatic BReast cancer study Assessing treatment of physician's Choice versus Eribulin E7389), pivotal phase III clinical trial (protocol ID: E7389-G000-305; NCT00388726) in which patients treated with Halaven survived a median of 2.5 months longer than patients treated with a single agent chosen by their physician. Overall survival (OS) was 13.12 months with Halaven versus 10.65 months with the comparator (p=0.041). In an updated survival analysis, conducted when 77% of events had been observed, the result was consistent with the primary analysis. EMBRACE was a multicenter, global, open label, randomized phase III clinical trial designed to compare overall survival in patients treated with Halaven versus a treatment of physician’s choice defined as any single agent chemotherapy, hormonal treatment or biologic therapy approved for the treatment of cancer; or palliative treatment or radiotherapy administered according to local practice. The trial included 762 patients with metastatic breast cancer who had been previously treated with an average of 4 chemotherapies. The vast majority of patients in the comparator arm were treated with chemotherapy. Halaven is expected to be available in the USA within 10 business days after approval. In addition, Eisai has submitted regulatory applications for approval of eribulin mesylate for the treatment of metastatic breast cancer to regulatory agencies in Japan, the European Union (EU), Switzerland and Singapore.

In August 2010, the FDA notified Eisai that the agency expects to complete priority review of the eribulin mesylate NDA for locally advanced or metastatic breast cancer on or before December 30, 2010, representing a 3-month extension from the original PDUFA action date of September 30, 2010. The extension is a result of the agency classifying recent responses to questions regarding the chemistry, manufacturing and controls (CMC) section of the NDA as a major amendment to the NDA. The new action date will give the agency additional time to review the information submitted for this complex synthetic process. Eribulin is also currently under active regulatory review in Japan, the European Union (EU), Switzerland and Singapore.

In the open label, parallel group, phase I clinical trial (protocol ID: (protocol ID: E7389-E044-108; NCT00706095) of eribulin mesylate in patients with advanced solid tumors that have progressed following standard therapy or for which no standard therapy exists and have normal or reduced hepatic function according to the Child-Pugh system, patients with normal hepatic function (n=6), mild (Child-Pugh A, n=7) or moderate (Child-Pugh B, n=4) hepatic impairment were treated with IV eribulin mesylate on day 1 at doses of 1.4, 1.1, and 0.7 mg/m², respectively. Hepatic impairment decreased clearance (4.57, 2.75, and 1.96 L/hour for normal, mild and moderate hepatic impairment, respectively) and prolonged elimination half-life (36.1, 41.1, and 65.4 L/hour for normal, mild and moderate hepatic impairment, respectively). Mean dose-normalized Cmax for eribulin was comparable between patients with normal and mildly impaired hepatic function (72 versus 84 ng/mL/mg, ratio estimate 1.1), but moderate hepatic impairment increased Cmax 1.5-fold (111 ng/mL/mg). Eribulin exposure was increased in patients with mild and moderate hepatic impairment. Mean dose-normalized AUC(0-infinity) increased 1.7-fold (420 ng*hr/mL/mg) and 2.8-fold (720 ng*hr/mL/mg), compared with patients with normal hepatic function (229 ng*hr/mL/mg). Overall, most common treatment-emergent AE were alopecia (n=7), nausea (n=5) and fatigue (n=4). AE probably related to treatment included neutropenia (n=3) and peripheral neuropathy (n=1). Majority of AE probably related to treatment (3/4) resolved without dose reduction. Highest incidence of AE was reported in patients with mild hepatic impairment. No deaths, treatment-related serious AE, or drug discontinuations were reported. Eribulin exposure increased with decreasing hepatic function. Eribulin was generally safe and well tolerated (Witteveen P, etal, ASCO10, Abs. 2582).

In stage 1 of the open label, dose-finding, phase I clinical trial (protocol ID: E7389-A001-104; NCT00268905) of eribulin mesylate combined with carboplatin in patients with advanced solid tumors, patients were administered IV carboplatin (AUC=5) and escalating doses of eribulin mesylate (0.7, 0.9, 1.1, and 1.4 mg/m²) in 2 schedules differing by the order of administration. In stage 2, eribulin dose was escalated (1.1 and 1.4 mg/m²) with carboplatin (AUC=6) using the preferred schedule from stage 1. In both stages, MTD was defined as the highest dose where <2/6 patients had DLT. A total of 52 patients (median age=60 years) were treated. In stage 1, DLT of diarrhea was experienced in 1/5 patients at 1.4 mg/m² in the carboplatin-first schedule and in 0/3 patients in the eribulin-first schedule, defining MTD as 1.4 mg/m² (same as the monotherapy dose) with eribulin administered first. In stage 2, eribulin was administered first and DLT of febrile neutropenia occurred in 1/6 patients at 1.1 mg/m² and febrile neutropenia and neutropenia in 2/3 patients at 1.4 mg/m², defining MTD as 1.1 mg/m². PK analyses for both agents suggest the absence of any PK interaction. Most frequent AE across doses/cycles were neutropenia (52%, Grade 3/4=40), thrombocytopenia (29%, Grade 3/4=13), fatigue (58%, Grade 3/4=4), and nausea (40%, Grade 3/4=0). PR was observed in 2 patients with prostate cancer and CR in 1 patient with tonsillar cancer. Combination of eribulin with carboplatin was tolerated and showed preliminary activity. An extension arm with the combination at recommended phase II doses (eribulin mesylate 1.1 mg/m², carboplatin AUC=6) is enrolling patients with chemotherapy naive, advanced nsclc (Swami U, etal, ASCO10, Abs. 2589).

A nonrandomized, open label, phase I clinical trial (protocol ID: E7389-E044-103; NCT00908908; http://clinicaltrials.gov/ct2/show/NCT00908908 ) was initiated in March 2009 in Europe at the Netherlands Cancer Institute (Amsterdam, Netherlands), to determine the metabolism and elimination of radiolabeled 14C-eribulin in patients with advanced solid tumors that progressed following standard therapy including surgery and radiation therapy. The trial’s primary objective is to measure excretion balance and metabolic pathway of radiolabeled 14C-eribulin as determined by PK analysis of plasma, blood, urine, and feces. Secondary objectives are to determine safety and tolerability and to evaluate efficacy of eribulin determined by objective tumor response. According to the protocol, the trial will be conducted in 2 phases. During the initial trial phase, patients are administered radiolabeled 14C-eribulin (2 mg flat dose) IV infusion over 2-5 minutes on cycle 1, on day 1. Following the initial dose, patients remain in the research unit until day 8 to complete collections of urine, blood, and feces for PK analysis and determination of 14C-eribulin concentrations between days 1 and 8. On day 8, patients are re-assessed, discharged, and return on day 15 for physical exam, AE evaluation, and lab tests. Patients then enter the extension phase of the trial and continue to be administered non-radiolabeled eribulin (1.4 mg/m²) on days 1 and 8 of every 21-day cycle. The trial, to enroll about 10 patients, was completed in November 2009.

A multicenter (n=28), randomized, open label, phase II clinical trial (protocol ID: E7389-G000-209; NCT00879086; http://clinicaltrials.gov/ct2/results?term=+NCT00879086 ) was initiated in March 2009, in the USA, to evaluate the safety and efficacy of E7389 versus ixabepilone in causing or exacerbating neuropathy in patients with advanced, locally recurrent or metastatic breast cancer who have been treated with prior taxane therapy and at least one prior cytotoxic chemotherapy regimen. Patients must not undergo prior treatment with ixabepilone therapy, must not participate in a prior eribulin clinical trial, and must not have history of diabetes mellitus Type 1 or 2. The trial’s primary objective is to determine the percent of patients with neuropathy AE. Secondary objectives are to evaluate neuropathy, incidence of myalgia/arthralgia AE, general safety, response rate, clinical benefit rate, and PFS. According to protocol, patients in arm I are administered E7389 (1.4 mg/m²) as a 2-5 minute IV bolus on days 1 and 8 of a 21-day cycle. The treatment phase will include six cycles. Patients may enter the extension phase for additional cycles following the sixth cycle of treatment. Patients in arm II are treated with ixabepilone (32 or 40 mg/m²) as a 3-hour IV infusion on day 1 of a 21-day cycle. The treatment phase will include six cycles. Patients may enter the extension phase for additional cycles following the sixth cycle of treatment. The trial is to enroll about 98 patients. This trial was closed in October 2010

A multicenter (n=2), nonrandomized, open label, phase I clinical trial (protocol ID: E7389-E044-108; NCT00706095; http://clinicaltrials.gov/ct2/results?term=NCT00706095 ) was initiated in February 2008, in Europe (Netherlands), to evaluate the PK of E7389 in treating patients with advanced solid tumors that have progressed following standard therapy or for which no standard therapy exists and have normal or reduced hepatic function according to the Child-Pugh system. Patients must not have brain or subdural metastases, known positive HIV status, or hypersensitivity to halichondrin B and/or halichondrin B-like compounds, and must not participate in a prior E7389 clinical trial. The trial’s primary objective is to collect blood samples for PK analysis for up to day 7 during cycle 1 beginning day 1 pre-dose and post-dose. Secondary objective is to evaluate tumor assessments. According to protocol, patients will be assigned to one of three groups to be administered IV doses of E7389. The three groups are: normal hepatic function, mild hepatic impairment (Child-Pugh A) and moderate hepatic impairment (Child-Pugh B). Patients are treated on day 1 with starting doses of 0.7 mg/m² and 1.0 mg/m² for moderate and mild hepatic dysfunction and 1.4 mg/m² for normal hepatic function. This trial, to enroll about 18 patients, is being conducted under PI, J.H.M Schellens, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (Amsterdam, Netherlands).

PK data from 2 phase I clinical trials of E7389 in patients with advanced solid tumors were presented. In the first phase I clinical trial (protocol ID: E7389-A001-101; E7389, BOLD; NCT00069264), E7389 was administered every 7 days x 3 on a 28-day cycle. In the second phase I clinical trial (protocol ID: E7389-A001-102; NCT00069277), E7389 was administered every 21 days on a 21-day cycle. A total of 26 patients and 18 patients were enrolled in the 2 clinical trials, respectively. Doses ranged from 0.5-2.8 mg/m² in the first clinical trial, and 0.25-4 mg/m² in the second clinical trial. In the first phase I clinical trial, IV E7389 disposition was bi-exponential, exhibiting a rapid distribution phase with mean t1/2 of 0.45 +/- 0.20 hour (median=0.39 hour), followed by a slow elimination phase with mean t1/2 of 36 +/- 12 hours (median=33 hours). Mean systemic clearance (CL) and volume of distribution at steady state (Vss) were 1.7 +/- 0.9 L/hour/m² (median=1.5 L/hour/m²) and 55 +/- 25 L/m² (median=46 L/m²), respectively. Approximately 6-7% of unchanged E7389 was excreted (0-72 hours) into the urine. In the second clinical trial, E7389 disposition followed linear kinetics over the dose range studied. The plasma concentration-time profile of IV E7389 exhibited a rapid distribution phase with t1/2 of 0.40 +/- 0.15 hour (median=0.37 hour), followed by a slow elimination phase with t1/2 of 41 +/- 13 hours (median=37 hours). Mean CL and Vss of E7389 were 2.0 +/- 1.0 L/hour/m² (median=1.6 L/hour/m²) and 72 +/- 27 L/m² (median=75 L/m²), respectively. A small fraction (7%) of E7389 was excreted unchanged into the urine. Mean renal clearance of E7389 in the second clinical trial (188 +/- 133 mL/hr/m²) was 66% greater than that reported in the first clinical trial (113 +/- 87 mL/hr/m²). The disposition of E7389 follows linear kinetics over the dose range studied, and PK in patients is characterized by an extensive volume of distribution, slow to moderate clearance, and slow elimination. There was great inter-subject variability in urinary recovery and renal clearance in both studies (Wong N, etal, ASCO05, Abs. 2013).

A multicenter (n=24), dose escalation, phase I clinical trial (protocol ID: CDR0000518290; CCC-PHI-55; NCT00415324; http://clinicaltrials.gov/ct2/results?term=NCT00415324 ) was initiated in the USA, in December 2006, to evaluate the side effects and best dose of E7389 and cisplatin in treating patients with advanced solid tumors. The trial’s primary objective is to determine MTD. Other objectives are to determine the DLT, survival, and time to failure. According to procedure, patients are treated with E7389 IV over 5 minutes on days 1, 8, and 15 and cisplatin IV over 30-60 minutes on day 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients are treated with escalating doses of E7389 and cisplatin until MTD is determined. Patients undergo blood collection periodically in course 1 for PK studies. After completion, patients are followed for up to 8 weeks. The trial, to enroll about 30 patients, is being conducted under Study Chair Marianna Koczywas, MD, at City of Hope Beckman Research Institute (Duarte, CA).

A 2-center, dose escalation phase I clinical trial (protocol ID: CDR0000520315; PMH-PHL-048; NCT00410553; http://clinicaltrials.gov/ct2/results?term=NCT00410553 ), was initiated in November 2006, to evaluate the side effects and best dose of E7389 and gemcitabine in treating patients with metastatic or inoperable solid tumors. The primary objectives are to determine MTD, recommended phase II dose, safety, tolerability profile, and DLT, and to characterize the PK profile. Other objectives are to determine the preliminary clinical antitumor activity, objective response rate, and the duration of response and TTP. According to the protocol, patients are treated with E7389 IV and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15 OR on days 1 and 8. Treatment repeats every 28 or 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients are treated with escalating doses of E7389 and gemcitabine until MTD is determined. If the MTD is determined at the first dose level of the 28-day schedule, subsequent patients are treated on a 21-day schedule on days 1 and 8. After completion, patients are followed at 4 weeks. The trial, to enroll about 36 patients, is being conducted in Canada under Study Chair Rakesh Goel, MD (613-737-7700 ext. 70171; rgoel@ottawahospital.on.ca), at Ottawa Hospital Regional Cancer Centre.

A multicenter (n=3), randomized, open label, 2-arm, dose finding, phase Ib clinical trial (protocol ID: E7389-A001-104; NCT00268905; http://clinicaltrials.gov/ct2/results?term=NCT00268905 ) was initiated in October 2006, to evaluate E7389 in combination with carboplatin in patients with refractory advanced solid tumors. The primary objective is to determine MTD. Secondary objectives include safety, activity, and PK. Total expected enrollment is 60. Participating institutions include Cancer Institute of New Jersey (New Brunswick, NJ), Columbia University Medical Center (New York, NY), Montefiore Medical Center (Bronx, NY).

A non-randomized, open label, uncontrolled, phase I clinical trial (protocol ID: E7389-J081-105; NCT00326950; http://clinicaltrials.gov/ct2/results?term=NCT00326950 ) was initiated in May 2006, in Japan, to evaluate the efficacy and tolerability of IV E7389, administered on days 1 and 8 of a 21 day cycle, in patients with solid tumors. The trial’s primary objectives are to determine DLT and MTD. Other objectives are to investigate the PK, safety and anti-tumor effects in patients. The trial is to enroll about 24 patients. This trial was closed in December 2007 and completed in December 2009.

A phase I clinical trial (protocol ID: E7389-A001-102; E7389 BOLD; NCT00069277) was designed to determine MTD, safety, and PK using a 1-hour IV infusion on day 1 of a 21-day cycle. A total of 13 patients with advanced solid tumors were enrolled at the Cancer Insitute of New Jersey (New Brunswick, NJ) and the Cancer Institute Medical Group (Los Angeles, CA). Tumor types include lung adenocarcinoma (n=3), renal cell (n=3), gall bladder (n=1), bladder (n=1), sarcoma (n=1), pancreas (n=1), nsclc (n=1), endometrial (n=1), prostate (n=1). Prior treatments include at most 2 prior chemotherapies. Doses ranged from 0.25-4 mg/m². A total of 3 out of 3 patients developed DLT at 4 mg/m². All had febrile neutropenia, accompanied by Grade 2 mucositis in 1. The first patient at the next lower dose of 2.8 experienced febrile neutropenia. A Grade 3 neutropenia attributed to extensive prior radiation occurred in every cycle (n=6) in 1 patient treated at 1 mg/m². Other drug-related toxicities reported include Grade 1/2 and included anorexia, fatigue, nausea, anemia, and thrombocytopenia (Grade 1), increased alkaline phosphatase, increased ALT, and hyperkalemia. Median number of cycles administered was 2 (range=1-6). No response has yet been observed, but there were 4 SD for 4 cycles or more. Enrollment continues. Preliminary PK (n=10) were best described by a 2-compartment model. There was rapid distribution, slow clearance, and prolonged elimination with a small fraction (5%-12%) excreted unchanged into the urine. Average Vss, CL, and MRT ranged from 53.2-218.5 L, 1.4-4.4 L/hour, 28.1-50.1 hours at the dose levels observed. Cmax and AUC increased in a dose-dependent manner between 0.25-1 mg/m². Higher dose levels are being evaluated. Ratios of Cmax to Ctrough, 96 hours ranging from 0.33%-1.5%, as well as calculated accumulation factor of 1 for all 10 subjects, indicated that despite prolonged elimination phase, repeated dosing is unlikely to cause drug accumulation with the regimen evaluated. Updated information will be provided. Phase II clinical trials will be initiated upon completion of phase I (Elsayed YA, etal, EORTC-NCI-AACR04, Abs. 535).

In August 2003, a nonrandomized, open label, uncontrolled, single group assignment, phase I clinical trial (protocol ID: E7389-A001-101, E7389; BOLD, NCT00069264; http://clinicaltrials.gov/ct2/results?term=NCT00069264 ) was initiated to examine E7389 in patients with advanced solid tumors. Total expected enrollment is 55. This trial was completed in August 2005.

In August 2003, a nonrandomized, open label, uncontrolled, single group assignment, phase I clinical trial (protocol ID: E7389-A001-102; E7389 BOLD, NCT00069277; http://clinicaltrials.gov/ct2/results?term=NCT00069277 ) was initiated in the USA, to examine E7389, administered once every 3 weeks in patients with advanced solid tumors. Total expected enrollment is 35. As of August 2005, this trial has been completed. To date, 18 patients have been treated (0.25 to 4 mg/m²). Median age at enrollment was 62 years (range=29-73), and all had a performance status of 0 or 1. The most common tumor types were nsclc (n=6) and renal cell carcinoma (n=3). A total of 3 of 3 patients at 4 mg/m², and 2/3 at 2.8 mg/m² developed febrile neutropenia, contributing to DLT at these doses. Only 1/3 patients enrolled at 2.0 mg/m² experienced febrile neutropenia or any other DLT, and enrollment continues at this dose level. Other drug-related toxicities have been minor, and no patient has experienced neurotoxicity. The median number of cycles is 3.5 (range=1-11). No CR or PR (by RECIST) has been observed. A patient with uterine sarcoma (previously treated with gemcitabine, paclitaxel, and carboplatin) had a 20% reduction in pelvic adenopathy, and 4 have had SD for 4 cycles or more. Analysis of plasma and urine E7389 concentrations indicates a prolonged elimination phase (average plasma half-life 34 to 73 hours), with a small fraction of drug (4-12%) excreted unchanged in the urine. Among the current dose levels, plasma Cmax and AUC appear to increase linearly with dose. Neutropenia is the DLT for E7389, with an expected MTD of 2 mg/m² administered every 21 days. An update on safety and efficacy will be provided (Synold TW, etal, ASCO05, Abs. 2054).

A multicenter, dose-escalation, phase I clinical trial (protocol ID: CDR0000257235; CCC-PHI-39; CHNMC-PHI-39; NCI-5730; NCT00047034; http://clinicaltrials.gov/ct2/results?term=NCT00047034 ) was intiated in October 2002, in the USA, to examine E7389 in patients with advanced solid tumors. Objectives are to determine MTD, toxic effects, PK, in vivo antimitotic activity, target validation feasibility, and clinical response. Patients are treated with E7389 IV over 1-2 minutes on days 1, 8, and 15. Treatment repeats every 4 weeks, for at least 4 courses, in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients are treated with escalating doses of E7389 until the MTD is determined. Additional patients with biopsy-accessible tumors are accrued and treated as above at the MTD. Approximately 31 patients will be accrued for this trial. Trial centers include City of Hope Comprehensive Cancer Center (Duarte, CA), City of Hope Medical Group (Pasadena, CA), University of California, Davis (Sacramento, CA), and the USC/Norris Comprehensive Cancer Center and Hospital (Los Angeles, CA). This trial was completed in November 2007. This first-in-man trial included a rapid titration design with real-time PK to guide dose escalation. E7389 was administered as a weekly bolus 3 weeks out of 4, starting at 0.125 mg/m²/week. During the first phase, single patient cohorts were enrolled with intra and interpatient dose-doubling until toxicity was observed. The second phase consisted of a standard 3 x 3 dose escalation schedule. Once the MTD was determined, a cohort of patients with biopsiable tumors was enrolled. A total of 40 (38 evaluable) patients with refractory or advanced solid tumors were entered. The most common primary tumor sites were lung (n=9), breast (n=4), and bladder (n=2). Rapid escalation ended with a Grade 3 alkaline phosphatase at 0.5 mg/m²/week. The second phase ended at 2.0 mg/m2/week, with 2 DLT, including 1 Grade 3 febrile neutropenia and 1 Grade 4 neutropenia. Other serious nonhematological toxicities included hypoglycemia, hypophosphatemia, and fatigue. The MTD was 1.4 mg/m2/week. Responses included 2 PR (nsclc; bladder) and 3 MR (nsclc, breast, and thyroid). SD as best response was seen in 12 patients, lasting a median of 4 months (range=2-14). PK results demonstrate a triphasic elimination and a prolonged terminal t1/2 of 36-48 hours. At the MTD, plasma levels of E7389 are above concentrations required for in vitro cytotoxicity for >1 week. A cohort of 13 patients was treated at the MTD, and serial tumor biopsies were obtained. Fluorescent IHC analyses of these specimens demonstrate that E7389 disrupts microtubule structure in tumors in vivo. Phase II clinical trials of this novel, active agent are ongoing (Synold TW, etal, ASCO05, Abs. 3036).

Of 84 Japanese patients enrolled in the single arm, open label, phase II clinical trial (protocol ID: E7389-J081-221; NCT00633100) of IV eribulin mesylate (1.4 mg/m²) in advanced/metastatic breast cancer or locally advanced disease, 81 patients (median age=54 years) were treated. Median number of prior chemotherapy regimens was 3, and median number of treatment cycles with eribulin was 5. ORR was 21.3%, and PR was achieved by 17 patients. No CR was observed. Disease stabilized in 37.5% of patients and clinical benefit rate was 27.5%. Median duration of response was 119.0 days, median PFS was 112.0 days, and median OS was 331.0 days. PFS and OS rates at 6 months were 20.1% and 72.3%, respectively. Most frequent treatment-related Grade 3/4 toxicities were neutropenia (95.1%), leukopenia (74.1%), febrile neutropenia 13.6%, and lymphopenia (12.3%). Grade 3 peripheral neuropathy occurred in 3.7% of patients, with no Grade 4 peripheral neuropathy observed. Eribulin was effective and well tolerated in patients with heavily pretreated metastatic breast cancer or locally advanced disease (Iwata H, etal, ASCO10, Abs. 1081).

In August 2010, the FDA notified Eisai that the agency expects to complete priority review of the eribulin mesylate NDA for locally advanced or metastatic breast cancer on or before December 30, 2010, which is a 3 month extension from the original PDUFA action date of September 30, 2010. The extension is a result of the agency classifying recent responses to questions regarding the chemistry, manufacturing and controls (CMC) section of the NDA as a major amendment to the NDA. The new action date will give the agency additional time to review the information submitted for this complex synthetic process.

A multicenter (n=5), nonrandomized, open label, compassionate clinical trial (protocol ID: E7389-G000-399; NCT01142661; http://clinicaltrials.gov/ct2/show/NCT01142661 ) was initiated in August 2010, in the USA, to evaluate the safety of eribulin in treating patients with locally advanced or metastatic breast cancer refractory to all other marketed therapies. The trial’s primary objective is to evaluate safety. According to the protocol, patients are treated with a dose of eribulin (1.4 mg/m²) administered IV in 2 phases for up to 28 days. The trial is to enroll about 200 patients.

An open label, expanded access clinical trial (protocol ID: E7389-G000-398; NCT01240421; http://clinicaltrials.gov/ct2/show/NCT01240421 ) was initiated in August 2010, in Europe (Belgium), at the Institute Jules Bordet (Brussels, Belgium), to evaluate the efficacy of eribulin in treating patients with locally advanced or metastatic breast cancer that has progressed on or after the last anticancer therapy. Patients must have disease refractory to all other marketed therapies. According to the protocol, patients are administered eribulin (1.4 mg/m²) as a 2-5 minute IV bolus on days 1 and 8 of a 21-day cycle.

In June 2010, the FDA granted priority review status to the Eisai’s NDA for eribulin mesylate for the treatment of locally advanced or metastatic breast cancer previously treated with at least two chemotherapy regimens, including an anthracycline and a taxane. In addition to simultaneous regulatory applications in the USA, the Europe Union and Japan, Eisai submitted for the approval of eribulin to health authorities in Switzerland and Singapore.

The EMBRACE (Eisai Metastatic BReast cancer study Assessing physician’s Choice versus Eribulin E7389) phase III clinical trial (protocol ID: E7389-G000-305; NCT00388726) met its primary endpoint by significantly improving median OS compared with treatment of heavily pre-treated patients with metastatic breast cancer patients with physician’s choice regimens. EMBRACE was a multicenter, open-label, randomized, phase III clinical trial that enrolled 762 patients with locally recurrent or metastatic breast cancer who were previously treated with at least 2 and a maximum of 5 chemotherapy drugs (>/=2 for advanced disease), including an anthracycline or a taxane. Eligible patients had refractory disease to the most recent chemotherapy, documented by progression on or within 6 months of therapy. The trial was designed to compare OS in patients treated with eribulin versus a physician’s choice arm, reflecting a real world clinical setting where a variety of agents are used to treat patients with advanced breast cancer. The trial’s primary endpoint was OS. Secondary endpoints were to determine the objective response rate (ORR), PFS by independent review, and duration of response, and to assess safety and tolerability. This final analysis was carried out after 422 deaths. Patients were randomized in a 2 (n=508) to 1 (n=254) ratio, to either eribulin (1.4 mg/m²), administered IV for 2 to 5 minutes on days 1 and 8 of a 21-day treatment cycle or a physician’s choice treatment defined as any single agent chemotherapy, hormonal treatment or biological therapy approved for the treatment of cancer, palliative radiotherapy administered according to local practice, or supportive care only. The median age of participants was 55 (range=27-85); 16% of patients had HEr2 positive breast cancer, 19% had triple negative breast cancer, and 73% had been previously treated with capecitabine. The EMBRACE trial met its primary endpoint of OS; patients treated with eribulin survived 13.12 months compared to 10.65 months (p=0.04) for those treated with a physician’s choice regimen, representing a median 2.5 months survival benefit. A secondary endpoint of overall response rate (ORR) was statistically significant while another secondary endpoint, PFS, was supportive of the primary endpoint but did not reach statistical significance. Median PFS was 3.7 months with eribulin compared to 2.3 months for standard treatments (p=0.09; HR 0.85), ORR was 12% (CR=0.4%, PR=11.5%) for eribulin and 5% (CR=0, PR=5%) for standard care (p=0.005). Median duration of response was 4.1 months for eribulin (n=56) versus 6.7 months for standard care (n=11). The most frequently reported AE in patients treated with eribulin were asthenia (53.7%), neutropenia (51.7%), alopecia (44.5%) and peripheral neuropathy (34.6%). Grade 3/4 treatment-related AE attributed to eribulin were asthenia/fatigue (7.6%), neutropenia (44%), and peripheral neuropathy (8.4%). Treatment-emergent SAE were reported in 25% of patients in the eribulin group and 25.9% of patients in the standard care arm (Twelves C, etal, ASCO10, Abs. CRA1004).

In March 2010, Eisai Europe submitted a marketing authorization application (MAA) to the European Medicines Agency (EMA) for approval of eribulin mesylate (E7389) for the treatment of locally advanced or metastatic breast cancer in Europe. Regulatory applications for eribulin mesylate have also been submitted in the USA and Japan. The submission is based primarily on data from a multicenter, international, open label, randomized, parallel 2-arm, pivotal, phase III clinical trial (protocol ID: E7389-G000-305; NCT00388726), known as EMBRACE (Eisai Metastatic BReast cancer study Assessing physician’s Choice versus E7389), conducted in 762 women with locally recurrent or metastatic breast cancer previously treated with at least two chemotherapy regimens, including an anthracycline and a taxane. According to results, the trial met its primary endpoint of demonstrating a statistically significant improvement in OS in eribulin-treated patients compared with those treated with physician’s choice regimens. Patients were treated either with eribulin, administered IV over 2 to 5 minutes on days 1 and 8 every 21 days, or with a physician's choice defined as any single agent chemotherapy, or hormonal or biologic therapy approved for the treatment of cancer; or palliative treatment, or radiotherapy administered according to local practice. EMBRACE is the first global phase III trial to compare a new agent, eribulin, to real world choices in heavily pretreated patients with metastatic breast cancer. The physician’s choice arm of the trial was included following recognition of the heterogeneous nature of the patient population, as well as the need for clinicians to tailor treatment regimens for individual patients. Ebulin is delivered as an IV infusion with an administration time of between 2 and 5 minutes on days 2 and 8 of a 21-day cycle. The infusion time is relatively short when compared to that of taxanes, such as docetaxel, which is administered IV over 1 hour every three weeks. In addition, treatment with eribulin did not require any premedication. The most frequent adverse events (AE) reported by patients treated with eribulin were asthenia, neutropenia, alopecia, nausea and peripheral neuropathy. The trial enrolled patients with pre-existing neuropathy.

In June 2008, positive data were reported from the phase II trial (protocol ID: E7389-G000-211; NCT00246090) of eribulin (E7389) in patients with locally advanced or metastatic breast cancer previously treated with anthracycline, taxane, and capecitabine, refractory to the last prior therapy for disease. Eribulin demonstrated activity and a manageable tolerability profile in these heavily pretreated patients with low incidence of Grade 3/4 neuropathy. The trial enrolled 299 patients (median age=56 years; Er/Pgr positive=71%; HEr2 positive=11%; triple Er/Pgr/HEr2 negative=21%; median prior chemotherapy regimens=4; ECOG PS 0-2; neuropathy <Grade 2). A total of 291 patients were administered eribulin (1.4 mg/m²) as a 2-5 IV infusion on days 1 and 8 of a 21-day cycle. Patients were treated with a median of 4 eribulin cycles (range 1-27). The primary efficacy endpoint was ORR assessed by independent review (IR) using RECIST. Among the 269 patients who met the inclusion criteria, ORR by IR was 9.3% and investigator assessed ORR was 14.1%. SD rate was 46.5% and the clinical benefit rate (CR + PR + SD>6 months) was 17.1%. Median duration of response was 3.5 months. Median PFS and OS were 2.6 months and 10.4 months, respectively; 6 PFS and OS rates were 12.4% and 72.3%, respectively. Treatment-related toxicities were Grade 3/4 neutropenia (54%), leukopenia (14%), and asthenia/fatigue (10%; no grade 4). Grade 3 peripheral neuropathy occurred in 5.5% of patients (Vahdat LT, etal, ASCO08, Abs. 1084). Updated results indicated a median duration of response of 4.2 months and a 6-month PFS rate of 16%. Of 291 patients, most frequently reported Grade 3/4 AE also included febrile neutropenia. No Grade 4 peripheral neuropathy was observed. There was no correlation between Grade 2 peripheral neuropathy and deterioration.

In the single arm, multicenter (n=16), phase II clinical trial (protocol ID: E7389-A001-201; NCT00097721) of E7389 in patients with chemotherapy refractory, advanced breast cancer, IV E7389 (1.4 mg/m²) was administered on days 1, 8, and 15 of a 28-day cycle in Group 1. The schedule was modified to days 1 and 8 of a 21-day cycle (Group 2) because of dose delays. Primary efficacy endpoint was ORR according to RECIST criteria based upon independent review (IR) of tumor assessment, and secondary outcome measures include safety, tolerability, duration of response, TTP, OS, QoL, and tumor pharmacogenetics relationship to patient response. Participating sites include Baylor Charles A. Sammons Cancer Center (Dallas, TX), Harrington Cancer Center (Amarillo, TX), University of Kansas Medical Center (Kansas City, KS), Texas Oncology PA and US Oncology (El Paso, TX), and Weill Cornell Medical College (New York, NY). Of 104 enrolled patients (median age=55 years), 103 were treated with E7389 (Group 1=70, Group 2=33). Patients had a median of 4 prior chemotherapy regimens. A total of 61% of tumors were Er+, 14% were HEr2/neu3+, and 29% were negative for Er, Pr, and HEr2. The incidence of dose interruption, delay, or omission during cycle 1 was 63% in Group 1 and 18% in Group 2. Drug related Grade 3/4 AE include neutropenia (Group 1=63%, Group 2=58%), febrile neutropenia (Group 1=4%, Group 2=3%), leukopenia (Group 1=20%, Group 2=15%), thrombocytopenia (Group 1=3%, Group 2=0), diarrhea (Group 1=1%, Group 2=3%), nausea (Group 1=0, Group 2=3%), stomatitis (Group 1=3%, Group 2=0), fatigue (Group 1=4%, Group 2=6%), and peripheral neuropathy (Group 1=6%, Group 2=3%). Peripheral neuropathy (all grades) was observed in 31/103 evaluable patients. Best overall response rate by IR was PR in 10.2% and 14.3% of patients in Groups 1 and 2, respectively. Disease stabilized in 35.6% of patients in Group 1, and in 57.1% of those in Group 2. Disease progressed in 49.2% of patients in Group 1 and in 25% of patients in Group 2. Combined ORR was 17.2%., and median duration of response is 162 days. Median PFS was 79 days, 6 month PFS rate was 27%, and median OS was 253 days (Blum JL, etal, ASCO07, Abs. 1034). Patients were previously treated with anthracyclines (100%), taxanes (100%), capecitabine (68%), vinorelbine (46%), and gemcitabine (55%). PR was achieved by 15% of Er+ and/or Pr+ patients, 8% of HEr2+ patients, and 7% of patients with Er-, Pr-, and HEr2- phenotype (Blum JL, etal, ASCOBC07, Abs. 223).

A multicenter (n=20), nonrandomized, open label, phase II clinical trial (protocol ID: E7389-J081-221; NCT00633100; http://clinicaltrials.gov/ct2/results?term=NCT00633100 ) was initiated in February 2008, in Japan, to evaluate the efficacy of E7389 in treating patients with advanced or relapsed breast cancer who have been treated with prior chemotherapy including anthracycline and taxane. Patients must have adequate bone marrow, liver, kidney and lung function, and must not have systemic infection with a fever, or brain metastasis, or active double cancer. The trial’s primary objective is to determine the ORR. Secondary objective is to evaluate the duration of objective response. According to protocol, patients are administered IV E7389 on days 1 and 8 of a 21 day cycle. One cycle consists of 3 weeks. E7389 will be administered for 2 cycles or more in principle. Administration can be continued as long as the patient does not meet the discontinuation criteria. The trial, to enroll about 82 patients, was closed in August 2009 and completed in February 2010.

In February 2008, Eisai changed the schedule for submission to FDA of an NDA for E7389 (eribulin mesylate) for third line treatment of advanced breast cancer in patients pretreated with anthracycline, taxane and capecitabine. Eisai had planned to submit an NDA under Subpart H, based on phase II clinical trial data, to seek accelerated approval for E7389 as a third line monotherapy for breast cancer, but was precluded from doing so, because the FDA approved another drug for this specific indication in October 2007. Eisai remains committed to advancing two phase III clinical trials for E7389, which are ongoing in the USA and Europe, a trial (protocol ID: E7389-G000-301; NCT00337103) as second line therapy, and a trial (protocol ID: E7389-G000-305; NCT00388726) as third line therapy in breast cancer. Eisai now plans to submit an NDA to FDA with data from these trials and phase II clinical trial data in fiscal year 2009-2010. In addition, Eisai continues to evaluate E7389 as a potential treatment for a variety of other solid tumors, including non-small cell lung cancer (nsclc), prostate cancer and sarcoma.

A multicenter (n=98), open label, randomized, two parallel arm, phase III clinical trial (protocol ID: E7389-G000-301; NCT00337103; http://clinicaltrials.gov/ct2/results?term=NCT00337103 ) was initiated in June 2006, to evaluate the efficacy of E7389 versus capecitabine (Xeloda; Roche) in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes and refractory to the most recent chemotherapy. The trial’s primary outcome measures are overall survival rate and PFS. The trial, to enroll 1100 patients, is being conducted in the USA, Argentina, Canada, Europe (Belgium, France, Hungary, Poland, Romania), Mexico, Russia, Singapore, South Africa, and Spain). This trial was cloced in November 2009.

A multicenter (n=62), open label, randomized, parallel, 2-arm, phase III clinical trial (protocol ID: E7389-G000-305; NCT00388726; http://clinicaltrials.gov/ct2/results?term=NCT00388726 ), known as EMBRACE (Eisai Metastatic BReast cancer study Assessing physician’s Choice versus E7389), was initiated in October 2006, to evaluate the efficacy of E7389 versus 'Treatment of Physician’s Choice' in patients with locally recurrent, metastatic breast cancer previously treated with at least 2 and a maximum of 5 chemotherapy regimens, including an anthracycline and a taxane. The trial’s primary objective is to compare overall survival in patients treated with E7389 versus such other treatments. Other objectives are to determine duration of response, safety parameters, PFS, and an objective tumor response rate. The trial, to enroll about 630 patients, is being conducted in the USA, Australia, Canada, Europe (Czech Republic, France, Italy, Spain, Russia), and South Africa. This trial was closed in March 2009.

In the nonrandomized, open label, phase II clinical trial (protocol ID: E7389-A001-201, NCT00097721), E7389 was evaluated as a monotherapy as an IV bolus dose of 1.4 mg/m² on days 1, 8, and 15 of a 28-day cycle as determined in phase I, for patients with advanced, metastatic, refractory breast cancer. Patients underwent >/=2 prior chemotherapy regimens, prior anthracycline plus taxane, and progressed within 6 months. No premedication was required. Participating institutions include Baylor Sammons Cancer Center (Dallas, TX), Weill Cornell Breast Center (New York, NY), the University of Kansas Cancer Center (Kansas City, KS), and Harrington Cancer Center (Amarillo, TX). Primary endpoint was response rate. Since ß-tubulin isotypes predict sensitivity of breast cancer cell lines to E7389, a secondary objective was to explore the relationship of ß-tubulin isotypes and related proteins. By June 2005, 30 patients were enrolled, and 29 were treated and completed a second cycle of treatment for which end of second cycle tumor assessment was available. Median age was 54 yearrs (range=36-73). Patients had an ECOG performance status 0-1. A total of 18 patients were Er+ and/or Pr+, and 3 were HEr2/neu 3+. All patients underwent prior anthracycline and taxane therapy, and a median of 4 prior chemotherapies (range=2-12). Prior hormonal therapy and experimental/biologic compounds were reported for 91% and 27% of patients, respectively. Major toxicity related to drug was myelosuppression. There was 1 Grade 3 febrile neutropenia, and 17 cases of Grade 3 or 4 neutropenia. Other Grade 3 toxicities include nausea (n=1), fatigue (n=1), dehydration (n=1), arthralgias (n=2), dyspnea (n=2), and peripheral neuropathy (n=1), in a patient who had a pre-existing drug-related neuropathy. There were 8 PR using RECIST out of 29 evaluable patients, with 6 confirmed at cycle 4. For 3 patients, best response is SD (range=4-7 cycles). Based on disruption of dosing at day 15 for many patients, a day 1 and 8 every 21 days schedule is being evaluated. An update on efficacy, safety, and new administration schedule will be provided, as well as an evaluation of ß tubulin isotypes as a possible biomarker for sensitivity to E7389 (Silberman SL, etal, SABCS05, Abs. 1063). In more mature data, of 65 evaluable patients, 10 PR were confirmed at the fourth cycle assessment. There were 21 SD. In patients who are treatment-refractory with advanced breast cancer, the preliminary response rate is 15%. Based on preliminary results, predominant serious side effect related to E7389 is neutropenia. Other side effects are considered mild to moderate and include nausea, fatigue, dehydration, arthralgias, dyspnea, and neuropathy. No patients discontinued because of hematologic toxicity. A total of 71 women were enrolled in the 28-day cycle patient group. Preliminary efficacy data for 65 patients and safety data on 48 patients are available. Final results may change from initial analysis.

In October 2005, a multicenter (n=35), nonrandomized, open label, phase II clinical trial (protocol ID: E7389-G000-211; NCT00246090; http://clinicaltrials.gov/ct2/results?term=NCT00246090 ) was initiated in the USA and Canada, to evaluate E7389 in patients with locally advanced or metastatic breast cancer, previously treated with anthracycline, taxane, and capecitabine, refractory to the last prior therapy for disease. Primary objectives are to evaluate efficacy and safety. Secondary objectives are to investigate PK and pharmacodynamics. Total expected enrollment is 300. This trial was reported closed as of November 2006.

In September 2004, a nonrandomized, open label, uncontrolled, single group assignment, phase II clinical trial (protocol ID: E7389-A001-201; NCT00097721; http://clinicaltrials.gov/ct2/results?term=NCT00097721 ) was intiated at multiple sites in the USA to examine E7389 in patients with advanced, metastatic breast cancer previously treated with chemotherapy, including an anthracycline and a taxane, with previously documented progression during or within 6 months following the last dose of prior chemotherapy. The primary objective of this trial is to determine the response rate to E7389 (1.4 mg/m²) monotherapy administered as an IV bolus on days 1, 8, and 15 of a 28-day cycle. Secondary objectives include safety and tolerability, duration of response, TTP, OS, and QoL. Total expected enrollment is 61. This trial was closed in November 2005, and completed in March 2008.

A multicenter (n=24), open label, phase II clinical trial (protocol ID: CDR0000514516; CCC-PHII-74; NCT00400829; http://clinicaltrials.gov/ct2/results?term=NCT00400829 ), was initiated in November 2006, to evaluate the efficacy of E7389 in treating patients with recurrent or progressive Stage IIIb or Stage IV non-small cell lung cancer (nsclc) previously treated with a taxane. Primary outcome is objective response rate. Other objectives are to determine overall survival, and TTP, and to evaluate the drug's toxicity profile. According to the protocol, patients are treated with E7389 IV over 1-2 minutes on days 1 and 8. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. After completion, patients are followed once monthly for at least 6 months and then periodically thereafter. The trial, to enroll about 39 patients, is being conducted in the USA under Study Chair Barbara J. Gitlitz, MD, at the USC/Norris Comprehensive Cancer Center (Los Angeles, CA). This trial was closed in December 2009.

In January 2005, a multicenter (n=13), nonrandomized, open label, uncontrolled, single group assignment, phase II clinical trial (protocol ID: E7389-A001-202; NCT00100932; http://clinicaltrials.gov/ct2/results?term=NCT00100932 ) was initiated in the USA to examine E7389 in patients with advanced nsclc , who progressed during or after platinum-based doublet chemotherapy stratified for prior taxane therapy. The primary objective of this trial is to determine response rate. Secondary objectives include OS, TTP, duration of response, and safety and tolerability. Total expected enrollment is 72 patients. This trial was reported closed in November 2005 and completed in September 2009.

In the multicenter (n=155), non-comparative, phase II clinical trial (protocol ID: CDR0000482413; ECOG-E5805; NCT00337077) of eribulin mesylate in patients with metastatic, castration resistant prostate cancer, patients were treated with IV eribulin (1.4 mg/m²) on days 1 and 8 of a 21-day cycle. Patients were stratified to either a chemotherapy naïve arm, prior taxane treatment arm, or 2 prior cytotoxic chemotherapy arm. Of 119 treated patients, 116 were eligible for the primary response determination in this clinical trial. Median age is 70 years, median number of treatment cycles is 4, and 90% of patients had ECOG 0-1. To date, only 1 patient is still on treatment. Among 115 eligible patients who discontinued treatment, 82 were off treatment due to disease progression. A total of 65 treated patients had dose modifications (both planned and unplanned). PSA response rate in the chemotherapy naïve arm was 24% (versus the anticipated 40% rate). Disease stabilized >/=9 weeks in 15 patients from the chemotherapy naïve arm, 20 patients in the prior taxane treatment arm, and 29 patients in the 2 prior cytotoxic chemotherapy arm. Median duration of PSA response was 7.1 months in the chemotherapy naïve arm and 3.6 months in the prior taxane treatment arm. Median OS was 11.4 months in patients from the prior taxane treatment arm and 13.7 months in the 2 prior cytotoxic chemotherapy arm. AE in the chemotherapy naïve arm (n=41) were Grade 3/4 neutropenia (52%), Grade 3/4 leukopenia (33%), Grade 3/4 sensory neuropathy (14%), fatigue (Grade 1/2=69%, Grade 3/4=17%), anorexia (Grade 1/2=33%, Grade 3/4=2%), and nausea (Grade 1/2=26%, Grade 3/4=2%). In the prior taxane treatment arm (n=51), AE were Grade 3/4 neutropenia (50%), Grade 3/4 leukopenia (44%), Grade 3/4 sensory neuropathy (16%), fatigue (Grade 1/2=66%, Grade 3/4=8%), anorexia (Grade 1/2=32%, Grade 3/4=6%), and nausea (Grade 1/2=38%, Grade 3/4=2%). In the 2 prior cytotoxic chemotherapy arm (n=24), AE were Grade 3/4 neutropenia (68%), Grade 3/4 leukopenia (52%), Grade 3/4 sensory neuropathy (4%), fatigue (Grade 1/2=52%, Grade 3/4=12%), anorexia (Grade 1/2=24%, Grade 3/4=4%), and nausea (Grade 1/2=36%). Eribulin demonstrated activity in taxane naïve, metastatic, castration resistant prostate cancer. Clinically significant myelosuppression was noted in all arms. Although single agent activity was observed, the overall response rate did not meet predetermined levels of activity sufficient to warrant further study in this patient population (Stein MN, etal, ASCO10, Abs. 4556).

In the phase II clinical trial (protocol ID: E7389-G000-204; NCT00278993) of E7389 in patients with hormone refractory prostate cancer (HRPC) with advanced and/or metastatic disease stratified by prior chemotherapy, patients were administered IV E7389 (1.4 mg/m²) on days 1 and 8 of 21-day cycles. Participating sites include Royal Marsden Hospital (Sutton, UK), Ocala Oncology Center (Ocala, FL), Central Indiana Cancer Centers (Indianapolis, IN), New York Oncology Hematology (Albany, NY), US Oncology Baylor Center (Webster, TX), Hospital Vall d’Hebron (Barcelona, Spain), and Columbia Presbyterian Medical Center (New York, NY), among others. Primary outcomes are PSA response using Bubley criteria, symptom assessment, PFS, overall tumor response rates, and duration of tumor response. To date, 57 patients (taxane pretreated patients=37, taxane naïve patients=20; median age=71 years) have been treated. A total of 160 treatment cycles have been administered (median=2). Drug-related serious AE were reported in 9 patients, including pulmonary embolism (n=2), melena (n=2), fever, neutropenia, febrile neutropenia, UTI, anemia, DVT, chest pain, and renal failure (n=1 each). There were 2 PSA responses in the first 21 patients from the taxane treated group, and 4 in the first 14 patients in the taxane naïve group, allowing progression to Stage 2 of the clinical trial with further accrual (Molife R, etal, ASCO07, Abs. 15513).

A multicenter (n=159), open label, phase II clinical trial (protocol ID: CDR0000482413; ECOG-E5805; NCT00337077; http://clinicaltrials.gov/ct2/results?term=NCT00337077 ) was initiated in November 2006, in the USA, by the Eastern Cooperative Oncology Group (ECOG), to evaluate the efficacy of E7389 in treating patients with metastatic hormone-refractory prostate cancer (HRPC). The primary objective is to determine the number of patients with a 50% decrease in PSA of >/=4 weeks duration. Other objectives are to determine the measurable disease response and the overall response. According to the protocol, patients are stratified according to prior chemotherapy (no prior chemotherapy versus prior taxane only versus 2 prior cytotoxic chemotherapy regimens). Patients are treated with E7389 IV over 5 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion, patients are followed periodically for 5 years. The trial, to enroll about 129 patients, is being conducted in the USA under PI Mark Stein, MD, at the Cancer Institute of New Jersey, and Gary R. Hudes, MD, at Fox Chase Cancer Center. This trial was closed in August 2009.

A multicenter (n=17), nonrandomized, open label, 2-stage design, single arm phase II clinical trial (protocol ID: E7389-G000-204; NCT00278993; http://clinicaltrials.gov/ct2/results?term=NCT00278993 ) was initiated in January 2006, in the USA and Europe (Spain, UK), to evaluate the efficacy of E7389 in patients with advanced and/or metastatic hormone-refractory prostate cancer (HRPC), previously treated with antiandrogen therapy and further explore the efficacy of E7389 by enrollment of patients into two strata, those who have had no prior systemic chemotherapy, except for mitoxanthrone and estramustine, and those who failed no more than one previous chemotherapeutic regimen with tubulin-binding agents such as docetaxel. The trial’s primary objectives are to determine an objective PSA response rate, duration of PSA response, tumor-related symptom assessment, PFS, overall tumor response rates, and duration of tumor response. Other objectives are to determine any adverse events, obtain laboratory parameters, evaluate concomitant medications, study drug exposure, and conduct physical examination, ECG, and PK analysis. The trial, to enroll about 110 patients, is being conducted in the USA. This trial was closed in December 2007 and completed in August 2009.

A multicenter (n=3, open label phase II clinical trial (protocol ID: CDR0000502291; PMH-PHL-049; NCT00383760; http://clinicaltrials.gov/ct2/results?term=NCT00383760 ), was initiated in April 2006, to evaluate the efficacy of E7389 as a second-line therapy in treating patients with locally advanced, inoperable, or metastatic pancreatic cancer. The primary outcome is objective response (CR or PR). Other objectives are to determine response or stable disease duration, objective stable disease rate, toxicity, TTP (median, 6 month, and 1 year), and overall survival (median, 6 month, and 1 year). According to the protocol, patients are treated with E7389 IV on days 1 and 8. Treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity. After completion, all patients are followed at 4 weeks. Responders or those with stable disease are followed every 3 months. The trial, to enroll about 37 patients, is being conducted in Canada under Study Chair Malcolm J. Moore, MD (tel: 416-946-2263), at Princess Margaret Hospital (Toronto, Canada). This trial was suspended in February 2008 and completed in October 2009.

Final results from the phase I portion of the California Cancer Consortium’s phase I/II clinical trial (protocol ID: CDR0000492014; U01CA062505; CCC-PHII-75; NCI-7435; NCT00365157) of eribulin mesylate in patients with renal dysfunction and advanced urothelial cancer showed that out of 21 treated patients (median age=71.7 years), 17 had transitional cell cancer and 4 had other tumor types. Median number of cycles was 6. MTD in patients with moderate renal dysfunction was 1.4 mg/m² and no DLT were seen. In patients with severe renal dysfunction (n=6), 1 patient at 1.4 mg/m² had DLT of Grade 3 weakness and fatigue. Of 20 evaluable patients, response rate was 18%, with PR achieved in 3 patients. Disease stabilized in 9 patients, and progressed at 12 weeks in 2 patients who had unconfirmed PR on 6 week scans. At median follow-up of 11 months, median PFS was 4.1 months and median OS was 9.7 months. Toxicities include Grade 3/4 neutropenia (n=5), febrile neutropenia (n=1), Grade 1 sensory neuropathy (n=7), and Grade 1 transaminitis (n=8). Eribulin has encouraging single agent activity in urothelial cancer at doses tolerated by patients with moderate and severe renal dysfunction. Tolerance of eribulin at full doses in patients with renal dysfunction may fulfill an unmet need across a spectrum of tumors (Synold TW, etal, ASCO10, Abs. 2527).

To date, a total of 40 patients (median age=67 years) have been enrolled in the open label, multicenter (n=24), phase II clinical trial (protocol ID: CDR0000492014; U01CA062505; CCC-PHII-75; NCI-7435; NCT00365157) of eribulin mesylate in patients with advanced and metastatic urothelial cancer. Patients were administered IV eribulin (1.4 mg/m²) on days 1 and 8, every 3 weeks. Histology types include transitional cancer (n=35), adenocarcinoma (n=3), squamous cell cancer (n=1), and small cell cancer (n=1). ORR was 38% in 37 evaluable patients, with CR achieved by 1 patient and PR in 14 patients. ORR in patients with transitional cell cancer (n=15) was 37%, with 13 patients achieving response. ORR in patients with prior neo/adjuvant chemotherapy was 34%. At median follow-up of 19.8 months, median PFS was 3.9 months, and disease progressed in 36 patients. Median OS was 9.4 months, with death in 25 patients. PFS was associated with Bajorin risk group (p=0.028 for trend). A total of 20 patients had Grade 3/4 neutropenia, and febrile neutropenia was not observed. Sensory neuropathy was observed in 19 patients, 18 of which were Grade 1/2. Other non-hematologic toxicities include hyperglycemia (n=14, Grade 3=3), hyponatremia (n=14, Grade 3=4), alopecia (n=37), and leg fatigue and pain (n=6, Grade 3=1). Eribulin mesylate has single agent activity in urothelial cancer, even in patients with prior neo/adjuvant chemotherapy. Accrual is ongoing for patients with creatinine clearance <40 mL/m in whom the 1.4 mg/m² dose studied here is also tolerable (Quinn DI, etal, ASCO10, Abs. 4539).

A multicenter (n=24), dose-escalation, phase I clinical trial followed by an open label phase II clinical trial (protocol ID: CDR0000492014; CCC-PHII-75; NCI-7435; NCT00365157; http://clinicaltrials.gov/ct2/results?term=NCT00365157 ) was initiated in October 2006, in the USA, to evaluate the side effects and best dose of E7389 in treating patients with locally advanced or metastatic cancer of the urothelium and kidney dysfunction. The trial’s primary objectives are to determine the safety and response rate of E7389. Other objectives are to determine the overall survival, PFS at 6 months, toxicity, and to characterize the drug's PK profile. According to the protocol, during phase I, patients are treated with E7389 IV over 1-2 minutes on days 1 and 8. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 2 to 6 patients per stratum are treated with escalating doses of E7389 until MTD is determined. Blood is collected periodically during course 1 for PK studies. During phase II, patients are treated with E7389 IV over 1-2 minutes on days 1 and 8 at MTD. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. Initially, only patients without renal insufficiency are enrolled in the phase II trial until the phase II dose (MTD) has been proven safe. Accrual of patients of patients with renal insufficiency then begins at this dose. After completion of treatment, patients are followed periodically for at least 6 months. The trial, to enroll about 77 patients, is being conducted under Study Chair David I. Quinn, MD, at USC/Norris Comprehensive Cancer Center (Los Angeles, CA).

A multicenter (n=4), open label, phase II clinical trial (protocol ID: CDR0000481534; MSKCC-06027; NCI-7431; NCT00334893; http://clinicaltrials.gov/ct2/results?term=NCT00334893 ), was initiated in April 2006, to evaluate the efficacy of E7389 in patients with recurrent ovarian epithelial, primary peritoneal cavity, or fallopian tube cancer. The trial’s primary objective is to determine the frequency of objective response. Another objective is to determine the toxicity profile. According to the protocol, patients are stratified according to prior platinum sensitivity (yes vs. no). Patients are treated with E7389 IV over 15 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion, patients are followed for 4 weeks. The trial, to enroll about 74 patients, is being conducted in USA, under Study Chair Martee L. Hensley, MD (tel: 212-639-6902) and Carol Aghajanian, MD, at Memorial Sloan-Kettering Cancer Center. This trial was closed in February 2010.

A multicenter (n=109), open label, phase II clinical trial (protocol ID: CDR0000481530; SWOG-S0618; NCT00337129; http://clinicaltrials.gov/ct2/results?term=NCT00337129 ), was initiated in May 2006, to evaluate the efficacy of E7389 in patients with metastatic or recurrent squamous cell carcinoma of the head and neck. The trial’s primary objectives are to determine the response probability (confirmed, CR and PR), PFS, overall survival, and toxicity. The trial, to enroll about 40 patients, is being conducted in the USA, under Study Chair Susanne M. Arnold, MD, University of Kentucky (Lexington, KY). This trial was closed in December 2007.