er-086526 and Neutropenia

In the new era of 'precision' cancer medicine, new drug development has shifted from cytotoxic chemotherapy to molecularly targeted agents. Eribulin mesylate, a microtubule-destabilizing agent, is the only 'classical' cytotoxic agent approved for the treatment of breast cancer in the last 7 years. This synthetic analogue of halichondrin B, isolated from the marine sponge 'Halicondria Okaida', was responsible for prolonging overall survival of heavily pretreated metastatic breast cancer patients in a large Phase III trial. Eribulin is now under clinical development in earlier settings such as the neo-adjuvant and adjuvant settings. Furthermore, its unique mechanism of action and the absence of cross-resistance with taxanes have led to the design of clinical trials in multiple indications: bladder cancer, lung cancer, prostate cancer… The main adverse events are neutropenia, fatigue and peripheral neuropathy.

Topics: Alopecia; Antineoplastic Agents; Breast Neoplasms; Carcinoma; Chemotherapy, Adjuvant; Clinical Trials as Topic; Drug Approval; Drug Resistance, Neoplasm; Drugs, Investigational; Ethers, Cyclic; Fatigue; Female; Furans; Humans; Ketones; Macrolides; Molecular Targeted Therapy; Multicenter Studies as Topic; Neoadjuvant Therapy; Neutropenia; Peripheral Nervous System Diseases; Tubulin Modulators; United States; United States Food and Drug Administration

Eribulin is a synthetic analog of halichondrin B, a non-taxane microtubule inhibitor extracted from the marine sponge, Halichondria okaida. It presents a novel mechanism of action and is active on cancer cells resistant to other antimicrotubule agents. It was granted approval in the USA and Europe for the treatment of heavily pretreated metastatic breast cancer. Early trials had shown activity in this setting with main toxicities being neutropenia and neuropathy in patients where quality of life is essential. Approvals were granted after a phase 3 trial demonstrated overall survival benefit in metastatic breast cancer previously treated with anthracyclines, taxanes, and capecitabine, in a setting where most treatments are failing to demonstrate a survival benefit. Recent data suggest that this survival benefit is also consistent in the elderly with no excess toxicity. Future strategies of eribulin are being tested in ongoing trials, evaluating this drug in earlier metastatic lines as well as in the adjuvant and the neoadjuvant settings.

Topics: Adult; Aged; Antineoplastic Agents; Breast; Breast Neoplasms; Clinical Trials as Topic; Drug Monitoring; Ethers, Cyclic; Female; Furans; Humans; Ketones; Macrolides; Microtubules; Neoplasm Metastasis; Neutropenia; Treatment Outcome

Despite advances in cancer biology, chemotherapy remains the backbone of treatment approaches for many patients with metastatic breast cancer (MBC). Halichondrins, derived from marine sponges, have significant potential as potent antimicrotubule agents. Eribulin, with proven preclinical activity, is a synthetic halichondrin analog with novel actions on tubulin including suppression of microtubule polymerization. Phase I and II studies in MBC identified neutropenia as the dose-limiting toxicity and a maximum tolerated dose of 1.4 mg/m2 on days 1 and 8 of a 21-day cycle. An encouraging response rate of 11.5% in refractory MBC led to the launch of the phase III Eisai Metastatic Breast Cancer Study Assessing Physician's Choice versus Eribulin trial, in which heavily pretreated patients with MBC were randomized 2 : 1 to intravenous eribulin or monotherapy of the investigator's choice. Recently, it was reported that this important study of 762 patients met its primary endpoint of overall survival: eribulin was associated with an improvement in median overall survival from 10.65 months to 13.12 months (hazard ratio 0.8; 95% confidence interval 0.66-0.99) and a response rate of 12.2%. In general, the side effect profile of eribulin seems to be acceptable, as although neutropenia occurred in 45% of the patients, febrile neutropenia was rare and the incidence of neuropathy was low. These findings show that eribulin is potentially a new active agent for MBC, although results of ongoing studies are awaited to confirm the reported benefit. Future studies will investigate the potential role of eribulin in other settings, including for early breast cancer, to ascertain how to optimally incorporate this new agent into current treatment paradigms.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Breast Neoplasms; Clinical Trials, Phase III as Topic; Ethers, Cyclic; Female; Furans; Humans; Infusions, Intravenous; Ketones; Macrolides; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neutropenia; Randomized Controlled Trials as Topic; Survival Rate; Treatment Outcome; Tubulin Modulators

Selinexor (KPT-330) is a potent inhibitor of exportin 1 (XPO1), in turn inhibiting tumor growth. Selinexor enhances the antitumor efficacy of eribulin in triple-negative breast cancer (TNBC) in vitro and in vivo. Given the unmet medical need in TNBC and sarcoma, the authors explored the safety and efficacy of this combination.. The authors conducted a phase 1b trial of combined selinexor and eribulin using a 3 + 3 dose-escalation design in patients who had advanced solid tumors and in those who had TNBC in a dose-expansion cohort.. Patients with TNBC (N = 19), sarcoma (N = 9), and other cancers (N = 3) were enrolled in the dose-escalation cohort (N = 10) and in the dose-expansion cohort (N = 21). The median number lines of prior therapy received was four (range, from one to seven prior lines). The most common treatment-related adverse events for selinexor were nausea (77%), leukopenia (77%), anemia (68%), neutropenia (68%), and fatigue (48%). One dose-limiting toxicity occurred at the first dose level with prolonged grade 3 neutropenia. The recommended phase 2 dose was 80 mg of selinexor orally once per week and 1 mg/m. Selinexor and eribulin had an acceptable toxicity profile and modest overall efficacy with durable responses in select patients.. Effective therapies for advanced, triple-negative breast cancer and sarcoma represent an unmet need. Exportin 1 is associated with the transport of cancer-related proteins. Preclinical studies have demonstrated tumor growth inhibition and enhanced tumor sensitivity in patients who receive selinexor combined with eribulin. In this phase 1b study, the authors evaluated the safety profile and clinical activity of the combination of selinexor, a potent oral inhibitor of exportin 1, and eribulin in patients with advanced cancers enriched for triple-negative breast cancer or sarcoma. The combination was well tolerated; most adverse events were mild or moderate, reversible, and managed with dose modifications or growth factor support. The combination of selinexor and eribulin produced an antitumor response, particularly in some patients with triple-negative breast cancer. This work lays the foundation for prospective investigations of the role of selinexor and eribulin in the treatment of triple-negative breast cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Neutropenia; Prospective Studies; Sarcoma; Soft Tissue Neoplasms; Triple Negative Breast Neoplasms

Metastatic breast cancer (MBC) is an incurable disease and its treatment focuses on prolonging patients' (pts) overall survival (OS) and improving their quality of life. Eribulin is a microtubule inhibitor that increases OS in pre-treated MBC pts. The most common adverse events (AEs) are asthenia, neutropenia and peripheral neuropathy (PN).. PAINTER is a single arm, phase IV study, aimed at evaluating the tolerability of eribulin in MBC pts. Secondary objectives were the description of treatment efficacy and safety, the assessment of the incidence and severity of PN and its association with genetic polymorphisms. Genomic DNA was isolated from blood samples and 15 Single Nucleotide Polymorphisms (SNPs) were genotyped by Taqman specific assays. The association between PN and SNPs were evaluated by Fisher exact test.. Starting from May 2014 until June 2018 180 pts were enrolled in this study by 20 Italian centers. 170 of these pts could be evaluated for efficacy and toxicity and 159 for polymorphisms analysis. The median age of pts was 60 years old and the biological subtypes were luminal type (64.7%), Her2 positive (18.3%) and triple negative (17%). Pts were pretreated with a median of 5 lines for MBC. The median follow up of this study was 15.4 months with a median number of 4.5 cycles administered (minimum-maximum 1-23). The median overall survival was 12 months. 48.8% of pts experienced a dose reduction, mainly for neutropenia (23.9%) and liver toxicity (12%). 65 pts (38.2%) reported at least one severe toxicity. Neutropenia and neurotoxicity were the most frequent severe AEs (15.3% and 14.7%, respectively); other reported toxicities were osteo-muscular, abdominal or tumor site pain (19.4%), liver toxicity (6.6%), pulmonary toxicity (6.5%) and dermatological toxicity (3.6%). Among the 15 evaluated SNPs, an association with PN was found for rs2233335 and rs7214723.. Eribulin is a well-tolerated treatment option in MBC. Schedule and dosage modifications were common, but toxicity rarely led to treatment discontinuation. SNPs rs2233335 (G/T and T/T) in the NDRG1 gene and rs7214723 (CC and CT) in the CAMKK1 gene were associated with PN. These findings, if validated, could allow a tailored treatment with eribulin in cancer patients.. ClinicalTrials.gov ID: NCT02864030.

Topics: Breast Neoplasms; Female; Humans; Middle Aged; Neoplasm Metastasis; Neutropenia; Peripheral Nervous System Diseases; Polymorphism, Genetic; Quality of Life; Treatment Outcome

Patients with human epidermal growth factor receptor-2-negative metastatic breast cancer (MBC), whose disease progressed on prior chemotherapy, have a poor prognosis. Eribulin, a microtubule dynamics inhibitor, extends overall survival in previously treated MBC. The most common adverse event associated with eribulin is neutropenia, which may result in dose interruptions or reductions. A modified biweekly dosing schedule of eribulin was assessed for efficacy as well as improvements in hematologic toxicity.. In this open-label, single-arm, multicenter, phase II study, previously treated (2-5 chemotherapy regimens for metastatic disease) patients with human epidermal growth factor receptor-2-negative MBC received intravenous eribulin 1.4 mg/m. Among 58 treated patients, the ORR was 12% (95% confidence interval [CI], 5%-24%), DCR (CR, n = 1; PR, n = 6; SD, n = 30) was 65%, and the median progression-free survival was 3.6 months (95% CI, 2.9-4.1 months). Grade 3 or 4 neutropenia was 31%; 50% of all patients, and 78% of patients with neutropenia (all grades), received hematopoietic growth-factor support.. The efficacy and safety results obtained with a biweekly eribulin schedule in this phase II trial appear similar to those associated with the approved eribulin schedule (1.4 mg/m

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Breast Neoplasms; Drug Administration Schedule; Female; Furans; Granulocyte Colony-Stimulating Factor; Humans; Injections, Intravenous; Ketones; Middle Aged; Neutropenia; Prognosis; Progression-Free Survival; Receptor, ErbB-2; Severity of Illness Index

Despite the survival benefit and acceptable tolerability of eribulin for advanced/metastatic breast cancer (MBC) patients pretreated with anthracyclines and taxanes, there is limited evidence of the clinical benefit of early eribulin use. We investigated the efficacy and safety of first- to third-line eribulin use in patients with MBC.. In this phase II, open-label, single-arm study conducted at 14 sites in Kyushu, Japan, women with histologically confirmed human epidermal growth factor receptor 2-negative MBC were enrolled between December 1, 2011 and November 30, 2013 (Data cut-off: November 30, 2014). Objective response rate (ORR; primary endpoint), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS), and safety were evaluated.. Of 53 recruited patients, 47 were enrolled. The ORR was 17.0% (95% confidence interval, 7.6-30.8), DCR was 66.0% (51.2-77.8), median PFS was 4.9 months (3.5-7.0), DOR was 6.6 months (1.9-14.3), and median OS was 17.4 months (10.1-not evaluable). The common grade 3/4 adverse events were neutropenia (25 patients; 53.2%), leucopenia (16 patients; 42.1%) and febrile neutropenia (4 patients; 8.5%). Toxicity did not increase during the long-term treatment. Subgroup analysis indicated that first-line treatment led to higher ORR and prolonged PFS and OS than second-/third-line treatment and that incidence of adverse events in patients of second-/third-line treatment was not higher than that in patients of first-line treatment.. Eribulin exhibited efficacy and manageable tolerability in Japanese women with pretreated MBC in first- to third-line use. (ID: UMIN000007121).

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Confidence Intervals; Disease-Free Survival; Female; Furans; Humans; Japan; Ketones; Middle Aged; Neoplasm Metastasis; Neutropenia; Taxoids; Time Factors; Treatment Outcome

Eribulin is a novel antimicrotubule drug, which is approved in the second line treatment of advanced breast cancer in patients who received anthracyclines and taxanes. The article presents the results of two huge phase III clinical trials (301, 305) and their pooled analysis. Eribulin monotherapy demonstates staistically significant improved overall survival compared to standart treatments (15.2 mnths vs 12.8 mnths, p = 0.03 in pooled analysis). Certain subgroups of patients--Her2-negative and triple-negative have the most survival benefit. According to own experience with Eribulin inside the clinical trials, presented in the article, the drug is effective and well tolerated even by older patients.

Topics: Antineoplastic Agents; Breast Neoplasms; Drug Administration Schedule; Female; Furans; Humans; Kaplan-Meier Estimate; Ketones; Leukopenia; Meta-Analysis as Topic; Microtubules; Neutropenia; Severity of Illness Index; Treatment Outcome; Triple Negative Breast Neoplasms

Eribulin mesylate is a synthetic microtubule inhibitor that showed cytotoxic synergy in combination with gemcitabine preclinically. This combination was assessed in a Phase I dose-finding trial in patients diagnosed with advanced solid tumours who had received up to two prior chemotherapy regimens for metastatic disease (CP cohort).. Dose escalation was performed in a 3+3 design to identify the recommended phase II dose (RP2D). Two additional expansion cohorts in women with gynaecologic cancers at the RP2D (G), and further dose escalation of metastatic chemotherapy-naive patients (CN), were evaluated.. 45 patients were treated: 21 (CP), 10 (G) and 14 (CN). The initial combination of eribulin and gemcitabine was administered on days 1, 8, and 15 of a 28-day cycle; however, due to 2 out of 6 dose-limiting haematological toxicities at the first dose level, a reduced dose-intense schedule was assessed. The RP2D was defined at 1.0 mg m(-2) eribulin and 1000 mg m(-2) gemcitabine day 1 and 8 q3 weeks. No other significant toxicities were observed in the G expansion cohort. Neutropenia prevented further dose escalation in the CN cohort. Objective responses were seen in all three cohorts - 2/21 (CP), 1/10 (G) and 2/14 (CN).. The combination of eribulin and gemcitabine was well tolerated at the RP2D.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Disease-Free Survival; Endometrial Neoplasms; Female; Furans; Gemcitabine; Humans; Ketones; Male; Middle Aged; Neoplasm Metastasis; Neoplasms; Neutropenia; Ontario; Ovarian Neoplasms; Response Evaluation Criteria in Solid Tumors; Treatment Outcome

Eribulin mesylate (Halaven™, E7389) is a synthetic analog of the marine natural product halichondrin B that acts via a mechanism distinct from conventional tubulin-targeted agents. This Phase I study (clinicaltrials.gov identifier: NCT00326950) was the first to investigate eribulin mesylate in Japanese patients. The study determined the recommended dose, MTD, DLTs, safety, pharmacokinetics, and antitumor activity of eribulin administered on Days 1 and 8 of a 21-day cycle in Japanese patients with advanced solid tumors. Fifteen patients received eribulin mesylate 0.7-2.0 mg/m(2) as a 2- to 10-min intravenous injection. Neutropenia was the principal DLT. DLTs were observed in two of six patients treated at 1.4 mg/m(2), and in all three patients at 2.0 mg/m(2). The recommended dose was 1.4 mg/m(2) and the MTD was 2.0 mg/m(2). Neutropenia (67%), lymphocytopenia (20%), febrile neutropenia (33%), and fatigue (13%) were the most common grade 3 or 4 toxicities. Eribulin exhibited triphasic pharmacokinetics with a long terminal half-life, high volume of distribution, and low urinary clearance. Three patients achieved partial responses (two with NSCLC, one with head and neck cancer) at 1.4 mg/m(2) dose level. Eribulin mesylate, administered on Days 1 and 8 of a 21-day cycle, exhibits manageable tolerability at 1.4 mg/m(2). DLT was neutropenia.

Topics: Adult; Aged; Antineoplastic Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Furans; Half-Life; Humans; Ketones; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Neutropenia

Eribulin mesylate is a tubulin inhibitor with activity superior to paclitaxel in NIH:OVCAR-3 human epithelial ovarian cancer xenograft models. In this study, the authors assessed the efficacy of eribulin in platinum-resistant and platinum-sensitive recurrent ovarian cancer.. Patients with recurrent, measurable epithelial ovarian cancer who had received ≤2 prior cytotoxic regimens and who had adequate organ function were enrolled into 2 separate cohorts: 1) platinum-resistant patients (who had a progression-free interval <6 months after their last platinum-based therapy) and 2) platinum-sensitive patients (who had a progression-free interval ≥6 months after their last platinum-based therapy). Eribulin 1.4 mg/m(2) was administered over 15 minutes intravenously on days 1 and 8 every 21 days. Efficacy was determined by objective response on computed tomography studies.. In the platinum-resistant cohort, 37 patients enrolled, and 36 patients were evaluable for response and toxicity. Two patients achieved a partial response (5.5%), and 16 patients (44%) had stable disease as their best response. The median progression-free survival was 1.8 months (95% confidence interval, 1.4-2.8 months). In the platinum-sensitive cohort, 37 patients enrolled, and all were evaluable for response. Seven patients achieved a partial response (19%). The median progression-free survival was 4.1 months (95% confidence interval, 2.8-5.8 months). The major toxicity was grade 3 or 4 neutropenia (42% of platinum-resistant patients; 54% of platinum-sensitive patients).. Eribulin produced an objective response in 5.5% of women with platinum-resistant, recurrent ovarian cancer and in 19% of women with platinum-sensitive disease. The median progression-free survival was 1.8 months in the platinum-resistant group and 4.1 months in the platinum-sensitive group.

Topics: Adult; Aged; Aged, 80 and over; Cohort Studies; Disease-Free Survival; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Furans; Humans; Ketones; Middle Aged; Neutropenia; Ovarian Neoplasms; Paclitaxel; Platinum; Recurrence; Retreatment; Tubulin Modulators

To evaluate the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of eribulin mesylate (E7389), a halichondrin B analogue, administered every 21 days in patients with advanced solid tumors.. Eribulin mesylate was given as a 1-hour infusion every 21 days at doses of 0.25, 0.5, 1, 2, 2.8, and 4 mg/m(2). The MTD was identified using an accelerated titration design. The pharmacokinetics of eribulin were evaluated in the plasma and urine with the first dose.. Twenty-one patients were enrolled. At 4 mg/m(2), three patients experienced a DLT of febrile neutropenia on day 7. The dose level was reduced to 2.8 mg/m(2) where two of three patients experienced dose-limiting febrile neutropenia. Six additional patients were enrolled at 2 mg/m(2) (seven patients in total received this dose) and one of these patients experienced a neutropenic DLT. The MTD of eribulin mesylate was therefore 2 mg/m(2). Nonhematologic toxicities included alopecia, fatigue, anorexia, and nausea. Pharmacokinetic analysis showed linear kinetics for eribulin over the dose range studied and a terminal half-life of 2 days. The plasma-concentration-time profile exhibited a rapid distribution phase followed by a slow elimination phase. Drug clearance was nonrenal. One patient with non-small cell lung cancer achieved an unconfirmed partial response and 12 patients had stable disease.. Eribulin mesylate administered as a 1-hour infusion every 21 days has a manageable toxicity profile at 2 mg/m(2), with further dose escalation limited by neutropenia.

Topics: Adult; Aged; Alopecia; Anorexia; Drug Administration Schedule; Fatigue; Female; Furans; Humans; Ketones; Male; Maximum Tolerated Dose; Middle Aged; Nausea; Neoplasms; Neutropenia; Tubulin Modulators

Eribulin mesylate (E7389), a non-taxane microtubule dynamics inhibitor, is a structurally simplified, synthetic analogue of halichondrin B that acts via a mechanism distinct from conventional tubulin-targeted agents. This phase I study determined the maximum tolerated dose (MTD) and pharmacokinetics of eribulin administered on a 3 of 4 week schedule in patients with advanced solid malignancies.. Patients received eribulin mesylate (1-hour i.v. infusion) on days 1, 8, and 15 of a 28-day cycle. Dosing began at 0.25 mg/m(2) with escalation guided by dose-limiting toxicities (DLT). MTD, DLTs, safety, pharmacokinetics, and antitumor activity were characterized.. Thirty-two patients received eribulin mesylate (0.25, 0.5, 0.7, 1.0, or 1.4 mg/m(2)). Neutropenia was the principal DLT: At 1.4 mg/m(2), two patients experienced grade 4 neutropenia, one of whom also developed grade 3 fatigue; three additional patients experienced grade 3 neutropenia and were not treated during cycle 1 on day 15. Therefore, the MTD was 1.0 mg/m(2). Fatigue (53% overall, 13% grade 3, no grade 4), nausea (41%, all grade 1/2), and anorexia (38% overall, 3% grade 3, no grade 4) were the most common eribulin-related adverse events. Eight patients reported grade 1/2 neuropathy (no grade 3/4). Eribulin pharmacokinetics were dose-proportional over the dose range studied. One patient (cervical cancer) achieved an unconfirmed partial response lasting 79 days. Ten patients reported stable disease.. Eribulin mesylate, given on days 1, 8, and 15 of a 28-day cycle, exhibits manageable tolerability at 1.0 mg/m(2) with further dose escalation limited by neutropenia and fatigue.

Topics: Aged; Anorexia; Fatigue; Female; Furans; Humans; Ketones; Male; Maximum Tolerated Dose; Middle Aged; Nausea; Neoplasms; Neutropenia; Tubulin Modulators

In this open-label, Phase 1 study, we explore the safety and efficacy of E7389-LF (liposomal formulation of eribulin) in Japanese patients with advanced solid tumors.. This open-label, Phase 1 study enrolled Japanese adult patients to receive E7389-LF for the treatment of advanced solid tumors. Treatment with E7389-LF 2.0 mg/m. As of October 16, 2020, 43 patients were enrolled (adenoid cystic carcinoma, n = 12; gastric cancer, n = 10; esophageal cancer, n = 11; small cell lung cancer, n = 10). Thirty-three patients experienced a Grade ≥3 treatment-related treatment-emergent adverse event, most commonly neutropenia (53.5%). Additionally, the incidence of hypersensitivity did not appear to change with a reduced number of infusion steps (2 vs. 4) and patients who were administered prophylactic pegylated granulocyte-colony stimulating factor had a noticeably lower incidence of Grade 3-4 neutropenia (although this did not have a proper control). The overall objective response rate was 11.6% (95% confidence interval: 3.9-25.1), corresponding to two partial responses in patients with adenoid cystic carcinoma, two partial responses in gastric cancer, and one partial response in esophageal cancer. Median progression-free survival was longer in the adenoid cystic carcinoma population (16.6 months) than in others.. E7389-LF 2.0 mg/m

Topics: Adult; Carcinoma, Adenoid Cystic; Esophageal Neoplasms; Humans; Lung Neoplasms; Neutropenia; Small Cell Lung Carcinoma; Stomach Neoplasms

This study aimed to examine the effectiveness and safety of eribulin used as an early-line (EL, i.e., first-/second-line) versus late-line (LL, i.e., third-line and beyond) chemotherapy for recurrent advanced or metastatic breast cancer (A/MBC) patients.. This study conducted a retrospective observation of A/MBC patients initiating eribulin between January 1, 2015, and June 30, 2019, using medical database at a university-affiliated teaching hospital in Taiwan. Patients were assigned into either the EL or LL group based on the timing of respective eribulin treatments and were observed for at least 6 months up to December 2019 for progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS), disease response, and occurrence of adverse events. The Kaplan-Meier and Cox proportional hazard regression survival analyses were performed.. Of 127 patients, 23.6% (n = 30) and 76.4% (n = 97) were assigned to the EL and LL groups, respectively, between which no difference in patient characteristics was noted. Median PFS and TTF were 6.5 months and 5.0 months for the EL and 4.2 months and 3.4 months for the LL, respectively. Median OS could not be estimated in the EL group and was 20.5 months in the LL group. Eribulin as an EL treatment was the only factor associated with longer TTF and OS, whereas the number of metastatic sites was additionally associated with PFS in the multivariate analysis. No complete response was reported in either group, but a partial response was obtained in 6.7% in the EL group and 3.1% in the LL group. The common adverse events between two groups were similar, including leukopenia (80.0%), neutropenia (76.7%), and anemia (60.0%).. The eribulin used as an EL of chemotherapy was effective for A/MBC patients with known toxicities in this study, while eribulin as the LL chemotherapy showed consistent results with previous reports.

Topics: Breast Neoplasms; Female; Furans; Humans; Neoplasm Recurrence, Local; Neutropenia; Retrospective Studies; Treatment Outcome

Neutropenia is a major dose-limiting toxicity of cancer chemotherapy. Semimechanistic mathematical models have been applied to describe the time course of neutrophil counts. The objectives of this study were to develop a mathematical model describing changes in neutrophil counts during eribulin treatment, to apply the empirical Bayes method to predict the probability of developing neutropenia ≥ grade 3 during eribulin treatment in each patient, and to propose the implementation of this mathematical tool in clinical practice for individual safety management.. The present model analysis and subsequent external evaluation were performed using the data of 481 patients with breast cancer, previously obtained from a postmarketing surveillance (training set) and a phase 2 clinical study (validation set). The model we previously reported (Kawamura et al 2018) was modified to improve its predictive capability. The individual time course of neutrophil changes during the treatment period was predicted by the empirical Bayes method using the observed neutrophil counts at baseline and the first measurement after the first eribulin dose. To evaluate the predictability of this method, the predicted neutrophil counts were compared with those of the observed values.. The developed model provided good individual predictions, as indicated by the goodness-of-fit plots between the predicted and observed neutrophil counts, especially for a lower neutrophil count range. Days required to reach the nadir after the dose were also well-predicted. The sensitivity, specificity, and accuracy of the prediction of neutropenia grade ≥3 were 76%, 53%, and 71%, respectively.. We developed a mathematical method for predicting and managing the risk of neutropenia during eribulin treatment. This method is generally applicable to other cases of chemotherapy-induced neutropenia and can be a new practical tool for individual safety management.

Topics: Bayes Theorem; Breast Neoplasms; Female; Humans; Ketones; Neutropenia

Eribulin is currently recommended for the treatment of patients with metastatic breast cancer (MBC) pre-treated with taxanes and anthracyclines. The aim of the present study was to evaluate the effectiveness and safety of eribulin and its impact on health-related quality of life in heavily pre-treated patients with MBC.. Data from MBC patients who had received eribulin-based therapy at Beijing Cancer Hospital between January 2020 and July 2022 were analyzed retrospectively. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), adverse effects (AEs) and health-related quality of life (HRQoL) were assessed.. Data from 118 patients who had received eribulin to treat MBC were included. Median PFS was 4.2 months and median OS had not been reached. The ORR was 13.6% (16/118) and DCR was 75.4% (89/118). The median PFS in patients who received eribulin in second-line (26/118), third-line (29/118), or fourth-line or later (63/118) was 4.5, 4.2, and 3.9 months, respectively. The median OS in patients who received eribulin in third- or later line (n = 92) was 14.1 months. Patients who received eribulin combination therapy had a significantly longer median PFS compared with those who received eribulin monotherapy (4.5 vs. 3.4 months, p = 0.007) and there was a trend towards a longer median OS (not reached vs. 12.1 months). The most common grade 3-4 adverse events were neutropenia (22.9%), leukocytopenia (13.6%) and asthenia/fatigue (8.5%), without significant differences in safety between eribulin monotherapy and combination therapy. Quality of life was similar in patients who received eribulin monotherapy and combination therapy, except for cognitive function and nausea and vomiting symptoms, which were better with combination therapy.. The present study suggests that eribulin-based therapy is an effective treatment option and well tolerated for heavily pre-treated patients with MBC. Eribulin combination therapy might improve PFS and HRQoL compared with eribulin monotherapy.

Topics: Breast Neoplasms; Female; Humans; Neutropenia; Quality of Life; Retrospective Studies; Treatment Outcome

Granulocyte colony-stimulating factors (G-CSF) are commonly given to limit chemotherapy-induced neutropenia, but, in case of weekly chemotherapy such as eribulin, their administration schedules remain empirical.. This pharmacokinetic/pharmacodynamic (PK/PD) study was conducted to establish the effect of different G-CSF regimens on neutropenia's incidence for patients treated by eribulin, to propose an optimal G-CSF dosing schedule.. A population PK/PD model was developed to describe absolute neutrophil counts' (ANC) time course in 87 cancer patients receiving eribulin. The structural model considered ANC dynamics, neutropenic effect of eribulin and stimulating effect of G-CSF. Final model estimates were used to calculate neutropenia's incidence following different G-CSF dosing schedules for 1000 virtual subjects.. The final model successfully described most of the ANC time course for all patients. Simulations showed that a single G-CSF administration 48 h after each eribulin injection reduced the risk of severe neutropenia from 29.7 to 5.2%. Five days of G-CSF only after the second eribulin injection or no G-CSF administration induces similar incidence of neutropenia.. Simulations showed a single G-CSF administration 48 h after the end of each eribulin injection seems to be the optimal schedule to reduce eribulin-induced neutropenia. However, the new administration scheme should be tested in real life to evaluate its pertinence.. Eudract 2015-001753-32, 2015/01/26.

Topics: Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Drug Administration Schedule; Female; Furans; Granulocyte Colony-Stimulating Factor; Humans; Ketones; Middle Aged; Models, Biological; Neutropenia

Eribulin is an effective chemotherapeutic agent for the treatment of metastatic breast cancer and advanced or metastatic soft-tissue sarcomas. However, severe adverse effects (SAEs) occur in 30-40% of the patients, and significantly reduce the patients' quality of life and disturb the recommended treatment schedules. Neutropenia is the main cause of treatment suspension, delay, and/or dose reductions, also leading to relative dose intensity reduction. This study aimed to examine the risk factors for SAE occurrence after eribulin treatment.. Eighty patients with metastatic breast cancer or advanced or metastatic soft tissue sarcoma who received eribulin were retrospectively evaluated. Risk factors for SAE occurrence in the first cycle were primarily assessed. In addition, factors associated with SAE occurrence during all treatment cycles were evaluated.. SAEs in the first cycle occurred in 45% of patients. The primary SAE was neutropenia (91.7%). The incidence of SAEs during all treatment cycles was 61.3%. Multivariate analyses suggested that lower baseline neutrophil and hemoglobin levels were risk factors for SAE occurrence and severe neutropenia incidence in the first cycle. An independent factor associated with SAE occurrence during all cycles was age ≥65 years and a tendency was confirmed for baseline anemia.. Baseline neutropenia and anemia were risk factors for SAE occurrence during the first eribulin treatment cycle. Age ≥65 years was also associated with SAE occurrence during all treatment cycles. Patients with these risk factors should be carefully monitored for assessment and prophylaxis.

Topics: Aged; Breast Neoplasms; Drug-Related Side Effects and Adverse Reactions; Factor Analysis, Statistical; Female; Furans; Humans; Ketones; Neutropenia; Quality of Life; Retrospective Studies; Risk Factors; Sarcoma

Background Data on eribulin as the first- or second-line treatment in a clinical setting, especially the overall survival (OS) of patients, are scarce. Therefore, we assessed the effectiveness and safety of eribulin as the first-, second-, and third- or later-line treatments in patients with human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer in Japan. Methods This multicenter, prospective, post-marketing, observational study enrolled patients from September 2014 to February 2016 in Japan and followed them for 2 years. Patients were categorized by eribulin use into the first-, second-, and third- or later-line treatment groups. Results Of 651 registered patients, 637 patients were included in the safety and effectiveness analysis. In all, first-, second-, and third or later-line treatment groups, median OS (95% confidence interval) were 15.6 (13.8-17.6), 22.8 (17.3-31.0), 16.3 (12.4-19.9), and 12.6 (11.2-15.1) months and time to treatment failure (TTF) (95% confidence interval) were 4.2 (3.7-4.4), 5.2 (3.7-5.9), 4.2 (3.7-5.1), and 3.8 (3.5-4.2) months, respectively. Prolonged TTF was associated with complications of diabetes and the development of peripheral neuropathy after eribulin treatment, according to multivariate Cox regression analysis. Grade ≥ 3 adverse drug reactions (ADRs) were reported in 61.7% of the patients. Neutropenia (49.5%) was the most common grade ≥ 3 ADR in all groups. Conclusions The effectiveness and safety results of eribulin as the first- or second-line treatment were favorable. Thus, these suggest eribulin may be a first-line treatment candidate for patients with HER2-negative advanced breast cancer in Japan.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Asian People; Breast Neoplasms; Female; Furans; Humans; Kaplan-Meier Estimate; Ketones; Middle Aged; Neutropenia; Product Surveillance, Postmarketing; Receptor, ErbB-2; Treatment Outcome

Eribulin therapy has recently attracted attention from various viewpoints, including quality of life, and is considered a standard therapy for inoperable or recurrent breast cancer. Although a reduction in renal function reportedly decreases total eribulin clearance, its association with dose-limiting toxicity and the reduction of neutrophils remain unclear.. This study was aimed at analyzing the association between decreased renal function prior to eribulin administration and the occurrence of neutrophil reduction and time to treatment failure in patients with breast cancer.. We retrospectively assessed patients with breast cancer, who underwent eribulin therapy between July 2011 and March 2018. Multivariate analysis revealed creatinine clearance <70 mL/min and serum albumin levels <3.9 mg/dL as predictive factors for neutrophil reduction. Even on increasing the relative dose intensity by these factors, no difference in time to treatment failure was observed, suggesting that treatment efficacy is potentially unaffected.. For continuous eribulin therapy, eribulin may need to be administered to individual patients in accordance with renal function and albumin levels before treatment initiation.

Topics: Adult; Aged; Breast Neoplasms; Disease Progression; Female; Furans; Glomerular Filtration Rate; Humans; Ketones; Kidney; Leukocyte Count; Middle Aged; Neoplasm Recurrence, Local; Neutropenia; Neutrophils; Renal Elimination; Retrospective Studies; Treatment Failure

Eribulin is a non-taxane, microtubule dynamics inhibitor approved for the treatment of patients with metastatic breast cancer (MBC) in Europe in March 2011.. For the purpose of an internal quality control, all patients with MBC treated with eribulin at Karolinska University Hospital were registered in a database. Clinical data were collected retrospectively for patients that were registered by August 2012 and safety and efficacy of eribulin were evaluated. Treatment toxicity including fatigue, neurotoxicity and infection was graded according to CTCAE v4.0. Objective response to treatment was investigated using routinely performed radiological assessments. When only clinical assessments were made, the evaluation of the treating physician was used. Furthermore, the efficacy of eribulin was investigated in different tumor subtypes.. Forty-eight patients who received at least one cycle of eribulin were identified. Most patients were heavily pretreated with a median of 3 (range 1-7) previous chemotherapy lines prior to eribulin. Median patient age was 56 years (range 35-74). At the end of the analysis, 23 patients were alive and two were still treated with eribulin. No hypersensitivity reactions and no toxic deaths were seen. Fatigue grade 3-4 was observed in three patients (6.3%). One patient experienced grade 4 neurotoxicity. Grade 3-4 neutropenia was documented in 18.8%, and three patients were treated for a grade 3 infection. Interestingly, three individuals developed Herpes zoster reactivation. One patient responded to treatment with complete remission, while 33.3% had a partial response. 48% of all patients had a clinical benefit (objective response or stable disease for more than six months).. Eribulin administered outside of a clinical trial in patients with advanced breast cancer was safe and well tolerated. A clinical benefit was seen in half of the cases. No statistically significant differences in objective response or survival were observed between histopathological subgroups.

Topics: Adult; Breast Neoplasms; Disease-Free Survival; Drug Administration Schedule; Fatigue; Female; Furans; Humans; Infections; Ketones; Ki-67 Antigen; Middle Aged; Neutropenia; Peripheral Nervous System Diseases; Receptor, ErbB-4; Receptors, Estrogen; Retrospective Studies; Sweden; Tubulin Modulators

Eribulin gained its approval in March 2011 for the treatment of patients with locally advanced or metastatic breast cancer (MBC) whose disease has progressed despite anthracycline and taxane-containing regimens. This study retrospectively assessed the efficacy, safety and cost of this treatment for all patients with MBC treated by eribulin in Franche-Comté. Ninety-four patients received eribulin between July 2006 and October 2013. The median age was 62 years (35-83). Median overall survival was 10.3 months [95% CI: 7.6 to 17.9]. Median progression-free-survival was 3.8 months [95% CI: 2.9 to 5.0]. Clinical benefit was obtained in 55% evaluable patients [95% CI: 43.1 to 66.9] by RECIST criteria. Most common grade 3-4 adverse events (AEs) were neutropenia (38%), asthenia (10%) and peripheral neuropathy (7%). Median cost of the treatment was 9767 € per patient (6344-17,517). This analysis found similar results to the EMBRACE study despite less selected population. A medico-economic evaluation cost-utility type would assess the effectiveness of this strategy compared to standard treatments.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Asthenia; Breast Neoplasms; Female; Furans; Humans; Ketones; Middle Aged; Neutropenia; Peripheral Nervous System Diseases; Retrospective Studies

Eribulin mesilate is an inhibitor of microtubule dynamics that is approved for the treatment of late-stage metastatic breast cancer. Neutropenia is one of the major dose-limiting adverse effects of eribulin. The objective of this analysis was to develop a population pharmacokinetic-pharmacodynamic model for eribulin-associated neutropenia.. A combined data set of 12 phase I, II and III studies for eribulin mesilate was analysed. The population pharmacokinetics of eribulin was described using a previously developed model. The relationship between eribulin pharmacokinetic and neutropenia was described using a semi-physiological lifespan model for haematological toxicity. Patient characteristics predictive of increased sensitivity to develop neutropenia were evaluated using a simulation framework.. Absolute neutrophil counts were available from 1579 patients. In the final covariate model, the baseline neutrophil count (ANC0) was estimated to be 4.03 × 10(9) neutrophils l(-1) [relative standard error (RSE) 1.2%], with interindividual variability (IIV, 37.3 coefficient of variation % [CV%]). The mean transition time was estimated to be 109 h (RSE 1.8%, IIV 13.9CV%), the feedback constant (γ) was estimated to be 0.216 (RSE 1.4%, IIV 12.2CV%), and the linear drug effect coefficient (SLOPE) was estimated to be 0.0451 μg l(-1) (RSE 3.2%, IIV 54CV%). Albumin, aspartate transaminase and receival of granulocyte colony-stimulating factor (G-CSF) were identified as significant covariates on SLOPE, and albumin, bilirubin, G-CSF, alkaline phosphatase and lactate dehydrogenase were identified as significant covariates on mean transition time.. The developed model can be applied to investigate optimal treatment strategies quantitatively across different patient groups with respect to neutropenia. Albumin was identified as the most clinically important covariate predictive of interindividual variability in the neutropenia time course.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Computer Simulation; Dose-Response Relationship, Drug; Furans; Humans; Ketones; Models, Biological; Models, Statistical; Neutropenia; Practice Guidelines as Topic; Risk

Eisai Co Ltd is developing eribulin, a simplified synthetic macrocyclic ketone analog of the tubulin inhibitor halichondrin B, for the potential treatment of cancer. Phase III trials are underway in the US and Europe for patients with breast cancer. Eribulin is currently in phase II trials for NSCLC and soft tissue sarcoma, and pancreatic, prostate, ovarian, fallopian tube, peritoneal and head and neck cancer, and phase I/II trials for urothelial cancers.

Topics: Alopecia; Animals; Antineoplastic Agents; Apoptosis; Cell Line; Cell Line, Tumor; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug Evaluation, Preclinical; Ethers, Cyclic; Fatigue; Furans; Humans; Hypoglycemia; Hypophosphatemia; Inhibitory Concentration 50; Ketones; Macrolides; Molecular Structure; Multicenter Studies as Topic; Nausea; Neoplasms; Neutropenia; Peripheral Nervous System Diseases; Randomized Controlled Trials as Topic; Survival Analysis; Tubulin Modulators; Xenograft Model Antitumor Assays