er-086526 and Fatigue

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

Health-related quality of life (HRQoL) enhances understanding of treatment effects that impact clinical decision-making. Although the primary end-point was not achieved, the BEACON (BrEAst Cancer Outcomes with NKTR-102) trial established etirinotecan pegol, a long-acting topoisomerase-1 (TOP1) inhibitor, as a promising therapeutic for patients with advanced/metastatic breast cancer (MBC) achieving clinically meaningful benefits in median overall survival (OS) for patients with stable brain metastases, with liver metastases or ≥ 2 sites of metastatic disease compared to treatment of physician's choice (TPC). Reported herein are the findings from the preplanned secondary end-point of HRQoL.. HRQoL, assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) (version 3.0) supplemented by the breast cancer-specific Quality of Life Questionnaire (QLQ-BR23), was evaluated post randomisation in 733 of 852 patients with either anthracycline-, taxane- and capecitabine-pretreated locally recurrent or MBC randomised to etirinotecan pegol (n = 378; 145 mg/m. Differences were seen favouring etirinotecan pegol up to 32 weeks for global health status (GHS) and physical functioning scales (P < 0.02); numerical improvement was reported in other functional scales. The findings from HRQoL symptom scales were consistent with adverse event profiles; etirinotecan pegol was associated with worsening gastrointestinal symptoms whereas TPC was associated with worsened dyspnoea and other systemic side-effects. Analysis of GHS and physical functioning at disease progression showed a decline in HRQoL in both treatment arms, with a mean change from baseline of -9.4 and -10.8 points, respectively.. There was evidence of benefit associated with etirinotecan pegol compared with current standard of care agents in multiple HRQoL measurements, including global health status and physical functioning, despite worse gastrointestinal symptoms (e.g. diarrhoea). Patients in both arms had a decline in HRQoL at disease progression.. NCT01492101.

Topics: Activities of Daily Living; Adult; Aged; Aged, 80 and over; Albumins; Anorexia; Antineoplastic Agents; Body Image; Bone Neoplasms; Brain Neoplasms; Breast Neoplasms; Cancer Pain; Deoxycytidine; Docetaxel; Dyspnea; Epothilones; Fatigue; Female; Furans; Gemcitabine; Health Status; Heterocyclic Compounds, 4 or More Rings; Humans; Ketones; Liver Neoplasms; Lung Neoplasms; Middle Aged; Nausea; Paclitaxel; Polyethylene Glycols; Quality of Life; Reproductive Health; Sleep Initiation and Maintenance Disorders; Taxoids; Vinblastine; Vinorelbine; Vomiting

To evaluate the effect of renal impairment on eribulin mesylate pharmacokinetics following a single dose in adults with advanced solid tumors.. Patients were grouped by renal function: moderate impairment (creatinine clearance [CrCl] 30-50 mL/min), severe impairment (CrCl 15-29 mL/min), or normal (CrCl ≥80 mL/min). During each 21-day cycle, eribulin mesylate doses (days 1 and 8) were administered intravenously: moderate, 1.1 mg/m(2) (except cycle 1 day 1, 1.4 mg/m(2)); severe, 0.7 mg/m(2); normal, 1.4 mg/m(2).. Nineteen patients were enrolled (normal, n = 6; moderate, n = 7; severe, n = 6). Renal impairment was associated with an increased mean dose-normalized area under the concentration-time curve (ratios for moderate/normal and severe/normal: 1.49; 90 % confidence interval [CI] 0.9, 2.45). CrCl and renal function correlated positively, with a numerically small slope (0.0184; 90 % CI -0.00254, 0.0394). A simulated dose reduction to eribulin 1.1 mg/m(2) in patients with moderate or severe renal impairment achieved the same exposure as 1.4 mg/m(2) in those with normal renal function. All groups had similar toxicity profiles, with no unexpected adverse events.. Renal impairment decreased eribulin clearance and increased exposure. Pharmacokinetic evaluation supports an eribulin dose reduction to 1.1 mg/m(2) in patients with moderate or severe renal impairment. CLINICALTRIALS.. NCT01418677.

Topics: Adult; Aged; Aged, 80 and over; Alopecia; Antineoplastic Agents; Area Under Curve; Creatinine; Fatigue; Female; Furans; Gastrointestinal Diseases; Hematologic Diseases; Humans; Infusions, Intravenous; Ketones; Kidney; Kidney Diseases; Male; Metabolic Clearance Rate; Middle Aged; Neoplasms; Salvage Therapy; 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

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

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