Ixabepilone Administered Weekly or Every Three Weeks in HER2-Negative Metastatic Breast Cancer Patients; A Randomized Non-Comparative Phase II Trial

Abstract

To explore the activity and safety of two schedules of ixabepilone, as first line chemotherapy, in patients with metastatic breast cancer previously treated with adjuvant chemotherapy, a randomized non-comparative phase II study was conducted. From November 2008 until December 2010, 64 patients were treated with either ixabepilone 40 mg/m2 every 3 weeks (Group A, 32 patients) or ixabepilone 20 mg/m2 on days 1, 8 and 15 every 4 weeks (Group B, 32 patients). Overall response rate (the primary end point) was 47% in Group A and 50% in Group B. The most frequent severe adverse events were neutropenia (32% vs. 23%), metabolic disturbances (29% vs. 27%) and sensory neuropathy (12% vs. 27%). Two patients in Group A and 3 in Group B developed febrile neutropenia. After a median follow-up of 22.7 months, median progression-free survival (PFS) was 9 months in Group A and 12 months in Group B. Median survival was 26 months in Group A, whereas it was not reached in Group B. Multiple genetic and molecular markers were examined in tumor and peripheral blood DNA, but none of them was associated with ORR or drug toxicity. Favorable prognostic markers included: the T-variants of ABCB1 SNPs c.2677G/A/T, c.1236C/T and c.3435C/T, as well as high MAPT mRNA and Tau protein expression, which were all associated with the ER/PgR-positive phenotype; absence of TopoIIa; and, an interaction between low TUBB3 mRNA expression and Group B. Upon multivariate analysis, tumor ER-positivity was a favorable (p = 0.0092) and TopoIIa an unfavorable (p = 0.002) prognostic factor for PFS; PgR-positivity was favorable (p = 0.028) for survival. In conclusion, ixabepilone had a manageable safety profile in both the 3-weekly and weekly schedules. A number of markers identified in the present trial appear to deserve further evaluation for their prognostic and/or predictive value in larger multi-arm studies.Trial RegistrationClinicalTrials.gov NCT 00790894

Eribulin in the Management of Advanced Breast Cancer: Implications of Current Research Findings

“…RR and median PFS or TTP for first-line monotherapies with chemotherapeutic drugs for metastatic breast cancer are presented in Table 3, including thrice weekly docetaxel, weekly gemcitabine, weekly intravenous vinorelbine, and thrice weekly ixabepilone. 22–25 In general, these studies show that weekly eribulin monotherapy for non-HER2-overexpressing locally advanced or metastatic breast cancer, or in combination with trastuzumab for HER2-positive disease, lead to outcomes that are comparable with other tubulin-targeted agents and gemcitabine.…”

Ixabepilone: Overview of Effectiveness, Safety, and Tolerability in Metastatic Breast Cancer

“…The results have been mixed. Fountzilas et al reported a randomized, non-comparative phase II trial in patients with mBC who had not previously received chemotherapy in the metastatic setting (42). In this trial, 32 participants received ixabepilone 40 mg/m 2 every 3 weeks and 32 participants received ixabepilone 20 mg/m 2 once weekly.…”

“…Early phase studies with ixabepilone in mBC tested a higher dose (50 mg/m 2 IV every 3 weeks) and/or a shorter infusion period (1 hour), but poor tolerability led investigators to treat with ixabepilone 40 mg/m 2 IV over a 3-hour infusion in subsequent trials ( 26 ). To further test the efficacy of lower doses, two phase II trials evaluated more frequent administration of ixabepilone at lower than standard dosing ( 42 , 43 ). The results have been mixed.…”

Ixabepilone: new perspectives for its use in breast cancer

“…В исследованиях II и III фаз изучались 2 основных режима терапии иксабепилоном: 3-недельные введения в дозе 40 мг/м 2 и введения препарата в дозе 16-20 мг/м 2 еженедельно в течение 3 нед., далее перерыв 1 нед. [11][12][13]. Во всех данных исследованиях было продемонстрировано превосходство 3-недельного режима относительно ЧОО.…”