Ixabepilone administered weekly or every three weeks in HER2-negative metastatic breast cancer patients; a randomized non-comparative phase II trial

• Published in: PloS one 2013-07, Vol.8 (7), p.e69256
• Main Authors: Fountzilas, George, Kotoula, Vassiliki, Pectasides, Dimitrios, Kouvatseas, George, Timotheadou, Eleni, Bobos, Mattheos, Mavropoulou, Xanthipi, Papadimitriou, Christos, Vrettou, Eleni, Raptou, Georgia, Koutras, Angelos, Razis, Evangelia, Bafaloukos, Dimitrios, Samantas, Epaminontas, Pentheroudakis, George, Skarlos, Dimosthenis V
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Biology; Biomarkers, Tumor - metabolism; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer; Cancer metastasis; Cancer patients; Cancer therapies; Care and treatment; Cell cycle; Chemotherapy; Clinical trials; Deoxyribonucleic acid; Disease-Free Survival; DNA; Drug Administration Schedule; Drug dosages; Epothilones - administration & dosage; Epothilones - adverse effects; Epothilones - pharmacology; Epothilones - therapeutic use; ErbB-2 protein; FDA approval; Female; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Group dynamics; Hospitals; Humans; Markers; Medical research; Medicine; Metastases; Metastasis; Middle Aged; Multivariate analysis; Neoplasm Metastasis; Neuropathy; Neutropenia; Oncology; Ovarian cancer; Pathology; Patient Compliance; Patients; Peripheral blood; Peripheral neuropathy; Product development; Proteins; Randomization; Receptor, ErbB-2 - metabolism; RNA; RNA, Messenger - genetics; RNA, Messenger - metabolism; Safety management; Schedules; Single-nucleotide polymorphism; Survival; Tau protein; Toxicity; Treatment Outcome; Tubulin - genetics; Tubulin - metabolism
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0069256

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/m(2) every 3 weeks (Group A, 32 patients) or ixabepilone 20 mg/m(2) 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. ClinicalTrials.gov NCT 00790894.