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

George Fountzilas, Vassiliki Kotoula, Dimitrios Pectasides, George Kouvatseas, Eleni Timotheadou, Mattheos Bobos, Xanthipi Mavropoulou, Christos Papadimitriou, Eleni Vrettou, Georgia Raptou, Angelos Koutras, Evangelia Razis, Dimitrios Bafaloukos, Epaminontas Samantas, George Pentheroudakis, Dimosthenis V Skarlos, George Fountzilas, Vassiliki Kotoula, Dimitrios Pectasides, George Kouvatseas, Eleni Timotheadou, Mattheos Bobos, Xanthipi Mavropoulou, Christos Papadimitriou, Eleni Vrettou, Georgia Raptou, Angelos Koutras, Evangelia Razis, Dimitrios Bafaloukos, Epaminontas Samantas, George Pentheroudakis, Dimosthenis V Skarlos

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/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.

Trial registration: ClinicalTrials.gov NCT 00790894.

Trial registration: ClinicalTrials.gov NCT00790894.

Conflict of interest statement

Competing Interests: We have the following interests. This study was supported by an Investigator Sponsored Research Agreement with Bristol-Myers Squibb Company. Ixabepilone is being developed by Bristol-Myers Squibb. George Kouvatseas is employed by Health Data Specialists Ltd. There are no further patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Figures

Figure 1. Consort diagram describing the main…
Figure 1. Consort diagram describing the main characteristics of the present clinical study.
Figure 2. Waterfall plot of best change…
Figure 2. Waterfall plot of best change in target-lesion size from baseline, assessed by central review.
In four patients (marked with a star), the best change in total lesion size from baseline showed an overall decrease but they were characterized as having progressive disease (PD) due to the development of new lesions. In four other patients (marked with a star as well), the best change in total lesion size from baseline was 100% but they were identified as partial response (PR) since in non-target lesions the response was stable disease (SD). CR: complete response.
Figure 3. PFS and survival for Groups…
Figure 3. PFS and survival for Groups A and B (red lines: PFS; blue lines: survival).
Figure 4. Predictive specificity of TUBB3 mRNA…
Figure 4. Predictive specificity of TUBB3 mRNA expression for survival in treatment Groups A (40 mg/m2, 3-weekly) and B (20 mg/m2, weekly).
TUBB3 RQ value cut-off was set at 75%. Among patients in Group B, those with tumors expressing high TUBB3 transcript levels had significantly shorter survival.

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