Ixabepilone as monotherapy or in combination for the treatment of advanced breast cancer

Figures & data

Figure 1 Phase I trials of single-agent ixabepilone.

Abbreviation: DLT, dose-limiting toxicities; MTD, maximum tolerated dose/recommended phase II dose.

Table 1 Phase II/III studies in ixabepilone

Study	Dose/schedule	No. patients/eligibility	Toxicities (grade 3–4, ≥10% of patients)	Results
Single agent – taxane-resistant disease
Perez et al^Citation25	Ixabepilone 40 mg/m^2 day 1 of 21-day cycle	126 patients (113 assessable for response) Locally advanced or metastatic breast cancer, resistant to anthracyclines, taxanes, and capecitabine. Exclusions: brain metastases, prior epothilone therapy, grade ≥2 neuropathy	Neutropenia (54%), peripheral sensory neuropathy (14%), fatigue (13%)	Partial responses: 11.5% (95% CI, 6.3%–18.9%) Stable disease: 50% Stable disease ≥6 months: 3.3% (95% CI, 7.6%–20.9%) PFS: 3.1 months Median OS: 8.6 months
Thomas et al^Citation33	Ixabepilone 40 mg/m^2 day 1 of 21-day cycle	66 patients Metastatic breast cancer, resistant to taxanes and anthracycline resistant/pre-treated Exclusions: more than 3 prior chemotherapy regimens for metastatic disease, grade ≥2 neuropathy, concurrent hormonal or trastuzumab therapy	Sensory neuropathy (12%), neutropenia (53%), fatigue (27%), myalgia (10%)	Partial response: 12% (95% CI, 5.4%–22.5%) Stable disease: 42% Median TTP: 2.3 months(95% CI, 1.5–3.1 months) Median OS: 7.9 months (95% CI, 6.1–14.5 months)
Single agent – taxane-naïve disease
Denduluri et al^Citation34	Ixabepilone 6 mg/m^2 for 5 consecutive days of 21-day cycle	23 patients Metastatic breast cancer, no prior taxane therapy in the adjuvant or metastatic setting	Neutropenia (22%), fatigue (13%)	Partial response: 57% (95% CI, 34.5%–76.8%) Stable disease: 26% Median TTP: 5.5 months
Roche et al^Citation35	Ixabepilone 40 mg/m^2day 1 of 21-day cycle	Exclusions: grade ≥ 2 neuropathy 65 patients Metastatic breast cancer, no prior taxane therapy, except adjuvant taxane therapy > 12 months prior to enrollment	Sensory neuropathy (20%), neutropenia (58%)	Partial response: 41.5% (95% CI, 29.4%–54.4%) Stable disease: 35% Median TTP:4.8 months (95% CI, 4.2–7.6 months) Median OS: 22 months (95% CI, 15.6–27.0 months)
Combination therapy
Bunnell et al^Citation40	Ixabepilone 40 mg/m^2 day 1 + capecitabine 2000 mg/m^2 days 1–14 of 21-day cycle	62 patients Metastatic breast cancer, resistant to taxanes and anthracycline resistant/pretreated	Sensory neuropathy (19%), neutropenia (69%), fatigue (34%), hand – foot syndrome (34%), nausea (16%), diarrhea (10%), vomiting (10%)	Objective response rate: 30% Median PFS: 3.9 months
Thomas et al^Citation41	Ixabepilone 40 mg/m^2 day 1 + capecitabine 2000 mg/m^2 days 1–14 of 21-day cycle vs Capecitabine 2500 mg/m^2 days 1–14 of 21-day cycle	737 patients Locally advanced or metastatic disease, resistant to taxanes and anthracycline resistant/pre-treated. Exclusions: brain metastases, liver dysfunction, grade ≥2 neuropathy, prior capecitabine therapy	Sensory neuropathy (21%), neutropenia (68%), hand–foot syndrome (18%)	Median PFS: Ixabepilone plus capecitabine: 5.7 months (95% CI, 4.8–7 months) Capecitabine alone: 4.1 months (95% CI, 3.1–4.3 months) Objective response rate: Ixabepilone and capecitabine: 35% Capecitabine alone: 14% (P < 0.001)
Neoadjuvant
Baselga et al^Citation44	40 mg/m^2 IV infusion day 1 of a 21 -day cycle, up to 4 cycles	161 patients T2-4, N0-3, M0 invasive breast adenocarinoma 3 cm or greater in size and not amenable to breast conserving therapy Exclusions: inflammatory breast cancer, prior chemotherapy, prior radiation therapy to breast area, grade > I neuropathy, unfit for breast or axillary surgery	Neutropenia (14%)	Clinical complete response: 21.1% Clinical partial response: 55.9% Pathologic complete response: All patients: 18% (95% CI, 12%–25%) ER-negative: 29% (95% CI, 19%–41%) ER/PR-negative: 33% (95% CI, 21%–46%) Triple-negative: 26% (95% CI, 14%–42%) ER-negative/Her-2 positive: 46.1 % Breast conserving therapy: 50 patients (32%)

Abbreviations: CI, confidence interval; OS, overall survival; PFS, progression-free survival; TTP, time to progression.

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