Novel Anti-Tubulin Cytotoxic Agents for Breast Cancer

Patrick G. Morris, MD; Monica N. Fornier, MD

Expert Rev Anticancer Ther. 2009;9(2):175-185.

Eribulin

A range of other agents with similar sites of action to taxanes and vinca alkaloids are under active investigation. Halichondrin B is a large polyether macrolide derived from the marine sponge Halichondria okadaic.^[52,53]In vitro studies have shown that halichondrins are potent antimicrotubule agents, possibly acting at the vinca alkaloid domain, although a distinct mechanism of tubulin binding has also been suggested.^[52] Eribulin mesylate (E7389) is a synthetic derivative of halichondrin, which obviates the difficulties with obtaining adequate supplies of halichondrin from natural sources. Eribulin strongly inhibits the growth of several human tumor xenografts in mice.^[54,55] Two Phase I studies have examined eribulin on days 1^[8] and 15 of a 28-day cycle in a variety of solid tumors.^[56,57] The main dose-limiting toxicities were neutropenia and febrile neutropenia, although there was some hypoglycemia, hypophosphatemia and fatigue. These studies identified a maximum tolerated dose of 1.4 mg/m². An alternative dosing schedule of treatment once every 3 weeks has also been investigated and, again, neutropenia has been the dose-limiting toxicity.^[58] This alternative schedule has not been favored in subsequent clinical trials, which have adopted the weekly dosing schedule.

In breast cancer, a large Phase II study of eribulin is ongoing in patients with MBC.^[59] Eligible patients were heavily pretreated with an anthracycline, a taxane and capecitabine, and received two to five chemotherapy regimens. A total of 299 patients have been enrolled on this study. Initially, patients were treated with eribulin 1.4 mg/m² as an intravenous infusion of up to 5 min on days 1, 8 and 15 of a 28-day cycle but, due to dose delays, this schedule was adjusted to treatment on days 1 and 8 of a 21-day cycle. To date, the response rate has been 9.3% (95% CI: 6.1-13.4%) and an additional 46.5% of patients have had disease stabilization. In this study, the most frequently reported treatment-related grade 3/4 toxicities so far have been neutropenia (54%; although only 5.5% of patients developed febrile neutropenia), leukopenia (14%) and fatigue (10%). Grade 3 peripheral neuropathy has occurred in 5.5% of patients, with no patients experiencing grade 4 neuropathy. These results are encouraging considering that these patients were heavily pretreated; in particular, the absence of severe neuropathy is notable.

The encouraging findings with eribulin in MBC have led to its investigation in ongoing Phase III trials for patients with heavily pretreated disease. In one study, 1100 patients will be randomized in a 1:1 ratio to either eribulin 1.4 mg/m² intravenously on days 1 and 8 or oral capecitabine 2500 mg/m²/day in two divided doses on days 1-14 every 21-day cycle.^[104] All patients must have received prior anthracyclines and taxanes and no more than two prior regimens for MBC are permitted. Prior capecitabine is not allowed. A second Phase III study is also ongoing. In this study, 630 patients will be randomized to eribulin 1.4 mg/m² intraenously on days 1 and 8 of a 21-day schedule or chemotherapy of the treating physician's choice.^[105] Patients must have received at least two and no more than five prior chemotherapy regimens, at least two of which must have been for MBC. All patients must have received anthracyclines and taxanes. The results of these studies will, hopefully, determine the activity and tolerability of eribulin in MBC refractory to taxanes and anthracyclines.

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Table 1. Selected Ongoing Phase II Studies in Metastatic Breast Cancer Involving the Combination of ABI-007 and Drugs Targeting VEGF
Study	Size	Inclusion	End point	Results	Ref.
ABI-007 125 mg/m² on days 1, 8 and 15 plus sorafenib 400 mg orally twice daily continuously every 28-day cycle	70	HER2-negative MBC First-line setting MBC Prior adjuvant taxanes ok	Primary: PFS Secondary: RR; 1- and 2-year survival; toxicity	Recruiting	^[109]
ABI-007 100 mg/m² days 1, 8 and 15 plus bevacizumab 10 mg/m² on days 1 and 15 every 28-day cycle	37	Triple-negative MBC Second-line setting MBC No taxanes within 12 months No prior VEGF therapy	Primary: PFS Secondary: RR; toxicity	Recruiting	^[110]
ABI-007 plus bevacizumab administered once every 3 weeks versus every 2 weeks versus weekly	210	First-line setting MBC No taxanes within 12 months	Primary: RR Secondary: PFS	No early safety concerns reported	^[63]
ABI-007 on days 1, 8 and 15 plus bevacizumab on day 1 and carboplatin on day 1 of every 21-day cycle	72	HER2-negative or if HER2 positive must have received prior trastuzumab First-line setting MBC	Primary: PFS Secondary: RR; OS; toxicity	Recruiting	^[111]
ABI-007 plus gemcitabine and bevacizumab on days 1 and 15 every 28-day cycle	30	HER2-negative MBC First-line setting MBC	Primary: PFS Secondary: OS	15 patients enrolled No additional safety concerns 10 out of 11 patients have responded	^[64]
ABI-007 125 mg/m² days 1, 8 and 15 plus bevacizumab 10 mg/m² on days 1 and 15 of every 28-day cycle	49	HER2-negative MBC First-line setting MBC No taxanes within 12 months	Primary: safety, PFS Secondary: RR, OS	27 patients assessed for response RR: 30%	^[65]
ABI-007 on days 1, 8 and 15, plus bevacizumab days 1 and 15 of every 28-day cycle	35	HER2-negative MBC First-line setting MBC	Primary: PFS Secondary: RR; OS; TTP; toxicity	Ongoing	^[112]

MBC = Metastatic breast cancer; OS = Overall survival; PFS = Progression-free survival; RR = Response rate; TTP = Time to progression.

Table 2. Selected Ongoing Adjuvant Studies With ABI-007 and Dose-dense Doxorubicin and Cyclophosphamide
Study	Size	Inclusion	End point/results	Ref.
Dose-dense AC every 2 weeks (four-times) then dose-dense ABI-007 260 mg/m² every 2 weeks (four-times)	66	Stage I, II or III breast cancer LVEF > 50%	ABI-007 cannot be administered without G-CSF support. Protocol amended to routinely use G-CSF.	^[66]
Dose-dense AC every 2 weeks (four-times) then dose-dense ABI-007 every 2 weeks (four-times)	30	Node-positive early breast cancer Tumor > 2 cm Tumor > 1 cm and both ER and PR negative	Safety and tolerability	^[113]
Dose-dense AC every 2 weeks (four-times)then dose-dense ABI-007 260 mg/m² every 2 weeks (four-times) plus Bevacizumab (10 mg/kg every 2 weeks in eight doses) in combination with chemotherapy then 15 mg/kg every 3 weeks (12-times)	80	HER2-negative early breast cancer LVEF > 50%	Grade III sensory neuropathy similar to that reported with paclitaxel No evidence of early cardiac toxicity	^[67,68,69]
Dose-dense AC every 2 weeks (four-times) then random assignment to either dose-dense paclitaxel 175 mg/m² every 2 weeks (four-times) or ABI-007 260 mg/m² every 2 weeks (four-times) plus Bevacizumab (10 mg/kg every 2 weeks in eight doses) in combination with chemotherapy then 15 mg/kg every 3 weeks (ten-times)	200	Node-positive early breast cancer or Tumor > 2 cm or Tumor > 1 cm and grade III and LVEF > 50%	Treatment-related toxicities Change in LVEF	^[114]

AC = Doxorubicin and cyclophosphamide; ER = Estrogen receptor; G-CSF = Granulocyte colony-stimulating factor; LVEF = Left ventricular ejection fraction; PR = Progesterone receptor.

Table 3. Selected Ongoing Studies With Larotaxel in Metastatic Breast Cancer
Study	Size	Inclusion	End point	Status	Ref.
Dose-escalation study of larotaxel in combination with capecitabine	30	MBC; prior anthracycline and taxane required	Determine MTD of combination Safety and tolerability Response rate	Ongoing	^[115]
Multinational randomized trial of larotaxel every 3 weeks and capecitabine orally twice daily for 2 weeks in 3-week cycles	438	MBC; prior anthracycline and taxane required	Time to progression Overall survival	Ongoing	^[116]
Larotaxel in combination with weekly trastuzumab	49	HER2-positive MBC; no more than one chemotherapy regimen for MBC	Response rate Progression-free and overall survival	Ongoing	^[117]
Larotaxel 90 mg/m² and trastuzumab 6 mg/kg once every 3 weeks	50	HER2-positive MBC; no more than one chemotherapy regimen for MBC	Response rate Progression-free survival CNS outcome	41 patients enrolled 11 out of 26 patients responded	^[70]

MBC = Metastatic breast cancer; MTD = Maximum tolerated dose.

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Novel Anti-Tubulin Cytotoxic Agents for Breast Cancer

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