Ixabepilone in Treating Patients With Locally Advanced or Metastatic Breast Cancer

A Phase II Clinical Trial Of BMS-247550 (NSC 710428), An Epothilone B Analog, In Patients With Breast Carcinoma

RATIONALE: Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die.

PURPOSE: This phase II trial is studying how well ixabepilone works in treating patients with locally advanced or metastatic breast cancer.

OBJECTIVES:

• Determine any antitumor activity of ixabepilone, in terms of objective response rate, in patients with incurable, locally advanced or metastatic breast cancer.
• Determine the toxicity of this drug in these patients.

OUTLINE: This is a multicenter study. Patients are stratified according to prior taxane therapy (yes vs no).

Patients (with or without prior taxane exposure) receive ixabepilone IV over 1 hour on days 1-5. An additional cohort of 37 patients who have received prior taxane therapy are then accrued to receive ixabepilone IV over 1 hour on days 1-3 at a higher starting dose. For all patients, courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients who receive more than 6 courses with satisfactory response may be treated every 4-5 weeks.

Patients removed for unacceptable toxicty are followed periodically.

PROJECTED ACCRUAL: A total of 105 patients (at least 74 with and 21 without prior taxane exposure) will be accrued for this study within 26 months.

DISEASE CHARACTERISTICS:

• Histologically confirmed* adenocarcinoma of the breast

  • Incurable, locally advanced or metastatic disease
  • Primarily stage IV disease, but some inoperable stage III disease may be eligible (e.g., a patient with T4 and/or N2-3 disease who cannot receive doxorubicin or who has already received other therapy) NOTE: *Patients with no available tissue for histologic confirmation but who have documentation of breast surgery and prior chemotherapy are eligible upon approval of the principal investigator

• Measurable disease

• No evidence of CNS metastases by brain MRI or contrast head CT scan

  • CNS metastases controlled by radiotherapy or surgical resection at least 6 months prior to study enrollment are allowed

• Hormone receptor status:

  • Not specified

PATIENT CHARACTERISTICS:

Age

• 18 and over

Sex

• Female or male

Menopausal status

• Not specified

Performance status

• ECOG 0-2

Life expectancy

• At least 3 months

Hematopoietic

• Granulocyte count at least 1,200/mm^3
• Platelet count at least 100,000/mm^3

Hepatic

• Bilirubin no greater than 1.5 times upper limit of normal (ULN) (3 times ULN if there is clinical evidence of Gilbert's disease)
• AST and ALT no greater than 2.5 times ULN

Renal

• Creatinine normal OR
• Creatinine clearance greater than 40 mL/min

Other

• No poor medical risk due to other nonmalignant systemic disease
• No active uncontrolled infection
• No sensory, motor, or cranial neuropathy or neuropathic pain grade 2 or greater (unless neuropathy is clearly due to underlying breast cancer)
• No other concurrent serious medical illness
• No prior severe hypersensitivity reactions to agents containing Cremophor EL
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 2 months after study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

• More than 4 weeks since prior filgrastim (G-CSF), pegfilgrastim, or thrombopoietin (or other platelet growth factors)
• No concurrent immunotherapy

Chemotherapy

• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)
• No other concurrent chemotherapy for breast cancer

Endocrine therapy

• More than 2 weeks since prior hormonal therapy
• No concurrent hormonal therapy

Radiotherapy

• See Disease Characteristics
• No prior craniospinal radiation
• No prior total body irradiation
• More than 4 weeks since prior radiotherapy

Surgery

• See Disease Characteristics

Other

• No other concurrent investigational drugs

• No concurrent cytochrome p450 3A4 inhibitors, including any of the following:

  • Clarithromycin
  • Erythromycin
  • Troleandomycin
  • Delaviridine
  • Nelfinavir
  • Amprenavir
  • Ritonavir
  • Indinavir
  • Saquinavir
  • Lopinavir
  • Itraconazole
  • Ketoconazole
  • Fluconazole (> 200 mg/day)
  • Voriconazole
  • Nefazodone
  • Fluvoxamine
  • Verapamil
  • Diltiazem
  • Amiodarone

• Concurrent bisphosphonates for bone metastases allowed