Cisplatin, Paclitaxel, and Everolimus in Treating Patients With Metastatic Breast Cancer

OBJECTIVES:

Primary

• To establish the safety profile and the maximum tolerated dose of the combination of cisplatin, paclitaxel, and everolimus in patients with metastatic breast cancer.

Secondary

• To explore the antitumor activity of this regimen, in terms of response rate and time to progression in these patients.

OUTLINE: This is a multicenter study.

Patients receive cisplatin intravenously (IV) over 1 hour and paclitaxel IV over 1 hour on days 1, 8, and 15. Patients receive oral everolimus on days 1, 8, 15, and 21. Courses repeat every 4 weeks in the absence of disease progression and unaccepted toxicity.

After completion of study therapy, patients are followed at 4 weeks.

Inclusion criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed invasive mammary carcinoma

• Stage IV disease
• No locally recurrent breast cancer
• Patients with HER2/neu overexpressing tumors must have received prior trastuzumab (Herceptin®) in first-line treatment of metastatic breast cancer
• Patients with estrogen receptor- or progesterone receptor-expressing tumors must have received prior endocrine therapy (i.e., aromatase inhibitors, fulvestrant, tamoxifen, or ovarian ablation) in first-line treatment of metastatic breast cancer
• No symptomatic brain metastases

• Patients with a history of brain metastases must be clinically stable and not taking steroids or therapeutic anticonvulsants that are CYP3A4 modifiers
• Patients with asymptomatic brain metastases on prophylactic convulsants that are CYP3A4 modifiers are not eligible
• Hormone receptor status not specified

PATIENT CHARACTERISTICS:

• Menopausal status not specified
• ECOG performance status 0-1
• Life expectancy ≥ 6 months
• ANC ≥ 1000/mm^3
• Platelet count ≥ 100,000/mm^3
• Creatinine ≤ 1.5 times upper limit of normal (ULN)
• Bilirubin ≤ 1.5 times ULN (3 times ULN if liver metastasis present)
• SGOT and SGPT ≤ 1.5 times ULN (3 times ULN if liver metastasis present)
• Alkaline phosphatase ≤ 3 times ULN if liver metastasis present
• Able to swallow and retain oral medication
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3 months after completion of study treatment
• Must be disease-free from prior invasive cancers for > 5 years with the exception of completely resected basal cell or squamous cell carcinoma of the skin or successfully treated cervical carcinoma in situ
• No malabsorption syndrome, disease significantly affecting gastrointestinal function, or ulcerative colitis
• No uncontrolled intercurrent illness including, but not limited to:

• Ongoing or active infection requiring parenteral antibiotics
• Impairment of lung function (i.e., chronic obstructive pulmonary disease or lung conditions requiring oxygen therapy)
• Symptomatic New York Heart Association class III-IV congestive heart failure
• Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within the past 6 months
• Uncontrolled hypertension (systolic blood pressure [BP] > 180 mm Hg or diastolic BP > 100 mm Hg)
• Clinically significant cardiac arrhythmia (i.e., multifocal premature ventricular contractions, bigeminy, trigeminy, or ventricular tachycardia that is symptomatic or requires treatment)
• Uncontrolled diabetes
• Psychiatric illness/social situations that would preclude compliance with study requirements
• No known history of uncontrolled or symptomatic neuropathy ≥ grade 2
• No hypersensitivity to paclitaxel, or drugs using the vehicle Cremophor, Chinese hamster ovary cell products, or other recombinant human antibodies

Exclusion criteria

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Recovered from all prior treatment
• Must not have exceeded a total cumulative dose of life-time exposure of doxorubicin hydrochloride ≤ 360 mg/m² or epirubicin hydrochloride ≤ 640 mg/m²
• At least 2 weeks since other prior investigational drugs
• No prior resection of the stomach or small bowel
• No more than 4 prior chemotherapy regimens in the metastatic setting

• This restriction does not include endocrine therapies or single agent biologic therapies (i.e., trastuzumab)
• Concurrent radiotherapy to painful bone metastases or areas of impending bone fracture allowed as long as radiotherapy is initiated prior to study entry
• No concurrent trastuzumab
• No concurrent endocrine therapy
• No concurrent CYP3A4 modifiers
• No concurrent herbal supplement
• No other concurrent anticancer therapy (chemotherapy, radiotherapy, surgery, immunotherapy, hormonal therapy, or biological therapy)