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

OBJECTIVES:

Primary

- Safety profile of cisplatin, paclitaxel, and everolimus (RAD001) in patients with
metastatic breast cancer. (Phase I)

- Progression-free survival (Phase II)

Secondary

- Overall response rate

- Time to progression

- Number of patients with worst-grade toxicities Tertiary

- To determine p53, p63, p73, and phosphatase and tensin homolog (PTEN) levels by
immunohistochemistry (IHC).

- To screen for exon 9 (E542K and E545K), exon 20 (H1047R), and phosphatidylinositol
3-kinase (PI3K) (p110α) mutations in DNA extracted from paraffin blocks.

- To correlate IHC results with clinical outcome and with the different subtypes of breast
cancer determined by molecular classification (basal-type vs luminal A vs luminal B)
based on microarrays of RNA extracted from formalin-fixed paraffin-embedded blocks.

- To generate microarrays of RNA extracted from fresh-frozen core biopsies (when
available) to identify a pretreatment gene signature that mirrors the established p63
and p73 gene signatures that predict response to treatment.

OUTLINE: This is a multicenter study.

Patients receive oral everolimus once daily on days 1-28 and cisplatin IV over 1 hour and
paclitaxel IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence
of disease progression or unacceptable toxicity.

Tumor tissue samples are collected at baseline for correlative studies.

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

DISEASE CHARACTERISTICS:

- Histologically confirmed invasive mammary carcinoma

- Stage IV disease

- Basal-like disease (triple-negative, hormone-refractory, HER2-negative)

- No locally recurrent breast cancer

- No symptomatic brain metastases

- Patients with a history of brain metastases are eligible provided they are
clinically stable for > 3 weeks after completion of radiotherapy and are not
taking steroids or therapeutic anticonvulsants that are cytochrome P450 3A4
(CYP3A4) modifiers

- Patients with asymptomatic brain metastases are eligible provided they are not
taking prophylactic anticonvulsants that are CYP3A4 modifiers

PATIENT CHARACTERISTICS:

- Pre- or post-menopausal

- European Cooperative Oncology Group (ECOG) performance status 0-1

- Life expectancy ≥ 6 months

- Absolute neutrophil count (ANC) ≥ 1,000/mm^3

- Platelet count ≥ 100,000/mm^3

- Creatinine ≤ 1.5 times upper limit of normal (ULN)

- Total bilirubin ≤ 1.5 times ULN (≤ 3 times ULN in the presence of liver metastasis)

- Direct bilirubin will be measured in patients with Gilbert syndrome

- serum glutamate oxaloacetate transaminase (SGOT) and serum glutamate pyruvate
transaminase (SGPT) ≤ 1.5 times ULN (≤ 3 times ULN in the presence of liver
metastasis)

- Alkaline phosphatase ≤ 3 times ULN (in the presence of liver metastasis)

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective barrier contraception during and for 3 months
after completion of study treatment

- Able to swallow and retain oral medication

- No malabsorption syndrome, disease significantly affecting gastrointestinal function,
or resection of the stomach or small bowel

- No concurrent uncontrolled illness including, but not limited to, any of the
following:

- Ongoing or active infection requiring parenteral antibiotics

- Impaired lung function (chronic obstructive pulmonary disease or lung conditions
requiring oxygen therapy)

- 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 BP > 180 mm Hg or diastolic BP > 100 mm Hg,
found on 2 consecutive measurements separated by a 1-week period and despite
adequate medical support)

- Clinically significant cardiac arrhythmia (multifocal premature ventricular
contractions, bigeminy, trigeminy, ventricular tachycardia that is symptomatic or
requires treatment [grade 3 according to NCI Common Toxicity Criteria for Adverse
Events v3.0])

- Uncontrolled diabetes (hyperosmolar state, ketoacidosis, etc.)

- Psychiatric illness or social situations that would compromise patient safety or
limit compliance with study requirements including maintenance of a
compliance/pill diary

- No symptomatic neuropathy ≥ grade 2

- No other invasive cancer within the past 5 years except for completely resected basal
cell or squamous cell carcinoma of the skin or successfully treated cervical carcinoma
in situ

- No hypersensitivity to paclitaxel or drugs using the vehicle Cremophor, Chinese
hamster ovary cell products, or other recombinant human antibodies

- No history of hepatitis B or C

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- Recovered from prior therapy

- Prior total cumulative life-time dose of doxorubicin ≤ 360 mg/m^2 or epirubicin ≤ 640
mg/m^2

- No more than 4 prior chemotherapy treatments in the metastatic setting (not including
endocrine therapy or single-agent biologic therapy)

- At least 2 weeks since prior investigational drugs

- At least 14 days since prior and no concurrent herbal or dietary supplements

- At least 14 days since prior and no concurrent CYP3A4 inducers

- At least 7 days since prior and no concurrent CYP3A4 inhibitors

- Concurrent radiotherapy to painful bone metastases or areas of impending bone fracture
allowed provided radiotherapy is initiated before study entry

- No other concurrent anticancer therapy (chemotherapy, radiotherapy, surgery,
immunotherapy, hormonal therapy, biologic therapy)