Phase I/II Study of Weekly Abraxane and RAD001 in Women With Locally Adv. or Metastatic Breast Ca

OBJECTIVES:

Primary

- To determine the maximum tolerated dose and recommended phase II dose of everolimus when
administered in combination with paclitaxel albumin-stabilized nanoparticle formulation
in women with locally advanced or metastatic breast cancer. (Phase I)

- To determine the antitumor activity of this regimen, as measured by clinical tumor
response according to RECIST criteria, in these patients. (Phase II)

Secondary

- To determine the safety and tolerability of everolimus when administered at the
recommended phase II dose in combination with paclitaxel albumin-stabilized nanoparticle
formulation in these patients.

OUTLINE: This is a multicenter, phase I dose-escalation study of everolimus followed by a
phase II study.

Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes on
days 1, 8, and 15. Patients also receive oral everolimus once daily or once every other day
on days 1-28. Courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

DISEASE CHARACTERISTICS:

- Histologically confirmed breast cancer

- Locally recurrent or metastatic disease

- Not amenable to surgery or radiotherapy

- HER2/neu-negative disease

- Has ≥ 1 measurable lesion, as defined by RECIST criteria

- No non-measurable lesions (e.g., pleural effusion or ascites) other than bone
metastases

- Bone metastases as the sole site of disease allowed provided there are ≥ 2
lytic bone lesions by x-ray, CT scan, or MRI

- Lesions irradiated in the advanced setting are not considered sites of measurable
disease unless clear tumor progression has been documented in these lesions since
the completion of radiotherapy

- No bilateral diffuse lymphangitis carcinomatosa of the lung (> 50% of lung
involvement) or evidence of liver metastases estimated as involving > one third of the
liver by sonogram and/or CT scan

- No unstable CNS metastases

- Hormone receptor status not specified

PATIENT CHARACTERISTICS:

- Menopausal status not specified

- ECOG performance status 0-2

- Life expectancy ≥ 3 months

- ANC ≥ 1,500/mm^3

- Platelet count ≥ 100,000/mm^3

- Hemoglobin > 9 g/dL

- Serum bilirubin ≤ 1.5 times upper limit of normal (ULN)

- ALT and AST ≤ 2.5 times ULN (≤ 5 times ULN in patients with liver metastases)

- INR < 1.5 times ULN

- Serum creatinine ≤ 1.5 mg/dL

- Fasting serum cholesterol ≤ 300 mg/dL (or 7.75 mmol/L) (levels outside this threshold
allowed provided statin therapy is initiated)

- Fasting triglycerides ≤ 2.5 times ULN (levels outside this threshold allowed provided
statin therapy is initiated)

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Oral, implantable, or injectable contraceptives are not considered effective
contraception

- No ascites or encephalopathy due to liver disease

- No neuropathy ≥ grade 2

- No impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of everolimus, including any of the following:

- Ulcerative disease

- Uncontrolled nausea, vomiting, or diarrhea

- Malabsorption syndrome

- No active, bleeding diathesis

- No known HIV seropositivity

- No known hypersensitivity to everolimus or sirolimus (rapamycin), paclitaxel
albumin-stabilized nanoparticle formulation, or lactose

- No history of noncompliance to medical regimens

- No severe and/or uncontrolled medical condition or other condition that could affect
study participation, including any of the following:

- Unstable angina pectoris, symptomatic congestive heart failure, myocardial
infarction within the past 6 months, or serious uncontrolled cardiac arrhythmia

- Severely impaired lung function

- Active (acute or chronic) or uncontrolled infections or disorders

- Nonmalignant medical illnesses that are uncontrolled or whose control may be
jeopardized by study treatment

- Liver disease (e.g., cirrhosis, chronic active hepatitis, or chronic persistent
hepatitis)

- No other malignancies within the past 5 years, except curatively treated carcinoma in
situ of the cervix or nonmelanoma skin cancer

PRIOR CONCURRENT THERAPY:

- Prior systemic endocrine therapy for advanced breast cancer allowed

- No prior chemotherapy for advanced breast cancer

- Prior adjuvant chemotherapy allowed

- No prior small bowel resection

- More than 5 days since prior strong CYP3A inhibitors or inducers (e.g., rifabutin,
rifampin, clarithromycin, ketoconazole, itraconazole, voriconazole, ritonavir, or
telithromycin)

- More than 30 days since prior radiotherapy and recovered (alopecia allowed)

- Prior localized radiotherapy for analgesic purposes allowed provided radiotherapy has
been completed and the patient's condition is stabilized

- No prior radiotherapy to ≥ 25% of the bone marrow

- More than 30 days since prior investigational drugs

- More than 1 week since prior and no concurrent immunization with attenuated live
vaccines

- No concurrent oral anti-vitamin K medication, except low-dose coumadin

- No concurrent systemic steroids or other immunosuppressive agents as chronic therapy

- Topical applications, inhaled sprays, eye drops, or local injections allowed

- A short duration (< 2 weeks) of systemic corticosteroids allowed

- No concurrent hormone replacement therapy, topical estrogens (including any
intra-vaginal preparations), megestrol acetate, or selective estrogen-receptor
modulators (e.g., raloxifene)

- No other concurrent investigational or anticancer agents

- Concurrent antiangiogenic agents allowed

- Concurrent bisphosphonates allowed