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

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as paclitaxel albumin-stabilized nanoparticle formulation, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving paclitaxel albumin-stabilized nanoparticle formulation together with everolimus may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of everolimus when given together with paclitaxel albumin-stabilized nanoparticle formulation and to see how well it works in treating women with locally advanced or metastatic breast cancer.

Detailed Description
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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.

Official Title
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Phase I/II Study of Weekly Abraxane and RAD001 in Women With Locally Advanced or Metastatic Breast Cancer. A Study of the Cancer Institute of New Jersey Oncology Group (CINJOG)

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: everolimus
* Drug: abraxane


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I / Phase II<br>Phase I: Abraxane will be given by IV for 30 minutes on the first day of the first three weeks of each 28 day cycle. RAD001 will be given by tablet. The first group of patients will receive RAD001 once daily depending on side effects seen drug could be increased later to twice a day for a 28 day cycle. Once a safe and effective drug range is established, the study moves into Phase II. Phase II: The maximum tolerated dose (established in Phase I) will be given as scheduled below and we will measure the effectiveness of the study drug combination. Abraxane will be given by IV (intravenous infusion) for 30 minutes on the first day of the first three weeks of each 28 day cycle (Day 1, Day 8, and Day 15 of each cycle). RAD001 will be given by tablet based on the dose established in the Phase I part of the study. | Drug: everolimus<br>* Orally administered RAD001 will be initiated at 5 mg daily. Each cohort Phase I: administration will proceed based on escalation criteria. RAD001 will be given initially once every day. Doses will be adjusted per the dosing regimen for each cohort throughout the Phase I portion of the study<br>* Other names: RAD001;Drug: abraxane<br>* Doses of Abraxane will be calculated on Day 1 of each cycle using the patient's actual weight in the determination of body surface area. A variance of 5% of the calculated total dose will be allowed.<br>* Other names: nab paclitaxel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To Determine the Maximum Tolerated Dose (MTD) of RAD001 in Combination of Weekly Abraxane and Determine the Phase II Dose of RAD001. |  | 5 yrs | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer, stage IV breast cancer, HER2-negative breast cancer, recurrent breast cancer