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

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as cisplatin and paclitaxel, 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 cisplatin and paclitaxel together with everolimus may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects of giving cisplatin and paclitaxel together with everolimus and to see how well it works in treating patients with metastatic breast cancer.

Detailed Description
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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.

Official Title
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A Phase Ib/II Study of Cisplatin, Paclitaxel, and RAD001 in Patients With Metastatic Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: cisplatin
* Drug: everolimus
* Drug: paclitaxel
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: Treatment<br> | Drug: cisplatin<br>* Given through a vein in the arm 1 time a week for 3 weeks, then a one week break and then begin the process again.<br>Drug: everolimus<br>* Taken daily by mouth.<br>Drug: paclitaxel<br>* Given through a vein in the arm 1 time a week for 3 weeks, then a one week break and then begin the process again.<br>Other: laboratory biomarker analysis<br>* Blood collection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Feasible Dose in Milligrams Per Meter Squared of Body Surface Area (mg/m2) of Cisplatin and Paclitaxel for Women With Metastatic Breast Cancer | The recommended dose for the Phase II trial will be the most prevalent dose delivered per week in Phase I that allows for safe and feasible administration of the medications.The maximum tolerated dose (MTD) is defined as the dose preceding that at which 2 or more of 3 patients experience dose-limiting toxicity (DLT) during the initial cycle of therapy. DLTs include Common Toxicity Criteria (CTC) Grade 4 neutropenia (absolute neutrophil count [ANC] < 0.5 x 10 9/L for > 5 days), febrile neutropenia (ANC < 1.0 x 10 0/L with fever > 38.5 degrees Centigrade) or documented infection associated with Grade 3-4 neutropenia, CTC Grade 4 thrombocytopenia < 25 x 10 9/L or CTC Grade 3 < 50-25 x 10 9/L thrombocytopenia with bleeding, and Grade 3-4 non-hematologic toxicity despite symptomatic therapy. | at 8 weeks | 
| Maximum Feasible Dose in mg of RAD001 (Everolimus)for Women With Metastatic Breast Cancer | The recommended dose for the Phase II trial will be the most prevalent dose delivered per day in Phase I that allows for safe and feasible administration the medication. The MTD is defined as the dose preceding that at which 2 or more of 3 patients experience dose-limiting toxicity (DLT) during the initial cycle of therapy. DLTs include Common Toxicity Criteria (CTC) Grade 4 neutropenia (absolute neutrophil count [ANC] < 0.5 x 10 9/L for > 5 days), febrile neutropenia (ANC < 1.0 x 10 0/L with fever > 38.5 degrees Centigrade) or documented infection associated with Grade 3-4 neutropenia, CTC Grade 4 thrombocytopenia < 25 x 10 9/L or CTC Grade 3 < 50-25 x 10 9/L thrombocytopenia with bleeding, and Grade 3-4 non-hematologic toxicity despite symptomatic therapy | at 8 weeks | 
| Patients With Progression-free Survival | Patients who had not experienced disease progression and who were alive at 6 months after study entry | at 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients With Overall Response | Per Response Evaluation Criteria in Solid Tumor (RECIST) criteria v. 1.0: measurable lesions: complete response (CR) disappearance of target lesions, partial response (PR) > 30% decrease in the sum of the longest diameter (LD) of target lesions, progressive disease (PD) > 20% increase in the sum of the LD of target lesions or appearance of new lesions, stable disease (SD) neither sufficient decrease nor increase of the sum of smallest sum of the LD of target lesions | every 12 weeks | 
| Time to Progression | Duration in months from date on-study to date patient exhibited progressive disease | Up to 64 weeks | 
| Time to Progression in Patients With Metastatic Basal-like Breast Cancer. | Median duration in months from on-study to disease progression in patients with metastatic basal-like breast cancer. All patients with basal-like breast cancer are negative for estrogen, progesterone, and human epidermal growth factor (HER2) receptors. | Up to 64 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IV breast cancer, Human epidermal growth factor (HER2)-negative breast cancer, triple-negative breast cancer, hormone-resistant breast cancer