Cisplatin and Paclitaxel With or Without Everolimus in Treating Patients With Stage II or Stage III 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 chemotherapy together with everolimus before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. It is not yet known whether cisplatin and paclitaxel are more effective when given together with or without everolimus in treating patients with breast cancer. PURPOSE: This randomized phase II trial is studying how well cisplatin and paclitaxel work when given together with or without everolimus in treating patients with stage II or stage III breast cancer.

Detailed Description
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OBJECTIVES: Primary To determine the pathological complete response in patients with triple-negative, stage II or III breast cancer treated with neoadjuvant cisplatin and paclitaxel with or without everolimus. Secondary To determine the safety profile of these treatment regimens. To evaluate tumor response to these treatment regimens as measured by ultrasound before definitive surgery. To evaluate the rate of breast conservation surgery after treatment with these regimens. To determine treatment-mediated changes in cell cycle position, proliferation, and apoptosis as well as status, levels, and phosphorylation state of S6K, p53, p73, and p63 and select p53 family target genes before and after initiation of paclitaxel. To isolate RNA and generate microarray data sets from pre- and post-treatment biopsy material to identify a pre-treatment gene signature that will predict response. To isolate RNA and generate microarray data sets from pre- and post-treatment biopsy material to identify a change in gene signature after the first treatment that will predict response. To isolate RNA and generate microarray data sets from pre- and post-treatment biopsy material to determine if previously established p63 and p73 gene signatures predict response to treatment. To isolate RNA and generate microarray data sets from pre- and post-treatment biopsy material to determine if a change will be observed in p63 and p73 gene signatures between pre- and post-treatment biopsies. To isolate RNA and generate microarray data sets from pre- and post-treatment biopsy material to determine if triple-negative breast cancers can be clustered into different subtypes on the basis of gene expression, given the size of the microarray data set that will be generated from this clinical trial and previous clinical trials (> 100 tumors). To isolate RNA and generate microarray data sets from pre- and post-treatment biopsy material to determine if p63 and p73 gene signatures can sub-classify triple-negative breast cancers. OUTLINE: This is a multicenter study. Patients are stratified according to initial lymph node status (positive vs negative involvement) and tumor grade (low or intermediate vs high). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive cisplatin IV over 1 hour and oral everolimus once weekly in weeks 1-12 and paclitaxel IV over 1 hour once weekly in weeks 4-12 in the absence of disease progression or unacceptable toxicity. Arm II: Patients receive cisplatin IV over 1 hour and oral placebo once weekly in weeks 1-12 and paclitaxel IV over 1 hour once weekly in weeks 4-12 in the absence of disease progression or unacceptable toxicity. Approximately 3-6 weeks after the completion of neoadjuvant therapy, patients undergo partial or total mastectomy with lymph node evaluation. Patients may then receive additional chemotherapy or radiotherapy. Patients undergo ultrasound-guided core biopsies at baseline and in weeks 1, 4, and 12 for analysis of proliferation, apoptosis, and pathway activity markers via IHC or western blotting and RNA microarrays. Patients are followed up within 3 weeks after surgery.

Official Title
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A Phase II Neo-Adjuvant Study of Cisplatin, Paclitaxel With or Without RAD001 in Patients With Triple-negative Locally Advanced Breast Cancer.

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: cisplatin
* Drug: everolimus
* Drug: paclitaxel
* Other: placebo
* Procedure: Venous blood draw


Participation Criteria
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Eligibility Criteria
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Eligibility criteria -Maximum number of patients will include two-thirds of the patients in Arm 1 and one-third of the patients for Arm 2 (total of 145 patients). Estimated time for accrual with   3 patients/month would be   3.5 years. Inclusion criteria: Patients must provide informed written consent. Patient must be ≥ 18 years of age. ECOG performance status 0-1. Clinical stage II or stage III triple-negative (ER and/or PR no staining or weak staining in less than or equal to 10% cells by immunohistochemistry [IHC] and HER2-negative by Herceptest [0, 1+] or FISH) invasive mammary carcinoma, confirmed by histological analysis. Patients who have measurable* residual tumor at the primary site *Measurable disease: any mass that can be reproducibly measured by physical examination, mammogram, and/or ultrasound and can be accurately measured in at least one dimension (longest diameter to be recorded) as 10 mm (1 cm), either in the breast or axillary lymph nodes. Available core biopsies from the time of diagnosis. Fresh tissue must be obtainable at baseline or fresh tissue biopsy prior to treatment initiation. Patients who will undergo surgical treatment with either segmental resection or total mastectomy. Patients must have adequate hematologic, hepatic, and renal function. All tests must be obtained less than 4 weeks from study entry. This includes: ANC >/=1500/mm3 Platelet count >/=100,000/mm3 Creatinine </=1.5X upper limits of normal Bilirubin, SGOT, SGPT </=1.5X upper limits of normal* * for patients with Gilberts syndrome, direct bilirubin will be measured instead of total bilirubin. The patient must have not had anyprior chemotherapy for primary breast cancer. Patients with a prior history of contra-lateral breast cancer are eligible if they have no evidence of recurrence of their initial primary breast cancer within the last 5 years. Able to swallow and retain oral medication. Four days prior to biopsy procedures patients must be off medications that could increase risk of bleeding (i.e. ASA, NSAIDS, Coumadin, heparin products) Potential subjects must complete all screening assessments as outlined in the protocol. The pre-menopausal patient of childbearing potential must have had a negative pregnancy test and agreed to use birth control methods while participating in the study. Note: Women of childbearing potential and their male counterparts should use a barrier method of contraception during and for 3 months following protocol therapy. Ineligibility Criteria Exclusion Criteria: Locally recurrent breast cancer. Pregnant or lactating women. Evidence of distant metastatic disease (i.e. lung, liver, bone, brain, etc.) Use of CYP3A4 modifiers (Appendix A) Serious medical illness that in the judgment of the treating physician places the patient at high risk of operative mortality. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. History of other malignancy. Subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinomas are eligible. History of hepatitis B or hepatitis C. If patient is judged to be at risk for having had exposure to viral B or C hepatitis (i.e. illicit IV drug use, blood transfusion prior to 1990, body piercing, tattoos, etc.), appropriate testing should be performed (i.e. Hepatitis B surface antigen antibody, and Hepatitis C antibody) Active or uncontrolled infection requiring parenteral antibiotics. Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent. Symptomatic neuropathy (≥ grade 2). Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, hormonal therapy, or any other biologic therapy) other than the ones specified in the protocol. Concurrent treatment with an investigational agent. Used an investigational drug within 15 days or 5 half-lives, whichever is longer, preceding the first dose of randomized 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cisplatin and Paclitaxel + RAD001<br>Cisplatin 25 mg/m2 IV weekly + RAD001 5 mg PO daily for 1 week followed by Cisplatin 25 mg/m2 IV + Paclitaxel 80 mg/m2 IV weekly + RAD001 5 mg PO daily for 11 weeks | Drug: cisplatin<br>* Given IV<br>Drug: everolimus<br>* Given orally<br>Drug: paclitaxel<br>* Given IV<br>Procedure: Venous blood draw<br>* Venous blood (2-3 tablespoons) will be taken for germline DNA analysis to complement the correlative studies in the tumor tissue. Blood can be drawn at any time prior, during, or after completion of study treatment<br>|
| Active Comparator: Cisplatin and Paclitaxel + Placebo<br>Cisplatin 25 mg/m2 IV weekly + placebo PO daily for 1 week followed by Cisplatin 25 mg/m2 IV + Paclitaxel 80 mg/m2 IV weekly + placebo PO daily for 11 weeks | Drug: cisplatin<br>* Given IV<br>Drug: paclitaxel<br>* Given IV<br>Other: placebo<br>* Given orally<br>Procedure: Venous blood draw<br>* Venous blood (2-3 tablespoons) will be taken for germline DNA analysis to complement the correlative studies in the tumor tissue. Blood can be drawn at any time prior, during, or after completion of study treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Pathological Complete Response | Pathological complete response is defined as no residual tumor on histopathological analysis of both breast and axillary contents. | at time of surgery, week 15-18 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients That Underwent Breast Conservation Surgery | Defined as patients that did not undergo complete removal of a cancerous breast (mastectomy). | at the time of surgery, week 15-18 | 
| Clinical Tumor Response to Neoadjuvant Therapy as Measured by Ultrasound Immediately Before Surgery | Per 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 | After treatment, week 12-15 | 
| Number of Patients With Each Worst-grade Toxicity Response | Tables represent the number of patients with their worst-grade toxicity at each of five grades (grade 1, least severe to grade 5, most severe) following NCI Common Toxicity Criteria. Not all participants necessarily have an adverse event, thus not everyone will be accounted for in worst-grade toxicities. Likewise, one participant can potentially have more than one event in various grades 1-5 which accounts for the difference in number of patients analyzed and total number in the worst-grade toxicity tables. | week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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triple-negative breast cancer, stage II breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer, male breast cancer