Cisplatin and Paclitaxel With or Without Everolimus in Treating Patients With Stage II or Stage III Breast Cancer
- Conditions
- Breast Cancer
- Interventions
- Registration Number
- NCT00930930
- Lead Sponsor
- Vanderbilt-Ingram Cancer Center
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 145
Not provided
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Cisplatin and Paclitaxel + RAD001 Venous blood draw 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 Cisplatin and Paclitaxel + Placebo Venous blood draw 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 Cisplatin and Paclitaxel + RAD001 paclitaxel 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 Cisplatin and Paclitaxel + Placebo placebo 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 Cisplatin and Paclitaxel + RAD001 cisplatin 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 Cisplatin and Paclitaxel + RAD001 everolimus 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 Cisplatin and Paclitaxel + Placebo cisplatin 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 Cisplatin and Paclitaxel + Placebo paclitaxel 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
- Primary Outcome Measures
Name Time Method Number of Patients With Pathological Complete Response at time of surgery, week 15-18 Pathological complete response is defined as no residual tumor on histopathological analysis of both breast and axillary contents.
- Secondary Outcome Measures
Name Time Method Number of Patients With Each Worst-grade Toxicity Response week 12 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.
Number of Patients That Underwent Breast Conservation Surgery at the time of surgery, week 15-18 Defined as patients that did not undergo complete removal of a cancerous breast (mastectomy).
Clinical Tumor Response to Neoadjuvant Therapy as Measured by Ultrasound Immediately Before Surgery After treatment, week 12-15 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
Trial Locations
- Locations (8)
University of Alabama
🇺🇸Birmingham, Alabama, United States
Hershey Medical Center
🇺🇸Hershey, Pennsylvania, United States
The Methodist Hospital Research Institute
🇺🇸Houston, Texas, United States
MBCCOP - Meharry Medical College - Nashville
🇺🇸Nashville, Tennessee, United States
University of Virginia Health Sciences Center
🇺🇸Charlottesville, Virginia, United States
University of Mississippi Medical Center Research Institute
🇺🇸Jackson, Mississippi, United States
Vanderbilt-Ingram Cancer Center - Cool Springs
🇺🇸Nashville, Tennessee, United States
Vanderbilt-Ingram Cancer Center
🇺🇸Nashville, Tennessee, United States