A Phase II Neo-Adjuvant Study of Cisplatin, Paclitaxel With or Without RAD001 in Patients With Triple-negative Locally Advanced Breast Cancer.
Overview
- Phase
- Phase 2
- Intervention
- cisplatin
- Conditions
- Breast Cancer
- Sponsor
- Vanderbilt-Ingram Cancer Center
- Enrollment
- 145
- Locations
- 8
- Primary Endpoint
- Number of Patients With Pathological Complete Response
- Status
- Completed
- Last Updated
- 10 years ago
Overview
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.
Investigators
Ingrid Mayer, MD
Assistant Professor of Medicine; Clinical Director, Breast Cancer Program; Medical Oncologist
Vanderbilt-Ingram Cancer Center
Eligibility Criteria
Inclusion Criteria
- Not provided
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.
Arms & Interventions
Cisplatin and Paclitaxel + RAD001
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
Intervention: cisplatin
Cisplatin and Paclitaxel + RAD001
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
Intervention: everolimus
Cisplatin and Paclitaxel + RAD001
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
Intervention: paclitaxel
Cisplatin and Paclitaxel + RAD001
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
Intervention: Venous blood draw
Cisplatin and Paclitaxel + 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
Intervention: cisplatin
Cisplatin and Paclitaxel + 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
Intervention: paclitaxel
Cisplatin and Paclitaxel + 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
Intervention: placebo
Cisplatin and Paclitaxel + 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
Intervention: Venous blood draw
Outcomes
Primary Outcomes
Number of Patients With Pathological Complete Response
Time Frame: 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 Outcomes
- Number of Patients With Each Worst-grade Toxicity Response(week 12)
- Number of Patients That Underwent Breast Conservation Surgery(at the time of surgery, week 15-18)
- Clinical Tumor Response to Neoadjuvant Therapy as Measured by Ultrasound Immediately Before Surgery(After treatment, week 12-15)