Cisplatin and Paclitaxel With or Without Everolimus in Treating Patients With Stage II or Stage III Breast Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Ingrid Mayer, MD, Vanderbilt-Ingram Cancer Center
ClinicalTrials.gov Identifier:
NCT00930930
First received: July 1, 2009
Last updated: June 27, 2013
Last verified: June 2013
  Purpose

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.


Condition Intervention Phase
Breast Cancer
Drug: cisplatin
Drug: everolimus
Drug: paclitaxel
Other: placebo
Procedure: Venous blood draw
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase II Neo-Adjuvant Study of Cisplatin, Paclitaxel With or Without RAD001 in Patients With Triple-negative Locally Advanced Breast Cancer.

Resource links provided by NLM:


Further study details as provided by Vanderbilt-Ingram Cancer Center:

Primary Outcome Measures:
  • Pathological complete response [ Time Frame: at time of surgery, week 15-18 ] [ Designated as safety issue: No ]
    Pathological complete response is defined as no residual tumor on histopathological analysis of both breast and axillary contents.


Secondary Outcome Measures:
  • Number of patients that underwent breast conservation surgery [ Time Frame: at the time of surgery, week 15-18 ] [ Designated as safety issue: No ]
    Defined as patients who did not undergo complete removal of their cancerous breast (mastectomy).

  • Clinical tumor response to neoadjuvant therapy as measured by ultrasound immediately before surgery [ Time Frame: After treatment, week 12-15 ] [ Designated as safety issue: No ]
    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

  • Number of Patients With Each Worst-grade Toxicity Response [ Time Frame: week 12 ] [ Designated as safety issue: Yes ]
    Tables represent the number of patients with 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.


Other Outcome Measures:
  • Therapy-mediated changes in cell cycle position, proliferation, and apoptosis as well as status, levels, and phosphorylation state of p53, p73, and p63 and select p53 family target genes [ Time Frame: Before treatment, on day 3-5 of week 1, and at week 12 ] [ Designated as safety issue: No ]
    To determine the relevance of pathway modulation in triple negative breast cancer cell networking

  • Ability of p63 and p73 gene signatures to predict patient response [ Time Frame: Before treatment, on day 3-5 of week 1, and at week 12 ] [ Designated as safety issue: No ]
    To determine the levels of P63 and p73 in order to correlate these levels with patient response to treatment to help define a biomarker signature associated with p63/p73 dependence in triple negative breast cancers


Enrollment: 145
Study Start Date: June 2009
Estimated Study Completion Date: October 2014
Estimated Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I
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
Given IV
Drug: everolimus
Given orally
Drug: paclitaxel
Given IV
Procedure: Venous blood draw
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
Active Comparator: Arm II
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
Given IV
Drug: paclitaxel
Given IV
Other: placebo
Given orally
Procedure: Venous blood draw
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

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 Gilbert‟s 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00930930

Locations
United States, Alabama
University of Alabama
Birmingham, Alabama, United States, 35249
United States, Mississippi
University of Mississippi Medical Center Research Institute
Jackson, Mississippi, United States, 39213
United States, Pennsylvania
Hershey Medical Center
Hershey, Pennsylvania, United States, 17033
United States, Tennessee
MBCCOP - Meharry Medical College - Nashville
Nashville, Tennessee, United States, 37208
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, United States, 37232-6838
Vanderbilt-Ingram Cancer Center - Cool Springs
Nashville, Tennessee, United States, 37064
United States, Texas
The Methodist Hospital Research Institute
Houston, Texas, United States, 77030
United States, Virginia
University of Virginia Health Sciences Center
Charlottesville, Virginia, United States, 22098
Sponsors and Collaborators
Vanderbilt-Ingram Cancer Center
Investigators
Principal Investigator: Ingrid Mayer, M.D. Vanderbilt-Ingram Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: Ingrid Mayer, MD, Assistant Professor of Medicine; Clinical Director, Breast Cancer Program; Medical Oncologist, Vanderbilt-Ingram Cancer Center
ClinicalTrials.gov Identifier: NCT00930930     History of Changes
Other Study ID Numbers: VICC BRE 0904, P30CA068485, VU-VICC-BRE-0904, IRB# 090291
Study First Received: July 1, 2009
Last Updated: June 27, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Vanderbilt-Ingram Cancer Center:
triple-negative breast cancer
stage II breast cancer
stage IIIA breast cancer
stage IIIB breast cancer
stage IIIC breast cancer
male breast cancer

Additional relevant MeSH terms:
Breast Neoplasms
Breast Diseases
Neoplasms
Neoplasms by Site
Skin Diseases
Cisplatin
Everolimus
Paclitaxel
Sirolimus
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antimitotic Agents
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Immunologic Factors
Immunosuppressive Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Radiation-Sensitizing Agents
Therapeutic Uses
Tubulin Modulators

ClinicalTrials.gov processed this record on October 30, 2014