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

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

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.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Other: placebo; Drug: paclitaxel; Drug: cisplatin; Drug: everolimus; Procedure: Venous blood draw

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.

• Study Type: Interventional
• Enrollment (Actual): 145
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35249
      • University of Alabama
  • Mississippi
    • Jackson, Mississippi, United States, 39213
      • University of Mississippi Medical Center Research Institute
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Hershey Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37208
      • MBCCOP - Meharry Medical College - Nashville
    • Nashville, Tennessee, United States, 37232-6838
      • Vanderbilt-Ingram Cancer Center
    • Nashville, Tennessee, United States, 37064
      • Vanderbilt-Ingram Cancer Center - Cool Springs
  • Texas
    • Houston, Texas, United States, 77030
      • The Methodist Hospital Research Institute
  • Virginia
    • Charlottesville, Virginia, United States, 22098
      • University of Virginia Health Sciences Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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	Drug: paclitaxel; Given IV; Drug: cisplatin; Given IV; Drug: everolimus; 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
Active Comparator: 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	Other: placebo; Given orally; Drug: paclitaxel; Given IV; Drug: cisplatin; 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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	To determine the relevance of pathway modulation in triple negative breast cancer cell networking	Before treatment, on day 3-5 of week 1, and at week 12
Ability of p63 and p73 Gene Signatures to Predict Patient Response	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	Before treatment, on day 3-5 of week 1, and at week 12

Collaborators and Investigators

• Sponsor: Vanderbilt-Ingram Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Ingrid Mayer, M.D., Vanderbilt-Ingram Cancer Center

Publications and helpful links

General Publications

• Jovanovic B, Sheng Q, Seitz RS, Lawrence KD, Morris SW, Thomas LR, Hout DR, Schweitzer BL, Guo Y, Pietenpol JA, Lehmann BD. Comparison of triple-negative breast cancer molecular subtyping using RNA from matched fresh-frozen versus formalin-fixed paraffin-embedded tissue. BMC Cancer. 2017 Apr 4;17(1):241. doi: 10.1186/s12885-017-3237-1.

Helpful Links

• Vanderbilt-Ingram Cancer Center, Find a Clinical Trial

Study record dates

Study Major Dates

• Study Start: June 1, 2009
• Primary Completion (Actual): October 1, 2013
• Study Completion (Actual): October 1, 2014

Study Registration Dates

• First Submitted: July 1, 2009
• First Submitted That Met QC Criteria: July 1, 2009
• First Posted (Estimate): July 2, 2009

Study Record Updates

• Last Update Posted (Estimate): May 7, 2015
• Last Update Submitted That Met QC Criteria: May 5, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Keywords: stage IIIA breast cancer; stage IIIB breast cancer; male breast cancer; stage II breast cancer; stage IIIC breast cancer; triple-negative breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Paclitaxel; Cisplatin; Everolimus
• Other Study ID Numbers: VICC BRE 0904; P30CA068485 (U.S. NIH Grant/Contract); VU-VICC-BRE-0904; IRB# 090291