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

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 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
- Bilirubin, SGOT, SGPT
* 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.