Neoadjuvant Study of Two Platinum Regimens in Triple Negative Breast Cancer

Sporadic and germline BRCA mutation associated triple-negative breast cancer share several
pathological and molecular similarities which have led to the exploration of DNA damaging
agents like platinum compounds in patients with triple-negative breast cancer. Recent studies
demonstrate that addition of neoadjuvant carboplatin to
doxorubicin/cyclophosphamide/taxane-based chemotherapy improves pathological complete
response in patients with stage I-III triple-negative breast cancer but also increase
toxicity.

A recent study reported encouraging pathological complete response rates with a
non-anthracycline carboplatin plus docetaxel neoadjuvant chemotherapy regimen in a cohort of
49 triple negative breast cancer patients. This chemotherapy regimen of carboplatin plus
docetaxel yielded an overall pathological complete response rate of 65% in unselected
triple-negative breast cancer with pathological complete response rates of 61% in sporadic
and 77% in germline BRCA-associated triple-negative breast cancer. The chemotherapy regimen
of carboplatin/docetaxel is well tolerated and should be studied further and compared with
regimens that add carboplatin to the standard anthracycline/taxane containing regimens.

This is the basis for the proposed randomized neoadjuvant phase II study to further estimate
and compare pathological complete response rates of carboplatin plus docetaxel x 6 cycles to
carboplatin plus paclitaxel x 4 cycles followed by doxorubicin plus cyclophosphamide x 4
cycles in stage I-III triple negative-breast cancer.

Inclusion Criteria:

- Patients with newly diagnosed stage I (T>1cm), II or III triple negative breast cancer
who have not had definitive breast surgery or received systemic chemotherapy

- The invasive tumor must be hormone receptor-poor, defined as both estrogen receptor
and progesterone receptor staining present in ≤ 10% of invasive cancer cells by
Immunohistochemistry.

- HER- 2 negativity will be based on the current ASCO-CAP guidelines for HER testing

- No prior chemotherapy, endocrine therapy or radiation therapy with therapeutic intent
for this cancer

- Female subjects age 18 - 70 years

- ECOG Performance Status of 0-1

- Adequate organ and marrow function as defined below:

- Leukocytes ≥ 3,000/uL

- Absolute neutrophil count ≥ 1500/uL

- Platelets ≥ 100,000/uL

- Total bilirubin ≤ 1.5mg/dL

- AST(SGOT)/ALT(SPGT) ≤ 2 x institutional upper limit of normal

- Creatinine ≤ 1.5mg/dl and/or Creatinine Clearance ≥ 60mL/min

- Serum albumin ≥ 3.0 g/dL

- Women of child-bearing potential must agree to use adequate contraception

- Pretreatment lab values must be performed within 14 days of treatment initiation, and
other baseline studies performed within 30 days prior to registration

- Subjects should have LVEF ≥ 50% by echocardiogram or MUGA scan performed within 4
weeks prior to treatment initiation

- Subjects should have breast and axillary imaging with breast MRI or breast and
axillary ultrasound within 4 weeks prior to treatment initiation

- Subjects with clinically/radiologically abnormal axillary lymph nodes should have
pathological confirmation of disease with image guided biopsy/fine needle aspiration.

- Subjects must be already enrolled in P.R.O.G.E.C.T observational registry

- Staging to rule out metastatic disease is recommended for subjects with clinical stage
III disease

- Subjects with bilateral disease are eligible if they meet other eligibility criteria.

- Neuropathy: No baseline neuropathy grade > 2

Exclusion Criteria:

- Current or anticipated use of other investigational agents

- Subject has received chemotherapy, radiotherapy or surgery for the treatment of breast
cancer

- Subject with metastatic disease

- History of allergic reactions to compounds of similar chemical or biologic composition
to carboplatin, docetaxel, doxorubicin, cyclophosphamide, paclitaxel, or other agents
used in the study

- Subjects with inflammatory breast cancer

- Uncontrolled intercurrent illness including, but not limited to ongoing or active
infection or psychiatric illness/social situations that would limit compliance with
study requirements

- Subject is pregnant or nursing

- Subjects with concomitant or previous malignancies within the last 5 years. Exceptions
include: adequately treated basal or squamous cell carcinoma of the skin, carcinoma in
situ of the cervix, and ductal carcinoma in situ (DCIS).

- Ejection Fraction <50% on ECHO or MUGA

- Cardiac function: Subjects with congestive heart failure, myocardial infarction,
unstable angina pectoris, an arterial thrombotic event, stroke or transient ischemia
attack within the past 12 months, uncontrolled hypertension (Systolic BP>160 or
Diastolic BP>90), uncontrolled or symptomatic arrhythmia, or grade ≥ 2 peripheral
vascular disease