Phase I/II Trial of Neoadjuvant Sunitinib Administered With Weekly Paclitaxel/Carboplatin in Patients With Locally Advanced Triple-Negative Breast Cancer

Inclusion Criteria:

1. Female patients, age ≥18 years

2. Histologically confirmed invasive ER-, PR-, and HER2-negative (triple-negative)
adenocarcinoma of the breast

3. Triple-negative tumors are defined as:

- For HER2-negative:

- Fluorescence in situ hybridization (FISH)-negative (defined by ratio <2.2)
OR

- Immunohistochemical (IHC) 0, IHC 1+, OR

- IHC 2+ or IHC 3+ and FISH-negative (defined by ratio <2.2)

- For ER- and PR-negative: <10% tumor staining by immunohistochemistry (IHC)

4. Primary palpable disease confined to a breast and axilla on physical examination. For
patients without clinically suspicious axillary adenopathy, the primary tumor must be
larger than 2 cm in diameter by physical exam or imaging studies (clinical T2-T3,
N0-N1, M0). For patients with clinically suspicious axillary adenopathy, the primary
breast tumor can be any size (clinical T1-3, N1-2, M0). T1N0M0 lesions are excluded.
Patients with metastatic disease are excluded

5. Patients without clearly defined palpable breast mass or axillary lymph nodes but
radiographically measurable tumor masses are eligible. Accepted procedures for
measuring breast disease are mammography, MRI, and breast ultrasound. Patients with
lesions measurable only by imaging will require repeat imaging after 3 cycles and
prior to surgery

6. Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2

7. Neuropathy grade <1 by the Common Terminology Criteria for Adverse Events version 3.0
(CTCAE v 3.0)

8. Resolution of all acute effects of surgical procedures to grade ≤1. For patients who
had, or will have sentinel lymph node and/or axillary dissection prior to initiation
of study treatment, completion at least 4 weeks prior to starting study treatment and
well-healed wound is required

9. Adequate hematologic function with:

- Absolute neutrophil count (ANC) >1500/μL

- Platelets ≥100,000/μL

- Hemoglobin ≥10 g/dL

10. Adequate hepatic and renal function with:

- Serum bilirubin ≤ the institutional upper limit of normal (ULN)

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x
institutional ULN

- Alkaline phosphatase ≤2.5 x institutional ULN

- Serum creatinine ≤1.5 x ULN or calculated creatinine clearance ≥40 mL/min

11. Left ventricular ejection fraction (LVEF) ≥50% by multigated acquisition (MUGA) or
echocardiogram (ECHO)

12. Bilateral, synchronous breast cancer is allowed if one primary tumor meets the
inclusion criteria

13. Knowledge of the investigational nature of the study and ability to provide consent
for study participation

14. Ability and willingness to comply with study visits, treatment, testing, and other
study procedures

Exclusion Criteria:

1. Previous treatment for this breast cancer

2. Previous treatment with paclitaxel or carboplatin

3. Previous treatment with sunitinib or other angiogenic inhibitors (including, but not
limited to bevacizumab, sorafenib, thalidomide)

4. Any of the following within the 12 months prior to starting study treatment:
myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass
graft, congestive heart failure, cerebrovascular accident including transient
ischemic attack, or pulmonary embolus

5. Uncontrolled hypertension (blood pressure >150/100 mmHg despite optimal medical
therapy)

6. Ongoing cardiac dysrhythmias grade ≥2, atrial fibrillation of any grade, or
prolongation of the QTc interval to >470 msec

7. Major surgery, significant traumatic injury, or radiation therapy within 4 weeks of
starting study treatment. An interval of at least 1 week is required following minor
surgical procedures, with the exception of placement of a vascular access device

8. Grade 3 hemorrhage within 4 weeks of starting study treatment

9. Pre-existing thyroid abnormality with thyroid function that cannot be maintained in
the normal range with medication

10. Known human immunodeficiency virus (HIV) infection or other serious infection

11. Concomitant treatment with drugs having proarrhythmic potential including
terfenadine, quinidine, procainamide, disopyramide, sotalol, probucol, bepridil,
haloperidol, risperidone, indapamide, and flecainide

12. Concurrent use of the potent CYP3A4 inhibitors ketoconazole, itraconazole,
clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir,
amprenavir, indinavir, nelfinavir, delavirdine and voriconazole and CYP3A4 inducers
rifampin, rifabutin, rifapentin, phenobarbital, phenytoin, carbamazepine, St. John's
Wort, and dexamethasone. Use of dexamethasone for study premedication is allowed.
Grapefruit and grapefruit juice is prohibited. Alternative therapies should be used
when available. If use of a potent CYP3A4 inhibitor or inducer is necessary, this
must be approved by the Study Chair

13. Known or suspected hypersensitivity to drugs containing Cremophor®EL
(polyoxyethylated castor oil) such as cyclosporine or teniposide

14. Pregnancy or breast-feeding. Negative serum pregnancy test is required within 7 days
prior to first study treatment (Day 1, Cycle 1) for all women of childbearing
potential. Patients of childbearing potential must agree to use a birth control
method that is approved by their study physician while receiving study treatment and
for three months after the last dose of study treatment. Patients must agree to not
breast-feed while receiving study treatment

15. Concurrent treatment with an ovarian hormonal replacement therapy or with hormonal
agents such as raloxifene, tamoxifen or other selective estrogen receptor modulator
(SERM). Patients must have discontinued use of such agents prior to beginning study
treatment

16. History of malignancy treated with curative intent within the previous 5 years with
the exception of skin cancer, cervical carcinoma in situ, or follicular thyroid
cancer. Patients with previous invasive cancers (including breast cancer) are
eligible if the treatment was completed more than 5 years prior to initiating current
study treatment, and there is no evidence of recurrent disease

17. Use of any investigational agent within 30 days of administration of the first dose
of study drug or concurrent treatment on another clinical study

18. Requirement for radiation therapy concurrent with study anticancer treatment.
Patients who require breast or chest wall radiation therapy after surgery are
eligible, but will have maintenance sunitinib interrupted while receiving radiation

19. Any other disease(s), psychiatric condition, metabolic dysfunction, or findings from
a physical examination or clinical laboratory test result that would cause reasonable
suspicion of a disease or condition, that contraindicates the use of study drugs,
that may increase the risk associated with study participation, that may affect the
interpretation of the results, or that would make the patient inappropriate for this
study