Phase Ib part:

▪ Primary objective: To demonstrate the recommended dose of the combination of paclitaxel, gemcitabine, and sunitinib (sutene®) (PGS) as preoperative chemotherapy in patients with HER2-negative operable breast cancer

• Secondary objective:

  1. To demonstrate the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of this regimen

  2. To determine the safety profile

     Phase II part

• Primary objective:

To evaluate the pathologic complete response rate (pCR) to preoperative administration of PGS

▪ Secondary objective:

1. To assess breast conserving rate after preoperative PGS
2. To evaluate clinical response rate, disease free survival (DFS), and overall survival (OS)
3. To assess the safety profiles of PGS

Unlike adjuvant chemotherapy, primary (preoperative) chemotherapy will shrink tumor and allow more patients to become candidates for conservative surgery and avoid mastectomy. It also is an in vivo chemosensitivity test and the result is a predictive marker for clinical outcomes.

Paclitaxel has been shown to be an effective agent in the treatment of breast cancer. Gemcitabine is a cytosine arabinoside prodrug analog and shows response rates of 15% to 46% as a single agent with very low toxicity. The combination of paclitaxel and gemcitabine (PG) resulted in improvement in objective response rate, time to progression and overall survival compared to paclitaxel monotherapy in patients with metastatic breast cancer. In addition, primary chemotherapies with PG and PGH (PG + trastuzumab) showed significant activity and very low toxicity in phase II studies performed at National Cancer Center, Korea (ASCO 2007 and SABCS 2008, respectively).

Sunitinib is an oral small molecular tyrosine kinase inhibitor that exhibits potent anti-angiogenic and antitumor activity. Sunitinib is a rationally designed small molecule that inhibits members of the split-kinase domain family of receptor tyrosine kinases (RTKs) including the vascular endothelial growth factors (VEGFs) types 1, 2, and 3, platelet-derived growth factor receptor (PDGFR)-α, and -β, stem cell factor receptor (KIT), colony stimulating factor 1 receptor (CSF-1R), Fms-like tyrosine kinase (FLT-3), and glial cell line-derived neurotrophic factor receptor (RET). Inhibition of these RTKs blocks signal transduction, thereby affecting many of the process involved in tumor growth, progression, metastasis, and angiogenesis. Angiogenesis plays a vital role in the growth and metastasis of solid tumors. Preclinical and indirect clinical evidence has accumulated to support the role of neo-angiogenesis in the pathogenesis and progression of breast cancer. Breast cancer neo-vascularization, as measured by an increase in microvessel density, is correlated with the extent of disease and is associated with vascular invasion of the tumor, a prerequisite for blood-borne metastasis. VEGFR signaling is also implicated in the pathobiology of breast cancer. Breast cancer patients exhibit high levels of circulating VEGF and other RTKs are very likely implicated in breast cancer pathogenesis.

Interestingly, a phase II study (Study A6181002) of single-agent sunitinib (50 mg/d on schedule 4/2) in breast cancer patients with anthracycline- and taxane-refractory metastatic disease revealed a response rate of approximately 14% in 51 assessable patients, leading to additional accrual.

When sunitinib is combined with paclitaxel, significant activity was noticed with tolerable toxicity profile in a phase I trial (SABCS 2007). Based on this trial, phase III trial of paclitaxel and sunitinib is ongoing. In addition, phase I trials of gemcitabine and sunitinib combination are ongoing.

Based both on the significant activity of PG combination regimens in the neoadjuvant and metastatic setting and on the phase I trials of combination regimens with sunitinib-paclitaxel and sunitinib-gemcitabine, we plan to conduct a phase IB/II study of primary chemotherapy with sunitinib, paclitaxel and gemcitabine in patients with HER2-negative stage II/III breast cancer. The goal of this phase IB/II study is to define the recommended dose and maximum tolerable dose of paclitaxel and gemcitabine in combination with sunitinib, and explore the activity of this combination as preoperative chemotherapy in patients with HER2-negative operable breast cancer.

Inclusion Criteria:

1. Age ≥ 18 years

2. ECOG performance status 0-2

3. Histologically confirmed and newly diagnosed breast cancer

4. Documented HER2/neu non-overexpressing or non-amplified disease

   • 0-1+ by HER2 IHC or
   • HER2 gene non-amplification by HER2 FISH

5. Clinical stage II or III operable breast cancer

6. Axillary node positivity determined by cytology

7. No prior hormonal, chemotherapy or radiotherapy is allowed

8. No breast operation other than biopsy to make diagnosis is allowed

9. Adequate hematologic, hepatic and renal function

   • Absolute neutrophil count ≥ 1,500/μL
   • Hemoglobin ≥ 10.0 g/dL
   • Platelet ≥ 100,000/μL
   • AST/ALT ≤ 2 X UNL (upper limit of normal)
   • Total bilirubin ≤ 1.5 mg/dL
   • Alkaline phosphatase ≤ 2 X UNL
   • Serum creatinine ≤ 1.5 mg/dL

10. Adequate cardiac function LVEF ≥ 50% and within the institutional range of normal as measured by echocardiogram or MUGA scan within 4 weeks of enrollment

11. Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to registration

12. Normal mental function to understand and sign the consent

Exclusion Criteria:

1. Patients with metastatic breast cancer

2. Patients who received hormonal, chemotherapy or radiotherapy for breast cancer

3. Patients who underwent surgery for breast cancer

4. Patients with T2N0, or inflammatory (T4d) breast cancer

5. Patients who have history of cancer other than in situ uterine cervix cancer or nonmelanotic skin cancer

6. Patients with GI tract disease resulting in an inability to take oral medication, malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's disease, ulcerative colitis)

7. Any of the following within the 12 months prior to starting study treatment

   • severe, unstable angina
   • Myocardial infarction
   • Uncontrolled or symptomatic congestive heart failure
   • coronary/peripheral artery bypass graft
   • cerebrovascular accident including transient ischemic attack
   • pulmonary embolism

8. Ongoing cardiac dysrhythmias of grade ≥2, atrial fibrillation of any grade, or QTc interval >470 msec.

9. Hypertension that cannot be controlled by medications (>150/100 mmHg despite optimal medical therapy)

10. Current treatment with therapeutic doses of Coumadin (low dose Coumadin up to 2 mg po daily for deep vein thrombosis prophylaxis is allowed).

11. Known HIV infection

12. Pregnancy or breastfeeding. Female patients who are pregnant or nursing, female of child-bearing potential who is unwilling to use adequate contraception to prevent pregnancy during the program. All female patients with reproductive potential must have a negative pregnancy test (serum or urine) prior to study entry.

13. Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that would impart, in the judgment of the investigator, excess risk associated with study participation or study drug during administration, or which, in the judgment of the investigator, would make the patient inappropriate for entry into this study.