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Phase Ib/II Study of Primary Chemotherapy With Paclitaxel, Gemcitabine, and Sunitinib in Patients With HER2-negative Stage II/III Breast Cancer

Phase 1/Phase 2
18 Years
Not Enrolling
Breast Cancer

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Trial Information

Phase Ib/II Study of Primary Chemotherapy With Paclitaxel, Gemcitabine, and Sunitinib in Patients With HER2-negative Stage II/III Breast Cancer

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

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.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Phase Ib part: To demonstrate the recommended dose of the combination of paclitaxel, gemcitabine, and sunitinib. Phase II part: To evaluate the pathologic complete response rate (pCR)

Outcome Time Frame:


Safety Issue:


Principal Investigator

Jungsil Ro

Investigator Role:

Principal Investigator

Investigator Affiliation:

Chief, Center for Breast Cancer, National Cancer Center, Korea


Korea: Food and Drug Administration

Study ID:




Start Date:

March 2009

Completion Date:

November 2010

Related Keywords:

  • Breast Cancer
  • Patients with HER2- stage II/III breast cancer
  • Breast Neoplasms