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
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.
Interventional
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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)
17Mar2009~08Apr2010
Yes
Jungsil Ro
Principal Investigator
Chief, Center for Breast Cancer, National Cancer Center, Korea
Korea: Food and Drug Administration
NCCCTS-08-369
NCT01070706
March 2009
November 2010
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