Phase Ib/II Study of Primary Chemotherapy With Paclitaxel, Gemcitabine, and Sunitinib (PGS)
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
- To demonstrate the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of this regimen
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:
- To assess breast conserving rate after preoperative PGS
- To evaluate clinical response rate, disease free survival (DFS), and overall survival (OS)
- To assess the safety profiles of PGS
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase Ib/II Study of Primary Chemotherapy With Paclitaxel, Gemcitabine, and Sunitinib in Patients With HER2-negative Stage II/III Breast Cancer|
- 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) [ Time Frame: 17Mar2009~08Apr2010 ] [ Designated as safety issue: Yes ]
|Study Start Date:||March 2009|
|Study Completion Date:||November 2010|
|Primary Completion Date:||December 2009 (Final data collection date for primary outcome measure)|
Experimental: Paclitaxel, Gemcitabine, Sunitinib
Paclitaxel, Gemcitabine, Sunitinib
To determine the MTD, only DLT occurring during the first cycle of treatment will be considered. And MTD is defined as the dose level at which at least one-third of patients experience a DLT during their first treatment course. The recommended dose level for the subsequent phase II study is defined as the preceding dose level before the MTD is attained.
If MTD is not reached, the recommended initial dose of the phase II part will be at the dose of paclitaxel 80 mg/m2 and gemcitabine 1200 mg/m2 (days 1, 8) with sunitinib 37.5 mg qd D2-D15.
Other Name: 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.
|Korea, Republic of|
|Center for breast cancer, National Cancer Center|
|Goyang, Kyeonggido, Korea, Republic of, 410-769|
|Principal Investigator:||Jungsil Ro||Chief, Center for Breast Cancer, National Cancer Center, Korea|