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Phase Ib/II Study of Primary Chemotherapy With Paclitaxel, Gemcitabine, and Sunitinib

2014-08-27 03:15:49 | BioPortfolio

Summary

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

Description

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.

Study Design

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

Conditions

Breast Cancer

Intervention

Paclitaxel,Gemcitabine,Sunitinib

Location

Center for breast cancer, National Cancer Center
Goyang
Kyeonggido
Korea, Republic of
410-769

Status

Recruiting

Source

National Cancer Center, Korea

Results (where available)

View Results

Links

Published on BioPortfolio: 2014-08-27T03:15:49-0400

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Medical and Biotech [MESH] Definitions

Abnormal accumulation of lymph in the arm, shoulder and breast area associated with surgical or radiation breast cancer treatments (e.g., MASTECTOMY).

Metastatic breast cancer characterized by EDEMA and ERYTHEMA of the affected breast due to LYMPHATIC METASTASIS and eventual obstruction of LYMPHATIC VESSELS by the cancer cells.

A infiltrating (invasive) breast cancer, relatively uncommon, accounting for only 5%-10% of breast tumors in most series. It is often an area of ill-defined thickening in the breast, in contrast to the dominant lump characteristic of ductal carcinoma. It is typically composed of small cells in a linear arrangement with a tendency to grow around ducts and lobules. There is likelihood of axillary nodal involvement with metastasis to meningeal and serosal surfaces. (DeVita Jr et al., Cancer: Principles & Practice of Oncology, 3d ed, p1205)

A deoxycytidine derivative and fluorouracil PRODRUG that is used as an ANTINEOPLASTIC ANTIMETABOLITE in the treatment of COLON CANCER; BREAST CANCER and GASTRIC CANCER.

Carbohydrate antigen elevated in patients with tumors of the breast, ovary, lung, and prostate as well as other disorders. The mucin is expressed normally by most glandular epithelia but shows particularly increased expression in the breast at lactation and in malignancy. It is thus an established serum marker for breast cancer.

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