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Posted: June 8, 2010
ASCO Presentations Offer New Insights into Role of nab-Chemotherapy Based Breast Cancer Chemotherapy Treatment
(Nanowerk News) Abraxis BioScience, Inc. presented abstracts describing 10 trials of nanoparticle albumin bound (nab®) driven chemotherapy, nab-paclitaxel (ABRAXANE® for Injectable Suspension; paclitaxel albumin protein-bound particles for injectable suspension), for the treatment of breast cancer at the 46th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago. Studies included three ongoing trials of nab-paclitaxel in the treatment of triple-negative breast cancer (TNBC), HER2-negative primary operable breast cancer, and elderly patients with an increased risk for relapse of a primary carcinoma of the breast, continuing the company's focus on developing treatments for difficult-to-treat cancers.
ABRAXANE is currently approved for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within six months of adjuvant chemotherapy. Abraxis BioScience is currently investigating the potential of its propriety nab-driven chemotherapy as monotherapy or in combination across a wide-range of advanced and hard-to- treat cancers, including in metastatic and triple-negative breast cancer. nab-chemotherapy is thought to leverage a previously unrecognized tumor-activated, albumin-specific biologic pathway to activate an albumin-specific (Gp60) receptor-mediated transcytosis path through the cell wall of proliferating tumor cells and deliver targeted cytotoxic drugs to the tumor.
"We continue to explore ABRAXANE's utility to treat breast cancer with an emphasis on the more difficult-to-treat sub-groups such as triple negative disease," said Patrick Soon-Shiong, M.D., Executive Chairman and founder of Abraxis BioScience.
About the Studies
I. Neoadjuvant bevacizumab with weekly nanoparticle albumin bound nab-paclitaxel plus carboplatin followed by doxorubicin plus cyclophosphamide (AC) for triple-negative breast cancer. (Abstract #TPS100)
In this phase 2 study, 60 patients with TNBC will be treated. Patients must be diagnosed with palpable and operable TNBC less than or equal to two centimeters.
The treatment regimen consists of 28-day cycles of nab-paclitaxel 100 mg/m(2) on days 1, 8 and 15 and carboplatin AUC 6 on day 1 for four cycles followed by dose dense AC for four cycles. Bevacizumab is given at 10mg/kg every two weeks with chemotherapy for the first six cycles and is continued post-operatively to complete one year of treatment. Definitive surgical resection and radiation therapy are based on institutional standards.
The study hypothesizes neoadjuvant weekly nab-paclitaxel plus carboplatin will demonstrate high pathologic complete remission (pCR) rates in TNBC patients due to the over-expression of the SPARC-protein in TNBC basal-like cancer with subsequent entrapment of albumin-bound nab-paclitaxel and DNA damage caused by carboplatin. Pathologic complete remission can be defined as the absence of invasive tumor cells in the breast specimen. The trial further hypothesizes that increased pCR rates will translate to improved disease-free survival (DFS) for the patients.
II. ICE II: An investigational randomized phase II study on epirubicin (E) plus cyclophospamide (C) (or CMF) versus nab-paclitaxel plus capecitabine (PX) as adjuvant chemotherapy for elderly nonfrail patients with an increased risk for relapse of a primary carcinoma of the breast. (Abstract #TPS104)
In this multicenter, controlled, open-label, randomized phase 2/3 study, 1,458 elderly patients (greater-than or equal to 65) with an ECOG Performance Status and Charlson Scale of 0-2 and histologically confirmed unilateral or bilateral primary carcinoma of the breast with high risk disease classification, that have achieved complete resection of the tumor and greater-than or equal to 10 maxillary nodes will be treated. In addition, no evidence for distant metastasis could be seen in any patient.
Patients will be randomized to receive either standard treatment (four cycles of either epirubicin plus cyclophospamideon (EC) day 1 q22 or six cycles intravenously; or cyclophosphamide/methotrexate/fluorouracil (CMF) on days 1 and 8 q29 intravenously -- based on investigators' decision) or six cycles of weekly nab-paclitaxel (100 mg/m(2)) on days 1, 8, 15 q22 with a week of rest every six weeks in combination with capecitabine (2000 mg/m(2)) days 1 to 14 orally, divided into two daily doses every three weeks for 6 cycles. The primary objective is to determine the safety and toxicity as well as the compliance of nab-paclitaxel plus capecitabine regimen. Main secondary objectives are disease free survival and overall survival with EC or CMF vs. nab-paclitaxel in combination with capecitabine.
The initial, phase 2 study will examine the safety of nab-paclitaxel in combination with capecitabine compared to EC or CMF in the first 400 patients (200 per arm). A first interim safety analysis will be performed after 200 patients have gone through all cycles of chemotherapy. The phase 3 study will examine efficacy and safety for the entire planned cohort of 1,458 patients (n=729/arm).
III. A multi-institutional double-blind phase II study evaluating response and surrogate biomarkers to carboplatin and nab-paclitaxel (CP) with or without vorinostat as preoperative systemic therapy (PST) in HER2-negative primary operable breast cancer (TBCRC008). (Abstract #TPS111)
In this multi-institutional double-blind phase 2 study, women with unresected stage II-III HER2-negative breast cancer will be treated. The study includes both a run-in phase to investigate the safety of 12 weekly doses of carboplatin (AUC 2) and nab-paclitaxel (100mg/m(2)) with vorinostat 400mg po daily (first 3 out of every 7 days) and a randomized phase 2 portion. The phase 2 treatment regimen consists of eligible women stratified by hormone receptor status and randomly assigned in a 1:1 ratio to nab-paclitaxel plus placebo or vorinostat, to include a sample size of 31 patients per arm.
The primary endpoint is rate of pathologic complete response (pCR) with secondary endpoints including correlation of baseline and change in standardized uptake values on positron emission tomography with pCR and clinical CR, evaluation of safety and long term outcomes. Exploratory endpoints include comparison of pCR and clinical CR in women with triple-negative/basal-like features versus those without and evaluation of baseline and change in candidate gene methylation, gene expression and histone acetylation in tumor tissue. A sample size of 31 patients per arm will enable detection of a 25% pCR rate from a null response rate of 10% using a Simon two-stage design with 80% power and a 10% Type I error rate.
To date, six women have completed the run-in phase without dose-limiting toxicities and one woman has completed the phase 2 portion.
About nab®-Driven Chemotherapy
Abraxis BioScience has developed a proprietary nanoparticle albumin-bound (nab) technology which leverages albumin nanoparticles for the active and targeted delivery of chemotherapeutics to the tumor. This nab-driven chemotherapy provides a new paradigm for penetrating the blood-stroma barrier to reach the tumor cell. The proposed mechanism of delivery of this nab-driven chemotherapy is thought to be by targeting a previously unrecognized tumor-activated, albumin-specific biologic pathway with a nanoshell of the human blood protein albumin. This nano-shuttle system is believed to activate an albumin-specific (Gp60) receptor-mediated transcytosis path through the cell wall of proliferating tumor cells, using caveolin-1 activated caveolar transport. Once in the stromal micro-environment, the albumin-bound drug may be preferentially localized by a second albumin-specific binding protein, SPARC, a protein secreted into the stroma by tumor cells. The resulting collapse of stroma surrounding the tumor cell may thus enhance the delivery of the nab-chemotherapeutic to the intracellular core of the tumor cell itself.
ABRAXANE is the first clinical validation of the nanoparticle albumin bound (nab) technology platform and is a treatment option for metastatic breast cancer. This protein-bound chemotherapy agent combines paclitaxel with albumin, a naturally-occurring human blood protein. ABRAXANE is currently in various stages of investigation for the treatment of the following cancers: expanded applications for metastatic breast, non-small cell lung, malignant melanoma, pancreatic and gastric.
The U.S. Food and Drug Administration approved ABRAXANE for Injectable Suspension (paclitaxel protein albumin-bound particles for injectable suspension) (albumin-bound) in January 2005 for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within six months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. For the full prescribing information for ABRAXANE please visit http://www.abraxane.com.
About Abraxis BioScience, Inc.
Abraxis BioScience is a fully integrated global biotechnology company dedicated to the discovery, development and delivery of next-generation therapeutics and core technologies that offer patients safer and more effective treatments for cancer and other critical illnesses. The company's portfolio includes chemotherapeutic compound (ABRAXANE®), which is based on the company's proprietary tumor targeting technology known as the nab® platform. The first FDA approved product to use this nab® platform, ABRAXANE, was launched in 2005 for the treatment of metastatic breast cancer and is now approved in 39 countries. The company continues to expand the nab® platform through a robust clinical program and deep product pipeline. Abraxis trades on the NASDAQ Global Market under the symbol ABII. For more information about the company and its products, please visit http://www.abraxisbio.com.