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Data from Pre-Clinical Studies to Be Presented at 101st Annual Meeting of the American Association for Cancer Research
Abraxis BioScience, Inc. (NASDAQ:ABII), a fully integrated biotechnology company, announced study results today that demonstrate a regimen of ABRAXANE® (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) given in combination with bevacizumab (Avastin®) may have potential in the treatment of triple-negative breast cancers. In the pre-clinical study, fifty percent of mice in the combination therapy group (n=10) had complete regressions of primary tumors and metastases at regional and distant sites. Nab-paclitaxel plus bevacizumab was shown to inhibit tumor growth by 100%, and reduced the incidence of lymph node and lung metastases by 50% and 87%, respectively. The findings were discussed during an oral presentation (Abstract #3852) on April 20 at the 101st Annual Meeting of the American Association for Cancer Research (AACR) being held in Washington, D.C.
The pre-clinical study established a new model of triple negative breast cancer, HCC1806-RR, double-tagged with Red Fluorescent Protein (RFP) and Renilla luciferase to allow for quantitative assessment of metastatic spread. Mice bearing orthotopic HCC1806-RR tumors of 150mm3 in size were treated with saline (control), bevacizumab (4 mg/kg, i.p., twice a week, for 10 weeks), nab-paclitaxel (10 mg/kg, i.v., qdx5), or with a combination of nab-paclitaxel and bevacizumab. Metastases were analyzed by measuring luciferase activity in the lymph nodes (LN) and lungs.
"This model was developed to increase our understanding of hard to treat triple negative breast cancer and improve our ability to develop new treatment approaches targeting this tumor type," said lead investigator Sophia Ran, Ph.D., Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL. "This preliminary study demonstrated a high sensitivity to nab-paclitaxel plus bevacizumab, suggesting there may be a role for this combination therapy to significantly improve the health outcome for patients with triple negative breast cancer."
A nab-paclitaxel and bevacizumab combination therapy also increased anti-tumor activity in new models of inflammatory breast cancer (IBC). Given the same dosing regimen, combination treatment inhibited tumor growth in mice by 96% and resulted in 22% (2/9) complete responses.
"These studies establish valuable models for better understanding the biology of these difficult to treat cancers, and indicate that combination therapy utilizing nab-paclitaxel and bevacizumab has potential usefulness in both the triple negative and inflammatory breast cancer populations," said Ran.
In the U.S. 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. Prior therapy should have included an anthracycline unless clinically contraindicated. ABRAXANE has also been granted orphan drug designation by the Food and Drug Administration for the treatment of pancreatic cancer as well as stage IIB-IV melanoma.
About the Studies
Combination treatment of nab-paclitaxel and bevacizumab in a new model of triple negative breast cancer (Abstract #3852)
In this study, HCC1806 cells were obtained and stably transfected with Red Fluorescent Protein (RFP) and Renilla luciferase to establish dual reporter termed RR (RFP and Renilla luciferase). The new derivative was designated as HCC1806-RR and characterized in proliferation and cytotoxicity assays. HCC1806-RR was also orthotopically implanted into the mammary fat pads of immunodeficient mice to determine tumor cell sensitivity to chemotherapy alone or in combination with anti-VEGF-A antibody. Mice bearing orthotopic HCC1806-RR tumors of 150mm3 in size were treated with saline (control), bevacizumab (4 mg/kg, i.p., twice a week, for 10 weeks), ABRAXANE (10 mg/kg, i.v., qdx5), or with combination of ABRAXANE and bevacizumab. Metastasis was analyzed by measuring luciferase activity in the lymph nodes (LN) and lungs.
Overall, combination therapy inhibited tumor growth by 100%. This result was highly significant compared with either control (p<0.001) or ABRAXANE (p=0.024) group; bevacizumab and ABRAXANE inhibited tumor growth by 0% and 90%, respectively. Only combination therapy significantly reduced incidence of LN and lung metastases by 50% (p=0.007) and 87% (p=0.001) respectively. Overall, 50% of the mice in the combination therapy group (n=10) had complete regressions of both primary tumors and metastases at both regional and distant sites.
nab-Paclitaxel and bevacizumab treatment in new models of inflammatory breast cancer (Abstract #3279)
In this study, SUM149 cells were stably transfected with Red Fluorescent Protein (RFP) and Renilla luciferase to establish dual reporter line termed RR, or infected with lentivirus encoding Green Fluorescent Protein (GFP) and Firefly luciferase to establish a line derivative termed GL. The new cell lines, SUM149-RR and SUM149-GL, were characterized in vitro and in vivo after orthotopic implantation into the mammary fat pads of immunodeficient mice. SUM149-RR was also examined for sensitivity to ABRAXANE alone or in combination with bevacizumab. Mice bearing tumors of 150mm3 in size were treated with saline (control), bevacizumab (4 mg/kg, i.p., twice a week, for 10 weeks), ABRAXANE (10 mg/kg, i.v., qdx5), or the combination. Metastasis was analyzed by measuring luciferase activity in the lymph nodes (LN) and lungs.
The results from luciferase measurements and in vivo imaging showed that both SUM149-RR and SUM149-GL clones were highly metastatic to LN, lungs, liver, brain, and spleen. Bevacizumab alone decreased tumor progression at later but not early stages of tumor growth, and ABRAXANE alone inhibited tumor growth by 73%. ABRAXANE and bevacizumab in combination increased inhibition to 96%, and resulted in 22% (2/9) complete responses.
IMPORTANT SAFETY INFORMATION
The use of ABRAXANE has not been studied in patients with hepatic or renal dysfunction. In the randomized controlled trial, patients were excluded for baseline serum bilirubin >1.5 mg/dL or baseline serum creatinine >2 mg/dL.
ABRAXANE can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with ABRAXANE.
Men should be advised to not father a child while receiving treatment with ABRAXANE.
It is recommended that nursing be discontinued when receiving ABRAXANE therapy.
ABRAXANE contains albumin (human), a derivative of human blood.
Caution should be exercised when administering ABRAXANE concomitantly with known substrates or inhibitors of CYP2C8 and CYP3A4.
ABRAXANE therapy should not be administered to patients with metastatic breast cancer who have baseline neutrophil counts of less than 1,500 cells/mm3. It is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE. Patients should not be retreated with subsequent cycles of ABRAXANE until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3.
In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, a dose reduction for subsequent courses is recommended.
Sensory neuropathy occurs frequently with ABRAXANE.
If grade 3 sensory neuropathy develops, treatment should be withheld until resolution to grade 1 or 2 followed by a dose reduction for all subsequent courses of ABRAXANE.
Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients in the randomized trial. These events included chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary embolism, and hypertension.
In the randomized metastatic breast cancer study, the most important adverse events included alopecia (90%), neutropenia (all cases 80%; severe 9%), sensory neuropathy (any symptoms 71%; severe 10%), asthenia (any 47%; severe 8%), myalgia/arthralgia (any 44%; severe 8%), anemia (all 33%; severe 1%), infections (24%), nausea (any 30%; severe 3%), vomiting (any 18%; severe 4%), diarrhea (any 27%; severe <1%), and mucositis (any 7%; severe <1%).
Other adverse reactions have included ocular/visual disturbances (any 13%; severe 1%), fluid retention (any 10%; severe 0%), hepatic dysfunction (elevations in bilirubin 7%, alkaline phosphatase 36%, AST [SGOT] 39%), renal dysfunction (any 11%; severe 1%), thrombocytopenia (any 2%; severe <1%), hypersensitivity reactions (any 4%; severe 0%), cardiovascular reactions (severe 3%), and injection site reactions (<1%). During postmarketing surveillance, rare occurrences of severe hypersensitivity reactions have been reported with ABRAXANE.
The statements contained in this press release that are not purely historical are forward-looking statements within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended. Forward-looking statements in this press release include statements regarding our expectations, beliefs, hopes, goals, intentions, initiatives or strategies, including statements regarding the clinical development plan, and the timing and scope of clinical studies and trials, for ABRAXANE and the global commercialization of ABRAXANE. Because these forward-looking statements involve risks and uncertainties, there are important factors that could cause actual results to differ materially from those in the forward-looking statements. These factors include, without limitation, the fact that results from pre-clinical studies may not be predictive of results to be obtained in other pre-clinical studies or future clinical trials; delays in commencement and completion of clinical studies or trials, including slower than anticipated patient enrollment and adverse events occurring during the clinical trials; decisions by regulatory authorities regarding whether and when to approve ABRAXANE or product candidates for various indications as well as their decisions regarding labeling and other matters that could affect the availability or commercial potential of ABRAXANE and other products and product candidates; unexpected safety, efficacy or manufacturing issues with respect to ABRAXANE or product candidates; the need for additional data or clinical studies for ABRAXANE or product candidates; regulatory developments (domestic or foreign) involving the company's manufacturing facilities; the market adoption and demand of ABRAXANE and other products, the costs associated with the ongoing launch of ABRAXANE; research and development associated with the nab® technology platform; the impact of pharmaceutical industry regulation; the impact of competitive products and pricing; the availability and pricing of ingredients used in the manufacture of pharmaceutical products; the ability to successfully manufacture products in a time-sensitive and cost effective manner; the acceptance and demand of new pharmaceutical products; and the impact of patents and other proprietary rights held by competitors and other third parties. Additional relevant information concerning risks can be found in the company's Annual Report on Form 10-K for the year ended December 31, 2009 and in other documents it has filed with the Securities and Exchange Commission.
The information contained in this press release is as of the date of this release. Abraxis assumes no obligations to update any forward-looking statements contained in this press release as the result of new information or future events or developments.
About Abraxis BioScience
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.
ABRAXANE is a solvent-free chemotherapy treatment option for metastatic breast cancer which was developed using Abraxis BioScience's proprietary nab® technology platform. This protein-bound chemotherapy agent combines paclitaxel with albumin, a naturally-occurring human protein. By wrapping the albumin around the active drug, ABRAXANE can be administered to patients at higher doses, delivering higher concentrations of paclitaxel to the tumor site than solvent-based paclitaxel. 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-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 www.abraxane.com.
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