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Clinical data exploring the expanded role of ABRAXANE in second-line treatment revealed during late-breaking presentation at the 2010 American Urological Association Annual Meeting
Abraxis BioScience, Inc. (NASDAQ:ABII) announced today that findings from a phase 1 randomized trial demonstrated that the nanoparticle albumin bound (nab®) driven chemotherapy, nab-paclitaxel (ABRAXANE® for Injectable Suspension; paclitaxel albumin protein-bound particles for injectable suspension) is well-tolerated and active in the second-line treatment of high-grade, non-muscle-invasive bladder cancer that has been refractory to standard intra-bladder infusion (intravesical) therapy. The results from a dose escalation trial of infusion of ABRAXANE directly into the bladder in these patients who have failed standard chemotherapy are being presented for the first time as a late-breaker during an oral session on June 1st at the 2010 American Urological Association Annual Meeting in San Francisco.
Non-muscle-invasive bladder cancer is difficult to treat and up to 50 percent of patients receiving drugs infused into the bladder (intravesical agents) will experience recurrence of the cancer. Typical second-line treatment for patients with high-grade, non-muscle-invasive bladder cancer who have failed standard intravesical therapy is surgical removal of the entire bladder, cystectomy. The American Cancer Society estimates that approximately 70,980 people were diagnosed with bladder cancer in the United States in 2009, and that approximately 18,170 died from the disease.i The prevalence of bladder cancer in the United States exceeds 500,000 people.ii
In this study of 18 patients who previously failed treatment with Bacillus Calmette-Guerin (BCG), patients were randomized to receive six weekly intravesicular-instillations of nab-paclitaxel beginning at a dose of 150 mg, with a dose escalation model used until a maximal deliverable dose (MDD) was identified. The drug was well-tolerated with no grade 2, 3 or 4 drug related local toxicities encountered and with 12 out of 18 patients (56 percent) experiencing only grade 1 local toxicities, dysuria being the most common. After 108 intravesical instillations, no systemic toxicities occurred. In addition, there was no systemic absorption of nab-paclitaxel up through the 375 mg dose. A preliminary examination of response rate found that five out of 18 patients (28 percent) demonstrated a complete response with nab-paclitaxel after 12 weeks in these patients who had failed BCG therapy.
"The preliminary results of this study suggest nab-paclitaxel may have a potential benefit for high-risk non-muscle-invasive bladder cancer patients who have failed prior intravesical treatment or who are unable or unwilling to undergo cystectomy," said James McKiernan, M.D., Director of Urologic Oncology, Department of Urology, Herbert Irving Comprehensive Cancer Center, Columbia University. Enrollment is ongoing for a phase 2 trial evaluating nab-paclitaxel for refractory non-muscle-invasive bladder cancer at the MDD.
"The promising results of ABRAXANE in the treatment of patients with bladder cancer support the efficacy of nab-driven chemotherapy across an increasing range of advanced and difficult-to-treat cancers," said Patrick Soon-Shiong, M.D., Executive Chairman and founder of Abraxis BioScience. "This study further supports our commitment to develop a deeper understanding of how albumin-bound ABRAXANE's unique affinity for the secreted protein SPARC may enable targeted cytoxotic agents to be delivered directly into the tumor microenvironment, supporting better patient outcomes."
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 Study
Phase I Trial of Intravesical Nanoparticle Albumin-Bound Paclitaxel in the Treatment of BCG Refractory Non-Muscle-Invasive Bladder Cancer
In this single institution, investigator-initiated, IRB-approved phase 1 study, 18 patients with BCG-refractory non-muscle-invasive bladder cancer were treated. Patients were diagnosed with high grade Ta, T1 and Tis transitional cell carcinoma and had an Eastern Cooperative Oncology Group Performance Status Scale (ECOG PS) of 0. Six weekly instillations of nab-paclitaxel were administered beginning at a dose of 150 mg at a concentration of 5mg/ml in normal saline with a dose escalation model used until a maximal deliverable dose (MDD) was identified (patients received dose levels of 150, 225, 300, 375, 450 and 500 mg). The primary endpoints were dose-limiting toxicity (NCI common toxicity criteria grade 3 or 4 toxicity) and MDD. The secondary endpoint was response rate. Efficacy was evaluated 12 weeks after the first intravesical instillation via cystoscopy with biopsy and cytology.
Twelve out of 18 patients (56%) experienced grade 1 local toxicities, with dysuria being the most common. No grade 2, 3 or 4 drug related local toxicities were encountered, and there was no apparent correlation between dose and toxicity. After 108 intravesical instillations, no systemic toxicities occurred. One patient demonstrated measurable systemic absorption of nab-paclitaxel at the 450 mg dose, which was three magnitudes lower than the mean serum levels detected after standard intravenous administration (16mg/ml, compared to mean of 19,600mg/ml after standard intravenous administrationiii).
In a preliminary examination of response rate, 5 out of 18 patients (28%) demonstrated a complete response with nab-paclitaxel after 12 weeks. Of 13 patients who recurred, one patient had evidence of stage progression at the post-treatment evaluation.
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. 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 preclinical 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 for various indications as well as their decisions regarding labeling and other matters that could affect the availability or commercial potential of ABRAXANE; unexpected safety, efficacy or manufacturing issues with respect to ABRAXANE; the need for additional data or clinical studies for ABRAXANE; regulatory developments (domestic or foreign) involving the company's manufacturing facilities; the market adoption and demand of ABRAXANE, 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.
i American Cancer Society. Cancer Facts & Figures 2009. Atlanta: American Cancer Society; 2009. Available at www.cancer.org/downloads/STT/500809web.pdf.
ii Altekruse SF, Kosary CL, Krapcho M, Neyman N, Aminou R, Waldron W, Ruhl J, Howlader N, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Cronin K, Chen HS, Feuer EJ, Stinchcomb DG, Edwards BK (eds). SEER Cancer Statistics Review, 1975-2007, National Cancer Institute. Bethesda, MD, seer.cancer.gov/csr/1975_2007/, based on November 2009 SEER data submission, posted to the SEER web site, 2010.
iii Gardner ER, Dahut WL, Scripture CD, Jones J, Aragon-Ching JB, Desai N, Hawkins MJ, Sparreboom A, and Figg WD. "Randomized crossover pharmacokinetic study of solvent-based paclitaxel and nab-paclitaxel." Clinical Cancer Research. 2008 Jul 1;14(13):4200-5.
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. For more information about the company and its products, please visit www.abraxisbio.com.
About nab®-Driven Chemotherapy
Abraxis BioScience has developed a proprietary nanoparticle albumin-bound (nab) technology which we believe leverages albumin nanoparticles for the active and targeted delivery of chemotherapeutics to the tumor. This nab-driven chemotherapy may provide 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 receptor (gp60) 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.
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.
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