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Analyses of MPACT Trial Evaluating ABRAXANE® Combination Therapy for the Treatment of Advanced Pancreatic Cancer Presented at ASCO 2013

<p class='bwalignc'> <i>Data Suggest Treatment with ABRAXANE plus Gemcitabine Reduces Levels of CA19-9 and Increases the Frequency of PET Responses; Both Tools Found to be Potential Prognostic Factors of Overall Survival</i> </p>

Monday, June 03, 2013

Analyses of MPACT Trial Evaluating ABRAXANE® Combination Therapy for the Treatment of Advanced Pancreatic Cancer Presented at ASCO 2013

12:30 EDT Monday, June 03, 2013

BOUDRY, Switzerland (Business Wire) -- Celgene International Sàrl, a subsidiary of Celgene Corporation (NASDAQ: CELG), announced several analyses of a phase III clinical trial of ABRAXANE® (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) in combination with gemcitabine in previously untreated patients with advanced pancreatic cancer. The data were presented at the American Society of Clinical Oncology (ASCO) 2013 annual meeting in Chicago.

The MPACT (Metastatic Pancreatic Adenocarcinoma Clinical Trial) overall trial results demonstrated that patients treated with ABRAXANE plus gemcitabine had a statistically significant improvement in overall survival compared with those treated with gemcitabine alone (median of 8.5 vs. 6.7 months; HR 0.72, p<0.0001). These data were initially presented at an oral session at ASCO GI in San Francisco on January 25, 2013.

In a June 3rd oral session, Dr. Daniel D. Von Hoff, M.D., F.A.C.P., lead principal investigator of the MPACT study, Chief Scientific Officer for Scottsdale Healthcare's Virginia G. Piper Cancer Center Clinical Trials, and Physician-In-Chief for Translational Genomics Research Institute (TGen), presented these overall survival results, as well as data from additional exploratory efficacy endpoints.

The metabolic response rate, as measured by the percentage of patients who had a reduction of their tumor signal on positron emission tomography (PET), was independently evaluated in the first 257 patients enrolled in centers that could perform PET scans. In addition, tumor response was also evaluated by measuring the decrease in levels of a key tumor marker called carbohydrate antigen 19-9 (CA19-9).

For the 257 patients in the PET cohort, 63% of those treated with ABRAXANE plus gemcitabine had a metabolic response versus 38% of those treated with gemcitabine alone (p=0.000051). The median overall survival in the PET cohort was greater for ABRAXANE plus gemcitabine as compared to gemcitabine alone (median of 10.5 vs. 8.3 months, HR 0.71, p<0.0096).

The CA19-9 findings were presented in further detail by Dr. Gabriela Chiorean, M.D., Associate Professor of Medicine, University of Washington School of Medicine, in a June 2nd poster presentation (abstract 4058). Of the 861 patients in the MPACT study, 750 had an evaluable CA19-9 sample at baseline and at least one follow-up sample.

More patients treated with ABRAXANE plus gemcitabine achieved at least a 20% reduction in CA19-9 (61%) compared with those treated with gemcitabine alone (44%) (p<0.0001). In a landmark analysis of survival in patients who achieved a 20% reduction in CA19-9 by week 8 of treatment, patients treated with ABRAXANE/gemcitabine with a CA19-9 response had significantly improved survival over patients treated with gemcitabine alone (13.2 months vs 9.4 months, respectively) (p<0.0001).

“As we evaluate potential new therapies for patients with advanced pancreatic cancer, we also have the opportunity to learn more about the biology behind this deadly disease and to develop a greater understanding of the challenges in treating it,” said Dr. Chiorean. “These new findings add to our understanding of what factors are important for investigators to use in designing future clinical trials in pancreatic cancer and help us understand better potential predictors of treatment outcome.”

The analysis of the potential influence of prognostic factors on predicting survival was also presented in more detail in a poster on June 2nd (abstract 4059) by Dr. Malcolm Moore, M.D., Head of Medical Oncology and Hematology, Princess Margaret Hospital. In this analysis, which included all 861 patients from MPACT, key predictors at baseline of improved overall survival were identified as follows: better performance status according to the Karnofsky Performance Scale index, age under 65 years, the absence of liver metastases, fewer metastatic sites and recruitment to trial sites in North America compared to Eastern Europe (Russia and Ukraine).

After correcting for these factors, treatment with ABRAXANE plus gemcitabine was a significant independent predictor of improved overall survival (HR 0.72: p < 0.0001) and progression-free survival (HR 0.66; p < 0.0001) compared with treatment with gemcitabine alone, according to the analysis.

The most common grade 3 or 4 adverse events in MPACT for ABRAXANE plus gemcitabine versus gemcitabine alone were neutropenia (38% vs. 27%, respectively), fatigue (17% vs. 7%) and peripheral neuropathy (17% vs. 1%). In the ABRAXANE plus gemcitabine arm, the median time to improvement to Grade 1 or no neuropathy was 29 days. There was no difference in serious life-threatening toxicity (4% for each arm).

These results are from an investigational phase III clinical study. ABRAXANE is not currently approved for the treatment of advanced pancreatic cancer. The U.S. Food and Drug Administration (FDA) has assigned a Priority Review designation to the supplemental New Drug Application (sNDA) for the use of ABRAXANE in combination with gemcitabine for the first–line treatment of patients with advanced pancreatic cancer. In April 2013, the European Medicines Agency (EMA) also accepted for review a Type II Variation to the current Marketing Authorization Application (MAA) for ABRAXANE in advanced pancreatic cancer.

The results presented support Celgene's plans for developing a phase III study investigating the activity of ABRAXANE plus gemcitabine in the adjuvant pancreatic cancer setting.

About the MPACT Study

In the MPACT (Metastatic Pancreatic Adenocarcinoma Clinical Trial) study, a Celgene-sponsored, open-label, randomized, international study, 861 metastatic pancreatic cancer patients were randomized to receive either ABRAXANE plus gemcitabine (125 mg/m2 followed by 1,000 mg/m2 gemcitabine given weekly for 3 weeks followed by a week of rest x2 in cycle 1 (56-day cycle) and in cycle 2 onward were given on Days 1, 8 and 15 of 28-day cycle) or gemcitabine alone (1,000 mg/m2 administered weekly for 7 weeks followed by a week of rest in cycle 1 (56-day cycle) and in cycle 2 onward was given on Days 1, 8 and 15 of 28-day cycle). The primary endpoint for the study was improvement in overall survival. Secondary endpoints were progression-free survival and overall response rate determined by independent radiological review. Other endpoints included progression-free survival and overall response rate as determined by the investigator, and the safety and tolerability of the combination in this patient population.

About Advanced Pancreatic Cancer

Pancreatic cancer is the eighth-leading cause of cancer-related death worldwide and the fourth-leading cause of cancer-related death in the US. The pancreas is composed of two main cell types: exocrine and endocrine. Exocrine tumors are by far the most common type of pancreatic cancer, with adenocarcinoma accounting for about 95% of cancers of the pancreas. For all stages of pancreatic cancer combined, the 5-year overall survival rate is about 6%, which is the lowest 5-year overall survival rate of any cancer in the U.S. In Europe, the reported survival rate is less than 10% at five years.

About ABRAXANE ®

ABRAXANE is an albumin-bound form of paclitaxel that is manufactured using patented nab ® technology. ABRAXANE is formulated with albumin, a human protein, and is free of solvents.

In the United States, ABRAXANE was first approved in January 2005 for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. ABRAXANE is also approved in Canada, India, European Union/European Economic Area (EU/EEA), South Korea, China, Australia, Bhutan, United Arab Emirates, Nepal, New Zealand, Japan, Russia, Sri Lanka, and Argentina for the treatment of metastatic breast cancer.

In October 2012, ABRAXANE was approved by the U.S. Food and Drug Administration for the first-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy. ABRAXANE is also approved in Japan and Argentina for the treatment of non-small cell lung cancer.

ABRAXANE is currently in various stages of investigation for the potential treatment of the following cancers: melanoma, bladder, ovarian and expanded applications for breast, lung and pancreatic cancer.

U.S. Regulatory Information for ABRAXANE

ABRAXANE ® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

Important Safety Information

WARNING - NEUTROPENIA

  • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm 3 . In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE
  • Note: An albumin form of paclitaxel may substantially affect a drug's functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS

CONTRAINDICATIONS

Neutrophil Counts

  • ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3

Hypersensitivity

  • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug

WARNINGS AND PRECAUTIONS

Hematologic Effects

  • Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC) and 47% of patients with non-small cell lung cancer (NSCLC)
  • Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 for MBC and Days 1, 8, and 15 for NSCLC
  • Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3
  • In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC
  • In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1,500 cells/mm3 and platelets recover to >100,000 cells/mm3
  • In patients with NSCLC, resume treatment if recommended at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1,500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle

Nervous System

  • Sensory neuropathy is dose- and schedule-dependent
  • The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification
  • If ≥ Grade 3 sensory neuropathy develops, treatment should be withheld until resolution to Grade 1 or 2 for MBC or until resolution to ≤ Grade1 for NSCLC followed by a dose reduction for all subsequent courses of ABRAXANE

Hypersensitivity

  • Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported
  • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be re-challenged with this drug

Hepatic Impairment

  • Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution
  • The starting dose should be reduced for patients with moderate or severe hepatic impairment

Albumin (Human)

  • ABRAXANE contains albumin (human), a derivative of human blood

Use in Pregnancy: Pregnancy Category D

  • ABRAXANE can cause fetal harm when administered to a pregnant woman
  • If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus
  • Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE

Use in Men

  • Men should be advised not to father a child while receiving ABRAXANE

ADVERSE REACTIONS

Randomized Metastatic Breast Cancer (MBC) Study

  • The most common adverse reactions (≥20%) with single-agent use of ABRAXANE vs. Paclitaxel injection in the MBC study were alopecia (90%, 94%), neutropenia (all cases 80%,82%; severe 9%,22%), sensory neuropathy (any symptoms 71%, 56%; severe 10%, 2%), abnormal ECG (all patients 60%, 52%; patients with normal baseline 35%, 30%), fatigue/asthenia (any 47%, 39%; severe 8%, 3%), myalgia/arthralgia (any 44%, 49%; severe 8%, 4%), AST elevation (any 39%, 32%), alkaline phosphatase elevation (any 36%, 31%), anemia (all cases 33%, 25%; severe 1%, <1%), nausea (any 30%, 22%; severe 3%, <1%), diarrhea (any 27%, 15%; severe <1%, 1%) and infections (24%, 20%), respectively
  • Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients
  • Other adverse reactions of note with the use of ABRAXANE vs. Paclitaxel injection included vomiting (any 18%,10%; severe 4%, 1%), fluid retention (any 10%,8%; severe 0%,<1%); mucositis (any 7%, 6%; severe <1%, 0%), hepatic dysfunction (elevations in bilirubin 7%, 7%), hypersensitivity reactions (any 4%,12%; severe 0%, 2%), thrombocytopenia (any 2%, 3%; severe <1%, <1%), and injection site reactions (<1%, 1%), respectively. Dehydration and pyrexia were also reported
  • Renal dysfunction (any 11%, severe 1%) were reported in patients treated with ABRAXANE (n = 229)
  • In all ABRAXANE treated patients (n=366) ocular/visual disturbances were reported (any 13%; severe 1%)
  • Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients and included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension
  • Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported

Non-Small Cell Lung (NSCLC) Cancer Study

  • Adverse reactions with a difference of ≥2%, Grade 3 or higher, with combination use of ABRAXANE and carboplatin vs. combination use of Paclitaxel injection and carboplatin in NSCLC were anemia (28%, 7%); neutropenia (47%, 58%); thrombocytopenia (18%, 9%), peripheral neuropathy (3%, 12%), and peripheral edema (0%, <1%), respectively
  • Adverse reactions with a difference of ≥5%, Grades 1-4, with combination use of ABRAXANE and carboplatin vs. combination use of Paclitaxel injection and carboplatin in NSCLC were anemia (98%,91%), neutropenia (85%, 83%), thrombocytopenia (68%, 55%), peripheral neuropathy (48%, 64%), peripheral edema (10%, 4%), and epistaxis (7%, 2%), respectively
  • The most common adverse reactions (≥20%) of ABRAXANE in combination with carboplatin for NSCLC were anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue
  • The most common serious adverse reactions of ABRAXANE in combination with carboplatin for NSCLC were anemia (4%) and pneumonia (3%)
  • The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%)
  • The most common adverse reactions resulting in dose reduction of ABRAXANE were neutropenia (24%), thrombocytopenia (13%), and anemia (6%)
  • The most common adverse reactions leading to withholding or delay in ABRAXANE dosing were neutropenia (41%), thrombocytopenia (30%), and anemia (16%)
  • The following common (≥10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin-treated and paclitaxel injection plus carboplatin-treated patients: alopecia 56%, nausea 27%, fatigue 25%, decreased appetite 17%, asthenia 16%, constipation 16%, diarrhea 15%, vomiting 12%, dyspnea 12%, and rash 10% (incidence rates are for the ABRAXANE plus carboplatin treatment group)

Post-marketing Experience with ABRAXANE and Other Paclitaxel Formulations

  • Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or to human albumin has not been studied
  • There have been reports of congestive heart failure and left ventricular dysfunction with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs
  • There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration

DRUG INTERACTIONS

  • Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4

USE IN SPECIFIC POPULATIONS

Nursing Mothers

  • It is not known whether paclitaxel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother

Pediatric

  • The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated

Geriatric

  • No toxicities occurred notably more frequently among patients ≥65 years of age who received ABRAXANE for MBC
  • Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients ≥65 years of age treated with ABRAXANE and carboplatin in NSCLC

Renal Impairment

  • The use of ABRAXANE has not been studied in patients with renal impairment

DOSAGE AND ADMINISTRATION

  • Dose adjustment is recommended for patients with moderate and severe hepatic impairment and patients who experience severe neutropenia or severe sensory neuropathy during treatment with ABRAXANE
  • Withhold ABRAXANE if AST >10 x ULN or bilirubin >5 x ULN
  • Dose reductions or discontinuation may be needed based on severe hematologic or neurologic toxicities
  • Monitor patients closely

Please see full Prescribing Information, including Boxed WARNING, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, please visit http://www.abraxane.com/docs/Abraxane_PrescribingInformation.pdf

About Celgene

Celgene Corporation, headquartered in Summit, New Jersey, is an integrated global pharmaceutical company engaged primarily in the discovery, development and commercialization of innovative therapies for the treatment of cancer and inflammatory diseases through gene and protein regulation.

Celgene International Sárl, located in Boudry, Switzerland, is a wholly owned subsidiary and international headquarters of Celgene Corporation.

For more information, please visit the Company's website at www.celgene.com.

Forward-Looking Statements

This press release contains forward-looking statements, which are generally statements that are not historical facts. Forward-looking statements can be identified by the words "expects," "anticipates," "believes," "intends," "estimates," "plans," "will," "outlook" and similar expressions. Forward-looking statements are based on management's current plans, estimates, assumptions and projections, and speak only as of the date they are made. We undertake no obligation to update any forward-looking statement in light of new information or future events, except as otherwise required by law. Forward-looking statements involve inherent risks and uncertainties, most of which are difficult to predict and are generally beyond our control. Actual results or outcomes may differ materially from those implied by the forward-looking statements as a result of the impact of a number of factors, many of which are discussed in more detail in our Annual Report on Form 10-K and our other reports filed with the Securities and Exchange Commission.

For Celgene International Sàrl
Investors:
+41 32 729 8303
ir@celgene.com
or
Media:
+41 32 729 8304
media@celgene.com

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