U.S. Food and Drug Administration Approves ABRAXANE® in Combination with Gemcitabine as First-Line Treatment of Patients with Metastatic Pancreatic Cancer

SUMMIT, NJ, USA I September 6, 2013 I Celgene Corporation (CELG) today announced that the U.S. Food and Drug Administration (FDA) has approved the Company’s supplemental New Drug Application (sNDA) of ABRAXANE^® (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) as first–line treatment for patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine. Adenocarcinoma, a sub-type of exocrine tumors, accounts for about 95% of cancers of the pancreas.

“For more than 15 years, treatment with gemcitabine has been the standard of care in this disease. The addition of ABRAXANE to gemcitabine demonstrated meaningful improvements across key efficacy outcomes, including overall survival, with a well-characterized safety profile,” said Jean-Pierre Bizzari, M.D., Executive Vice President of Hematology and Oncology for Celgene Corporation.

“We are pleased that patients with advanced pancreatic cancer now have a new treatment option helping to expand the treatment landscape for the fourth leading cause of cancer death in the United States,” said Julie Fleshman, president and CEO of the Pancreatic Cancer Action Network. “The FDA approval of ABRAXANE is an important step for a disease that desperately needs treatment advances to improve patient outcomes. The Pancreatic Cancer Action Network will continue to work with the medical community to build upon this success and advance our goals in the fight against pancreatic cancer.”

ABRAXANE in combination with gemcitabine is the first new treatment approved for metastatic adenocarcinoma of the pancreas in nearly eight years. The approval was based on results from MPACT (Metastatic Pancreatic Adenocarcinoma Clinical Trial), an open-label, phase III, randomized, international study, that were featured at this year’s ASCO annual meeting and have been submitted for publication in a peer-reviewed journal. Over the past two decades, more than 30 randomized, phase III studies have been conducted in patients with advanced pancreatic cancer and the MPACT study was one of four studies to show an overall survival benefit. In the MPACT study, which involved 861 chemotherapy-naïve patients with metastatic pancreatic cancer, ABRAXANE plus gemcitabine demonstrated a statistically significant improvement in median overall survival compared to gemcitabine alone (8.5 vs. 6.7 months) (HR 0.72, P

“Historically, patients with pancreatic cancer have not experienced benefit with many of the drugs so useful in other malignancies. This is beginning to change,” said Margaret A. Tempero, M.D., Director and Professor of Medicine, UCSF Pancreas Center. “The combination of ABRAXANE and gemcitabine represents an important new therapeutic option for patients with pancreatic cancer. It also provides a foundation for future clinical research.”

The most common adverse reactions (≥ 20%) with a ≥ 5% higher incidence in the ABRAXANE/gemcitabine treatment group are neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration. For additional safety information, please see Boxed Warning and Contraindications in the Important Safety Information.

The FDA had granted ABRAXANE a Priority Review designation in May 2013 with a PDUFA date of September 21, 2013. 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 combination with gemcitabine, for the first–line treatment of patients with metastatic adenocarcinoma of the pancreas. Celgene has submitted dossiers for registration in other countries/regions.

Note to editors: Additional information can be found at  http://smp.newshq.businesswire.com/pages/fda-approves-abraxane-paclitaxel-protein-bound-particles-injectable-suspension-metastatic-panc

About the MPACT Study

In the MPACT (Metastatic Pancreatic Adenocarcinoma Clinical Trial) study, a Celgene-sponsored, open-label, randomized, international study, a total of 861 patients were randomized 1:1 (431 patients to the ABRAXANE/gemcitabine group and 430 patients to the gemcitabine group). Patients randomized to ABRAXANE/gemcitabine received ABRAXANE as an intravenous infusion over 30-40 minutes at a dose of 125 mg/m² followed by gemcitabine as an intravenous infusion over 30-40 minutes at a dose of 1000 mg/m² given on Days 1, 8 and 15 of each 28-day cycle. In the comparator treatment group, gemcitabine monotherapy was administered at a dose of 1000 mg/m² given weekly for 7 weeks followed by a 1-week rest period in Cycle 1 and in Cycle 2 and onwards was administered on Days 1, 8 and 15 of a 28 day cycle. The primary endpoint for the study was 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 Pancreatic Cancer

Pancreatic cancer is the fourth-leading cause of cancer-related death in the U.S. The pancreas is composed of two main cell types: exocrine and endocrine. Exocrine tumors are by far the most common type of pancreatic cancer. Adenocarcinoma is a sub-type of exocrine tumors and accounts for about 95% of cancers of the pancreas. For all stages of pancreatic cancer combined, the five-year survival rate is about 6%, which is the lowest of any cancer in the U.S. For metastatic pancreatic cancer, the five-year survival is approximately 2%.

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 has been globally approved in more than forty countries for the treatment of metastatic breast cancer (MBC).

In October 2012, ABRAXANE was approved by the FDA 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 for the treatment of NSCLC in Argentina, Australia, Japan, and New Zealand. In addition, ABRAXANE is approved for gastric cancer in Japan.

In September 2013, the FDA approved ABRAXANE as first–line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine.

U.S. Regulatory Information for ABRAXANE

ABRAXANE 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

ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine.

Important Safety Information

WARNING – NEUTROPENIA

• Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm³. 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 3.

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), 47% of patients with non-small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer.
• 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 and for pancreatic cancer).
• 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 (3 for seven 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 a level >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 1500 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.
• In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm³ or platelets are less than 50,000 cells/mm³ and delay initiation of the next cycle if the ANC is less than 1500 cells/mm³ or platelet count is less than 100,000 cells/mm³ on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended.

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, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for MBC or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE.

Sepsis

• Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine.
• Biliary obstruction or presence of biliary stent, were risk factors for severe or fatal sepsis.
• If a patient becomes febrile (regardless of ANC), initiate treatment with broad spectrum antibiotics.
• For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥ 1500 cells/mm³, then resume treatment at reduced dose levels.

Pneumonitis

• Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine.
• Monitor patients for signs and symptoms and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis.
• Permanently discontinue treatment with ABRAXANE and gemcitabine upon making a diagnosis of pneumonitis.

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.
• For MBC and NSCLC, the starting dose should be reduced for patients with moderate or severe hepatic impairment.
• For pancreatic adenocarcinoma, ABRAXANE is not recommended 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 are 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 (any 33%, 25%; severe 1%,
• 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%,
• Renal dysfunction (any 11%, severe 1%) was 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 Cancer (NSCLC) Study

• The most common adverse reactions (≥ 20%) of ABRAXANE in combination with carboplatin are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue
• The most common serious adverse reactions of ABRAXANE in combination with carboplatin for NSCLC are anemia (4%) and pneumonia (3%)
• The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%)
• The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%)
• The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are 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)
• 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 are anemia (28%, 7%), neutropenia (47%, 58%), thrombocytopenia (18%, 9%), and peripheral neuropathy (3%, 12%), 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 are anemia (98%, 91%), thrombocytopenia (68%, 55%), peripheral neuropathy (48%, 64%), edema peripheral (10%, 4%), epistaxis (7%, 2%), arthralgia (13%, 25%), and myalgia (10%, 19%), respectively
• Neutropenia (all grades) was reported in 85% of patients who received ABRAXANE and carboplatin vs 83% of patients who received paclitaxel injection and carboplatin

Pancreatic Adenocarcinoma Study

• Among the most common (≥ 20%) adverse reactions in the phase III study, those with a ≥ 5% higher incidence in the ABRAXANE/gemcitabine treatment group compared to the gemcitabine treatment group are: neutropenia (73%, 58%), fatigue (59%, 46%), peripheral neuropathy (54%, 13%), nausea (54%, 48%), alopecia (50%, 5%), peripheral edema (46%, 30%), diarrhea (44%, 24%), pyrexia (41%, 28%), vomiting (36%, 28%), decreased appetite (36%,26%), rash (30%, 11%), and dehydration (21%, 11%)
• Of these most common adverse reactions, those with a difference of ≥ 2% for Grade 3-4 toxicity between treatment groups, respectively, are neutropenia (38%, 27%), fatigue (18%, 9%), peripheral neuropathy (17%, 1%), nausea (6%, 3%), diarrhea (6%, 1%), pyrexia (3%, 1%), vomiting (6%, 4%), decreased appetite (5%, 2%), and dehydration (7%, 2%)
• Thrombocytopenia (all grades) was reported in 74% of patients in the ABRAXANE/gemcitabine group vs 70% of patients in the gemcitabine group
• The most common serious adverse reactions of ABRAXANE (with a ≥ 1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%), and vomiting (4%)
• The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were peripheral neuropathy (8%), fatigue (4%), and thrombocytopenia (2%)
• The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%), and peripheral neuropathy (6%)
• The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%)
• Other selected adverse reactions with a difference of ≥ 5% for all-grade toxicity between treatment groups, respectively, are asthenia (19%, 13%), mucositis (10%, 4%), dysgeusia (16%, 8%), headache (14%, 9%), hypokalemia (12%, 7%), cough (17%, 7%), epistaxis (15%, 3%), urinary tract infection (11%, 5%), pain in extremity (15%, 6%), arthralgia (11%, 3%), myalgia (10%, 4%), and depression (12%, 6%)
• Other selected adverse reactions with a difference of ≥ 2% for Grade 3-4 toxicity are thrombocytopenia (13%, 9%), asthenia (7%, 4%), and hypokalemia (4%, 1%)

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.
• Diarrhea, decreased appetite, dehydration and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old who received ABRAXANE and gemcitabine in adenocarcinoma of the pancreas.

Renal Impairment

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

DOSAGE AND ADMINISTRATION

• For MBC and NSCLC, dose adjustment is recommended for patients with moderate and severe hepatic impairment. Withhold ABRAXANE if AST > 10 x ULN or if bilirubin > 5 ULN
• For adenocarcinoma of the pancreas, withhold ABRAXANE if bilirubin ≥ 1.26 x ULN or if AST > 10 x ULN.
• Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicity.
  Monitor patients closely.

Please see full Prescribing Information, including Boxed WARNING, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, please visit  http://www.celgene.com/pdfs/ABRAXANE_PI.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. For more information, please visit www.celgene.com.

SOURCE: Celgene