Five-Year Follow-Up Data for SPRYCEL (dasatinib) 100 mg Once Daily Demonstrated 78 Percent Overall Survival in Patients with Chronic-Phase Chronic Myeloid Leukemia Resistant or Intolerant to Gleevec®*

Results Presented at 47th Annual Meeting of the American Society of Clinical Oncology

PRINCETON, N.J.--(BUSINESS WIRE)--Jun 3, 2011 - Bristol-Myers Squibb Company (NYSE:BMY) and Otsuka America Pharmaceutical, Inc. today announced five-year follow-up results from a Phase 3 randomized, open-label, dose-optimization study of SPRYCEL® (dasatinib) in Philadelphia chromosome-positive (Ph+) chronic-phase chronic myeloid leukemia (CP-CML) adult patients resistant or intolerant to Gleevec®* (imatinib mesylate). At five years, for patients randomized to receive SPRYCEL 100 mg once daily (n=167), overall survival was 78% (95% CI: 72%-85%) and progression-free survival was 57% (95% CI: 48%-67%). Five percent of patients (n=8) randomized to SPRYCEL 100 mg once daily progressed to accelerated or blast phase on study at 5 years of follow-up.

The five-year safety data from this study are consistent with the previously-reported safety profile of SPRYCEL 100 mg once daily. The cumulative incidence of grade 3/4 pleural effusion was 4%. Other grade 3/4 adverse events (AEs) with cumulative rates greater than or equal to 5% included neutropenia (36%), thrombocytopenia (24%), leukopenia (18%), and anemia (13%). The cumulative incidence rates of the most common non-hematological AEs of all grades at five years of follow-up were: headache (33%), diarrhea (28%), fatigue (26%), dyspnea (24%) and pleural effusion (24%).

These data were presented today at the 47th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago (Abstract #6512).

“In this study, the five-year follow up data demonstrated the long-term efficacy and consistent safety profile for SPRYCEL 100 mg once daily in patients with CP-CML following prior Gleevec therapy,” said Neil Shah, MD, PhD, Assistant Professor, Division of Hematology/Oncology, University of California, San Francisco and principal investigator of the study. “Results from this SPRYCEL study are important as they provide long-term follow up of patients with CP-CML treated with SPRYCEL who are resistant or intolerant to Gleevec.”

About Study CA180-034

Study CA180-034 was designed to assess the efficacy and safety of SPRYCEL 100 mg once daily. The trial enrolled 670 CP-CML patients with resistance (n=497) or intolerance (n=173) to Gleevec who were randomized to one of four treatment arms: 100 mg once daily (n=167), 50 mg twice daily (n=168), 140 mg once daily (n=167), and 70 mg twice daily (n=168). In this heavily pre-treated population, the median time from onset of CML to randomization in patients on the 100mg once daily arm was 55 months and 46% of these patients had more than three years of prior Gleevec treatment. Data on the primary endpoint of the study, major cytogenetic response in Gleevec-resistant patients, have been previously reported. Thirty-four percent of patients randomized to receive SPRYCEL 100 mg once daily remained on treatment at 5 years.

About SPRYCEL

Discovered and developed by Bristol-Myers Squibb, SPRYCEL initially received accelerated FDA approval in June 2006 as a treatment for adults for all phases of Ph+ CML (chronic, accelerated, or myeloid or lymphoid blast phase) with resistance or intolerance to prior therapy including Gleevec. Full approval was granted in May 2009. Since then, SPRYCEL has been approved for this indication in more than 60 countries worldwide.

In 2010, SPRYCEL 100 mg once daily was approved by the FDA and European Commission for the treatment of adult patients with newly diagnosed Ph+ CML in chronic phase. In the U.S., SPRYCEL received accelerated FDA approval for this indication. The effectiveness of SPRYCEL is based on cytogenetic response and major molecular response rates. The first-line trial (known as DASISION) is ongoing and further data will be required to determine long-term outcome. Now, more than 40 countries have approved SPRYCEL for this indication.

SPRYCEL is also approved for the treatment of adults with Ph+ acute lymphoblastic leukemia with resistance or intolerance to prior therapy.

About Chronic Myeloid Leukemia

CML is a slow-growing type of leukemia in which the body produces an uncontrolled number of abnormal white blood cells. According to the most recent statistics, about 24,800 people are living with the disease in the United States. It is estimated that 4,870 new cases were diagnosed in 2010. CML occurs when pieces of two different chromosomes break off and attach to each other. The new chromosome is called the Philadelphia-positive chromosome, which contains an abnormal gene called BCR-ABL that signals cells to make too many white blood cells. There is no known cause for the genetic change that causes CML.

SPRYCEL® (dasatinib) INDICATIONS & IMPORTANT SAFETY INFORMATION

INDICATIONS

SPRYCEL® (dasatinib) is indicated for the treatment of adults with:

 

  • Newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of SPRYCEL is based on cytogenetic and major molecular response rates. The trial is ongoing and further data will be required to determine long-term outcome
  • Chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib
  • Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy

IMPORTANT SAFETY INFORMATION

Myelosuppression:

 

  • Treatment with SPRYCEL® (dasatinib) can cause severe (NCI CTC Grade 3/4) thrombocytopenia, neutropenia, and anemia, occurring more frequently in advanced phase CML or Ph+ ALL than in chronic phase CML. Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities
    • Perform complete blood counts (CBCs) weekly for the first 2 months and then monthly thereafter, or as clinically indicated
    • Myelosuppression was generally reversible and usually managed by dose interruption, dose reduction, or discontinuation
    • Hematopoietic growth factor has been used in patients with resistant myelosuppression

Bleeding Related Events:

 

  • SPRYCEL(dasatinib) caused platelet dysfunction in vitro and thrombocytopenia in humans
    • In all clinical trials, severe central nervous system (CNS) hemorrhage, including fatalities, occurred in 1% of patients. Severe gastrointestinal (GI) hemorrhage, including fatalities, occurred in 4% of patients receiving SPRYCEL, which generally required treatment interruptions and transfusions. Other cases of severe hemorrhage occurred in 2% of patients
  • Most bleeding events were associated with severe thrombocytopenia
    • Exercise caution in patients required to take medications that inhibit platelet function or anticoagulants

Fluid Retention:

 

  • SPRYCEL is associated with fluid retention
    • In clinical trials fluid retention was severe in up to 10% of patients. Ascites (<1%),generalized edema (<1%), and severe pulmonary edema (1%) were also reported
  • Patients who develop symptoms suggestive of pleural effusion such as dyspnea or dry cough should be evaluated by chest X-ray
  • Severe pleural effusion may require thoracentesis and oxygen therapy
  • Fluid retention was typically managed by supportive care measures that included diuretics or short courses of steroids

QT Prolongation:

 

  • In vitro data suggest that SPRYCEL (dasatinib) has the potential to prolong cardiac ventricular repolarization (QT interval)
  • In 865 patients with leukemia treated with SPRYCEL in five phase 2 single-arm studies, themaximum mean changes in QTcF (90% upper bound CI) from baseline ranged from 7.0 ms to13.4 ms
  • In clinical trials of CML patients treated with SPRYCEL (N=2440), 15 patients (<1%) had QTc prolongation as an adverse reaction. Twenty-two patients (1%) experienced a QTcF >500 ms
  • Administer SPRYCEL with caution to patients who have or may develop prolongation of QTc, including patients with hypokalemia, hypomagnesemia, or congenital long QT syndrome andpatients taking anti-arrhythmic drugs, other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy
    • Correct hypokalemia or hypomagnesemia prior to SPRYCEL administration

Congestive Heart Failure, Left Ventricular Dysfunction, and Myocardial Infarction:

Cardiac adverse reactions were reported in 5.8% of 258 patients taking SPRYCEL, including 1.6% of patients with cardiomyopathy, heart failure congestive, diastolic dysfunction, fatal myocardial infarction, and left ventricular dysfunction. Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately.

Pregnancy:

SPRYCEL (dasatinib) may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of SPRYCEL in pregnant women. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant when taking SPRYCEL.

Nursing Mothers:

It is unknown whether SPRYCEL is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue SPRYCEL.

Drug Interactions:

SPRYCEL is a CYP3A4 substrate and a weak time-dependent inhibitor of CYP3A4

 

  • Drugs that may increase SPRYCEL plasma concentrations are:
    • CYP3A4 inhibitors: Concomitant use of SPRYCEL and drugs that inhibit CYP3A4 should be avoided. If administration of a potent CYP3A4 inhibitor cannot be avoided, close monitoring for toxicity and a SPRYCEL dose reduction or temporary discontinuation should be considered
      • Strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin,atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). If SPRYCEL must be administered with a strong CYP3A4 inhibitor, a dose decrease should be considered
      • Grapefruit juice may also increase plasma concentrations of SPRYCEL and should be avoided
  • Drugs that may decrease SPRYCEL plasma concentrations are:
    • CYP3A4 inducers: If SPRYCEL must be administered with a CYP3A4 inducer, a dose increase in SPRYCEL should be considered.
      • Strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital), should be avoided. Alternative agents with less enzyme induction potential should be considered. If the dose of SPRYCEL is increased, the patient should be monitored carefully for toxicity
      • St John's Wort may decrease SPRYCEL plasma concentrations unpredictably and should be avoided
    • Antacids. Antacids may decrease SPRYCEL drug levels. Simultaneous administration of SPRYCEL and antacids should be avoided. If antacid therapy is needed, the antacid dose should be administered at least 2 hours prior to or 2 hours after the dose of SPRYCEL
    • H2 antagonists/proton pump inhibitors, such as famotidine and omeprazole. Long-term suppression of gastric acid secretion by use of H2 antagonists or proton pump inhibitors is likely to reduce SPRYCEL exposure. Therefore, concomitant use of H2 antagonists or proton pump inhibitors with SPRYCEL is not recommended
  • Drugs that may have their plasma concentration altered by SPRYCEL are:
    • CYP3A4 substrates such as simvastatin. CYP3A4 substrates with a narrow therapeutic index should be administered with caution in patients receiving SPRYCEL

Adverse Reactions:

The safety data reflect exposure to SPRYCEL (dasatinib) in 258 patients with newly diagnosed chronic phase CML in a clinical study (median duration of therapy was 18 months) and in 2182 patients with imatinib resistant or intolerant CML or Ph+ ALL in clinical studies (minimum of 2 years follow-up).

The majority of SPRYCEL-treated patients experienced adverse reactions at some time. Patients aged 65 years and older are more likely to experience toxicity. In the newly diagnosed chronic phase CML study, SPRYCEL was discontinued for adverse reactions in 6% of patients. In patients resistant or intolerant to prior imatinib therapy, SPRYCEL was discontinued for adverse reactions in 15% patients in chronic phase, 16% in accelerated phase, 15% in myeloid blast phase, 8% in lymphoid blast phase CML, and 8% in Ph+ ALL.

 

  • In newly diagnosed chronic phase CML patients:
    • The most frequently reported serious adverse reactions included pleural effusion (2%), hemorrhage (2%), congestive heart failure (1%), and pyrexia (1%)
    • The most frequently reported adverse reactions (reported in ‰¥10% of patients) included myelosuppression, fluid retention events (pleural effusion, superficial localized edema,generalized edema), diarrhea, headache, musculoskeletal pain, and rash
    • Grade 3/4 laboratory abnormalities included neutropenia (22%), thrombocytopenia (19%), anemia (11%), and hypophosphatemia (5%), hypocalcemia (3%), and elevated bilirubin (1%)
  • In patients resistant or intolerant to prior imatinib therapy:
    • The most frequently reported serious adverse reactions included pleural effusion (11%), gastrointestinal bleeding (4%), febrile neutropenia (4%), dyspnea (3%), pneumonia (3%), pyrexia (3%), diarrhea (3%), infection (2%), congestive heart failure/cardiac dysfunction (2%), pericardial effusion (1%), and CNS hemorrhage (1%)
    • The most frequently reported adverse reactions (reported in ‰¥20% of patients) included myelosuppression, fluid retention events, diarrhea, headache, dyspnea, skin rash, fatigue, nausea, and hemorrhage
    • Grade 3/4 laboratory abnormalities in chronic phase CML patients resistant or intolerant to prior imatinib therapy who received SPRYCEL 100 mg once daily included neutropenia (36%), thrombocytopenia (23%), anemia (13%), hypophosphatemia (10%), and hypokalemia (2%)
  • Grade 3/4 elevations of transaminase or bilirubin and Grade 3/4 hypocalcemia, hypokalemia and hypophosphatemia were reported in patients with all phases of CML, but were reported with an increased frequency in patients with myeloid or lymphoid blast phase CML
    • Elevations in transaminase or bilirubin were usually managed with dose reduction or interruption
    • Patients developing Grade 3/4 hypocalcemia during the course of SPRYCEL therapy often had recovery with oral calcium supplementation

The full Prescribing Information is available at www.bms.com.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol-Myers Squibb, visit www.bms.com, or follow us on Twitter at http://twitter.com/bmsnews.

About Otsuka America Pharmaceutical, Inc. (OAPI)

Otsuka America Pharmaceutical, Inc. (OAPI) is a successful, innovative, fast-growing healthcare company that commercializes Otsuka-discovered and other product opportunities in North America, with a strong focus on and commitment to neuroscience, cardiovascular, oncologic, and gastrointestinal therapeutic treatments. OAPI is dedicated to improving patients' health and the quality of human life. OAPI is part of the Otsuka Group companies. For more information, visit www.otsuka-us.com.

OAPI is a subsidiary of Otsuka America, Inc. (OAI), which is wholly owned by Otsuka Pharmaceutical Co., Ltd. (OPC).

Gleevec® is a registered trademark of Novartis AG.

SPRYCEL® is a registered trademark of Bristol-Myers Squibb Company.

Contact: Bristol-Myers Squibb
Media:
Sarah Koenig, 609-252-4145
sarah.koenig@bms.com
or
Investors:
John Elicker, 609-252-4611
john.elicker@bms.com
or
Otsuka
US:
Otsuka America Pharmaceutical Inc.
David Caruba, 609-524-6798
david.caruba@otsuka-us.com

 

 

Posted: June 2011

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