Follow-Up Results from Study Comparing SPRYCEL (dasatinib) to Imatinib in First-Line Treatment of Adults with Ph+ CP-CML Demonstrate Improved Response Rates Consistent with 12 Month Data
18-Month Data Presented at 52nd Annual Meeting of the American Society of Hematology
Results Further Support SPRYCEL 100mg Once Daily as First-Line Treatment Option for Patients with Ph+ CP-CML
PRINCETON, N.J. & TOKYO--(BUSINESS WIRE)--Dec 6, 2010 - Bristol-Myers Squibb Company (NYSE:BMY) and Otsuka Pharmaceutical Co., Ltd. today announced 18-month follow-up results from the Phase 3 DASISION study of SPRYCEL® (dasatinib) 100 mg once daily vs. imatinib (400 mg daily) in the first-line treatment of adults with Philadelphia chromosome-positive (Ph+) chronic phase chronic myeloid leukemia (CP-CML). Results at 18 months were consistent with 12 month data in which SPRYCEL demonstrated higher and faster rates of complete cytogenetic response (CCyR) and major molecular response 1 (MMR) compared to imatinib. Results from the 18-month follow up were presented today at the 52nd Annual Meeting of the American Society of Hematology.
Safety data from DASISION demonstrated that the most frequently reported serious adverse reactions with SPRYCEL included pleural effusion (2%), hemorrhage (2%), congestive heart failure (1%) and pyrexia ( 1%). Commonly reported adverse events (‰¥10%, of all grades) with SPRYCEL and imatinib included superficial edema (10% and 36%), pleural effusion (12% and 0%), myalgia (22% and 38%), nausea (9% and 21%), vomiting (5% and 10%), diarrhea (18% and 19%), fatigue (8% and 11%), headache (12% and 10%) and rash (11% and 17%). Overall rates of fluid retention observed in the study were 23% with SPRYCEL and 43% with imatinib.
“The follow up results from DASISION are important as they continue to support the use of SPRYCEL as a first-line treatment option for newly-diagnosed Ph+ CP-CML patients,” said Neil Shah, MD, PhD, Assistant Professor, Division of Hematology/Oncology, University of California, San Francisco, and presenter of the study results.
On October 28, 2010, the U.S. Food and Drug Administration (FDA) approved SPRYCEL 100 mg once daily for newly diagnosed adults with Ph+ CP-CML based on the twelve-month results from DASISION, which were published in the New England Journal of Medicine and presented at the 46th Annual Meeting of the American Society of Clinical Oncology earlier this year. The effectiveness of SPRYCEL is based on cytogenetic and major molecular response rates. The DASISION trial is ongoing and further data is required to determine long-term outcome.
Detailed Study Results From 18-Month Follow-Up
In the DASISION study, 78% of patients treated with SPRYCEL® (dasatinib) vs. 70% of patients treated with imatinib achieved confirmed CCyR (two consecutive assessments of CCyR at least 28 days apart) by 18 months (p=0.0366). MMR at any time was 57% for patients treated with SPRYCEL vs. 41% for patients treated with imatinib (p=0.0002). Transformation to accelerated or blast phase occurred in 6 patients receiving SPRYCEL and 9 patients receiving imatinib.
Pleural effusion (all grades) was reported in 12% of those treated with SPRYCEL, and in none treated with imatinib; Grade 3 pleural effusion was reported in <1% of patients receiving SPRYCEL. Thrombocytopenia occurred in 19% of those treated with SPRYCEL and 10% of those treated with imatinib. Neutropenia occurred in 22% of those treated with SPRYCEL and 20% of those treated with imatinib.
About the DASISION Study
DASISION (Dasatinib versus Imatinib Study in Treatment-Naïve CP-CML Patients) is an open-label, randomized, Phase 3 international trial of SPRYCEL 100 mg taken once daily vs. imatinib 400 mg taken once daily, in the treatment of newly diagnosed chronic phase Ph+ CML. The study enrolled 519 patients; 259 patients were randomized to receive SPRYCEL and 260 patients were randomized to receive imatinib. The primary study endpoint was the rate of confirmed CCyR by 12 months. Secondary endpoints included time-to confirmed CCyR, MMR rate and time-to MMR.
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+ CP-CML (chronic, accelerated, or myeloid or lymphoid blast phase) with resistance or intolerance to prior therapy including imatinib. Full approval was granted in May 2009. On October 28, 2010, the FDA approved SPRYCEL 100 mg once daily in newly diagnosed adults with Ph+ CP-CML. 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. About 24,800 people are living with the disease in the United States. It is estimated that 4,870 new cases will be diagnosed in 2010. CML occurs when pieces of two different chromosomes break off and attach to each other. The Philadelphia chromosome contains an abnormal gene called the bcr-abl gene. This gene produces the BCR-ABL protein, which causes the body to make too many abnormal white blood cells. There is no known cause for the genetic change that causes CML.
SPRYCEL® (dasatinib) INDICATION & 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
- Treatment with SPRYCEL 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 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
- SPRYCEL is associated with fluid
- 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 in these trials
- 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
- 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, the maximum mean changes in QTcF (90% upper bound CI) from baseline ranged from 7.0 ms to 13.4 ms
- In clinical trials of 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 and patients taking anti-arrhythmic drugs, other medicinal
products that lead to QT prolongation, and cumulative high-dose
- 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.
SPRYCEL 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
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
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 (e.g., 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
- 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
- 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 (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital), should be avoided. Alternative agents with less enzyme induction potential should be considered. If the dose of SPRYCEL® (dasatinib) is increased, the patient should be monitored carefully for toxicity
- St John's Wort may decrease SPRYCEL plasma concentrations unpredictably and should be avoided
- CYP3A4 inducers: If SPRYCEL must be administered with a CYP3A4 inducer, a dose increase in SPRYCEL should be considered.
- 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
- 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
- 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
The safety data reflect exposure to SPRYCEL 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
- 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 chronic phase CML 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 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
Please see the full Prescribing Information at www.SPRYCEL.com.
SPRYCEL is a registered trademark of Bristol-Myers Squibb Company.
About Bristol-Myers Squibb and Otsuka Pharmaceutical Co., Ltd.
Bristol-Myers Squibb and Otsuka Pharmaceutical Co., Ltd. are collaborative partners in the commercialization of SPRYCEL® (dasatinib) in the United States, Japan and major European countries. SPRYCEL was discovered and developed by Bristol-Myers Squibb.
Founded in 1964, Otsuka Pharmaceutical Co., Ltd. is a global healthcare company with the corporate philosophy: 'Otsuka-people creating new products for better health worldwide.' Otsuka researches, develops, manufactures and markets innovative and original products, with a focus on pharmaceutical products for the treatment of diseases and consumer products for the maintenance of everyday health. Otsuka is committed to being a corporation that creates global value, adhering to the high ethical standards required of a company involved in human health and life, maintaining a dynamic corporate culture, and working in harmony with local communities and the natural environment.
Otsuka Pharmaceutical Co., Ltd. is a wholly owned subsidiary of Otsuka Holdings Co., Ltd., the holding company for the Otsuka Group. The Otsuka Group comprises 145 companies and employs approximately 39,000 people in 23 countries and regions worldwide. Otsuka and its consolidated subsidiaries earned ¥1,084.2 billion (approx. US $11.7 billion) in annual revenues in fiscal 2009. Visit Otsuka Pharmaceutical Co., Ltd. at www.otsuka.co.jp/en.
1 Major molecular response (MMR) is defined as a BCR-ABL transcript level of ‰¤0.1% (3 log reduction) as measured by real-time quantitative polymerase chain reaction (RQ-PCR) of peripheral blood.
Contact: Bristol-Myers Squibb
Sarah Koenig, 609-252-4145
John Elicker, 609-252-4611
Otsuka America Pharmaceutical Inc.
David Caruba, 609-524-6798
Otsuka Pharmaceutical Co., Ltd.
Posted: December 2010