- Study results presented at the 48th Annual Meeting and Exposition of the
                   American Society of Hematology (ASH) -

    ORLANDO, Fla., Dec. 11 /PRNewswire-FirstCall/ -- Today, Bristol-Myers
Squibb Company (NYSE: BMY) announced results of a randomized Phase II study
showing that a substantial number of patients with chronic-phase chronic
myelogenous leukemia (CML) resistant to Gleevec achieved cytogenetic and
hematologic responses by three months and maintained these responses
through one year when treated with SPRYCEL. The open-label, multi-center
international trial was designed to examine the efficacy and safety of
SPRYCEL at 70 mg twice daily or an increased dose of Gleevec to 800 mg/day
(patients enrolled in the trial had been previously treated with Gleevec
less than or equal to 600 mg/day). Results were presented at the 48th
Annual Meeting and Exposition of the American Society of Hematology (ASH).
    Analysis of the data at three months and 15 months show that the number
of patients who achieved and maintained a major cytogenetic response
increased from 36 percent to 53 percent with SPRYCEL, and from 29 percent
to 33 percent with escalated doses of Gleevec.
    While the study was not powered to compare SPRYCEL to high-dose
Gleevec, analysis of the data after a median follow-up of 15 months show a
statistically significant difference between SPRYCEL and high-dose Gleevec
in progression-free survival (length of time during which the leukemia does
not progress) (p<0.0001), major and complete cytogenetic responses (p=0.023
and p=0.004, respectively) and major molecular response (p=0.038).
    "This study may help answer important questions about treating
resistant chronic-phase CML patients and suggests that physicians should
consider treatment with SPRYCEL in patients resistant to lower doses of
Gleevec," said Neil Shah, MD, PhD, Assistant Professor, Division of
Hematology/Oncology, University of California, San Francisco.
    Study Design and Results
    This international, open-label, randomized Phase II study (START R,
-017) was conducted in 23 countries. The study evaluated adult patients
with chronic-phase CML who had primary or acquired resistance to 400-600 mg
doses of Gleevec. Patients were randomized in a 2:1 ratio to start
treatment with SPRYCEL 70 mg twice a day (bid) (n=101) or Gleevec 400 mg
bid (n=49). The primary endpoint of the study was major cytogenetic
response rate at 12 weeks. Secondary efficacy endpoints included duration
of, and time to achieve, major cytogenetic response as well as complete
hematologic response. Major cytogenetic response is defined as complete (no
signs of Philadelphia chromosome-positive [Ph+] cells in the bone marrow)
plus partial (less than 35 percent of Ph+ cells in the bone marrow)
cytogenetic responses. Complete hematologic response is a measure of how
effective a treatment is in returning blood counts to normal and occurs
when blood counts appear normal and patients have no signs or symptoms of
disease.
    Important non-hematologic adverse events in the SPRYCEL arm included
diarrhea (35%), nausea (24%), pleural effusion (17%), superficial edema
(15%), vomiting (9%), pulmonary edema (3%), and muscle spasm (2%).
Important non- hematologic adverse events in the Gleevec arm included
superficial edema (39%), nausea (33%), diarrhea (29%), vomiting (25%), and
muscle spasm (12%). Grade 3 or 4 cytopenias observed in the SPRYCEL arm
included low absolute neutrophil blood count (59%), platelets (55%),
leukocytes (20%), and hemoglobin (18%). Grade 3 or 4 cytopenias observed in
the Gleevec arm included low absolute neutrophil white blood cells (39%),
leukocytes (16%), platelets (14%), and hemoglobin (8%).
    About SPRYCEL
    On June 28, 2006, the U.S. Food and Drug Administration (FDA) granted
accelerated approval of SPRYCEL, an oral inhibitor of multiple tyrosine
kinases, for the treatment of adults in all phases of CML (chronic,
accelerated, or myeloid or lymphoid blast phase) with resistance or
intolerance to prior therapy, including Gleevec. The FDA also granted full
approval of SPRYCEL for the treatment of adults with Philadelphia
chromosome- positive acute lymphoblastic leukemia (Ph+ ALL) with resistance
or intolerance to prior therapy. The effectiveness of SPRYCEL is based on
hematologic and cytogenetic response rates. There are no controlled trials
demonstrating a clinical benefit, such as improvement in disease-related
symptoms or increased survival.
    Resistance to Gleevec is often due to mutations of BCR-ABL, BCR-ABL
over- expression, or activation of new pathways. SPRYCEL is the first
approved oral multiple tyrosine kinase that, at nanomolar concentrations,
inhibits BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRB
kinases. By targeting these kinases, SPRYCEL inhibits the overproduction of
leukemia cells in the bone marrow of patients with CML and Ph+ ALL and
allows normal red cell, white cell, and blood platelet production to
resume.
    IMPORTANT SAFETY INFORMATION
    SPRYCEL is not recommended for use in pregnant women or those
contemplating pregnancy. Dasatinib may cause fetal harm. Sexually active
male/female patients taking SPRYCEL should use adequate contraception.
    Myelosuppression: Treatment with SPRYCEL is associated with severe CTC
Grade 3/4 thrombocytopenia, neutropenia, and anemia. Their occurrence is
more frequent in advanced 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 preexisting laboratory abnormalities.
Complete blood counts (CBC) should be performed weekly for the first 2
months and then monthly thereafter, or as clinically indicated. In clinical
studies, myelosuppression was managed by dose interruption, dose reduction,
or discontinuation of study therapy. Hematopoietic growth factor has been
used in patients with persistent myelosuppression.
    Hemorrhage: Dasatinib caused platelet dysfunction in vitro and
thrombocytopenia in humans. Severe CNS hemorrhage, including fatalities
occurred in 1% of patients. Severe GI hemorrhage occurred in 7% of patients
and generally required treatment interruptions and transfusions. Other
cases of severe hemorrhage occurred in 4% of patients. Most bleeding events
were associated with severe thrombocytopenia. Caution is advised in
patients required to take medications that inhibit platelet function or
anticoagulants.
    Fluid Retention: Fluid retention was severe in 9% of patients,
including pleural and pericardial effusions reported in 5% and 1%,
respectively. Severe ascites and generalized edema were each reported in
1%. Severe pulmonary edema was reported in 1% of patients. Patients who
develop symptoms suggestive of pleural effusion (dyspnea or dry cough)
should be evaluated by chest x-ray. Severe pleural effusion may require
oxygen therapy and thoracentesis. Fluid retention was typically managed by
supportive care measures that include diuretics or short courses of
steroids.
    QT Prolongation: In vitro data suggest that dasatinib has the potential
to prolong cardiac ventricular repolarization (QT interval). Nine patients
had QTc prolongation as an adverse event. Three patients (<1%) experienced
a QTcF >500 msec. SPRYCEL should be administered with caution in 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, or cumulative high-dose anthracycline therapy. Hypokalemia or
hypomagnesemia should be corrected prior to dasatinib administration.
    Drug Interactions: Dasatinib is a CYP3A4 substrate. Drugs that may
increase dasatinib concentrations are: CYP3A4 inhibitors (eg, ketoconazole,
itraconazole, erythromycin, clarithromycin, ritonavir, atazanavir,
indinavir, nefazodone, nelfinavir, saquinavir, and telithromycin).
Concomitant use of dasatinib and drugs that inhibit CYP3A4 should be
avoided. If systemic administration of a potent CYP3A4 inhibitor cannot be
avoided, close monitoring for toxicity and dose reduction should be
considered. Drugs that may decrease dasatinib concentrations are: CYP3A4
inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampicin,
phenobarbital). Alternative agents with less enzyme induction potential
should be used or a dose increase of SPRYCEL should be considered. St.
John's Wort (Hypericum perforatum) may decrease dasatinib plasma
concentrations unpredictably. Patients taking SPRYCEL should not take St.
John's Wort.
    Dasatinib is a time-dependent inhibitor of CYP3A4. Drugs that may have
their plasma concentration altered by dasatinib are: CYP3A4 substrates with
a narrow therapeutic index (eg, alfentanil, astemizole, terfenadine,
cisapride, cyclosporine, fentanyl, pimozide, quinidine, sirolimus,
tacrolimus, or ergot alkaloids [ergotamine, dihydroergotamine]) should be
administered with caution.
    Long-term suppression of gastric acid secretion by use of H2 blockers
or proton pump inhibitors (eg, famotidine and omeprazole) is likely to
reduce dasatinib exposure. Therefore, concomitant use of H2 blockers or
proton pump inhibitors with SPRYCEL is not recommended. The use of antacids
should be considered. 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.
    Nursing Mothers: Women who are taking SPRYCEL should avoid breast-
feeding.
    Adverse Reactions: The safety data reflect exposure to SPRYCEL in 911
patients with leukemia from one Phase I and five Phase II clinical studies.
The majority of SPRYCEL-treated patients experienced adverse drug reactions
at some time. Drug was discontinued for adverse drug reactions in 6% of
patients in chronic phase, 5% in accelerated phase, and 11% in myeloid
blast phase CML and in 6% in lymphoid blast phase CML or Ph+ ALL.
    The most frequently reported adverse events included fluid retention
events, such as pleural effusion, gastrointestinal events including
diarrhea, nausea, abdominal pain and vomiting and bleeding events. The most
frequently reported serious adverse events (SAEs) included pyrexia (9%),
pleural effusion (8%), febrile neutropenia (7%), gastrointestinal bleeding
(6%), pneumonia (6%), thrombocytopenia (5%), dyspnea (4%), anemia (3%),
diarrhea (2%), and cardiac failure (3%).
    Grade 3/4 elevations of transaminases or bilirubin were reported in all
patients, with increased frequency in patients with myeloid or lymphoid
blast CML or Ph+ ALL. Elevations in transaminases or bilirubin were managed
with dose reduction or interruption. Grade 3/4 hypocalcemia was reported in
patients with all phases of CML, but with an increased frequency in
patients with myeloid or lymphoid blast CML or Ph+ ALL. Patients developing
Grade 3/4 hypocalcemia during the course of SPRYCEL therapy often had
recovery with oral calcium supplementation.
    About Bristol-Myers Squibb
    Bristol-Myers Squibb is a global pharmaceutical and related health care
products company whose mission is to extend and enhance human life.
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    * Gleevec(R) is a registered trademark of Novartis AG

    Abstract #167

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