FDA Approved Drugs » 2006
Medical Areas: Oncology
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The following drug information is obtained from various newswires, published
medical journal articles, and medical conference presentations.
Company: Bristol-Myers Squibb
Approval Status: Approved June 2006
Treatment Area: Chronic Myeloid Leukemia
Sprycel is a multiply-targeted tyrosine kinase inhibitor.
Tyrosine kinases affect systems of cellular division and survival,
and are frequently over-expressed or abnormally active in cancer
cells. By targeting these systems, Sprycel is designed to reduce
the growth and viability of various types of cancer.
Sprycel is specifically indicated to treat adults with chronic,
accelerated, or myeloid or lymphoid blast phase chronic myeloid
leukemia (CML) with resistance or intolerance to prior therapy
including imatinib. It is also indicated for the treatment of
Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia
(ALL) with resistance or intolerance to prior therapy.
Sprycel is supplied as a white to off-white, biconvex,
film-coated tablet designed for oral administration. The
recommended initial dosing of Sprycel is 70 mg twice daily with or
without food. Incremental dose increase or decrease (in 20 mg
steps) is recommended based on individual safety and
Approval of Sprycel was based on four single-arm multicenter
studies which investigated the safety and efficacy of the drug in
treating imatinib-resistant or imatinib-intolerant CML and Ph+ ALL.
In all four trials, subjects received 70 mg Sprycel twice daily.
These trials were all ongoing at the time of approval. The four
studies each investigated the drug in the treatment of a single
Chronic Phase CML Study
This trial enrolled 186 patients with imatinib resistant (68%) or
intolerant (32%) chronic-phase CML. Subjects received treatment for
a median of 5.6 months (range: 0.03 to 8.3 months). Results yielded
efficacy in the trial's primary endpoint, with Sprycel
producing major cytogenetic response (MCyR) in 45% of subjects,
including complete cytogenic response (CCyR, defined as 0% Ph+
cells detected) in 33% of subjects. Further, complete hematologic
response (CHR) was achieved in 90% of subjects.
Accelerated Phase CML Study
This trial enrolled 107 patients with imatinib resistant (93%) or
intolerant (7%) accelerated-phase CML. Subjects received treatment
for a median of 5.5 months (range: 0.2 to 10.1 months). Results
yielded efficacy in the trial's primary endpoint, with Sprycel
producing major hematologic response (MaHR) in 59% of subjects,
including CHR in 33% of subjects and no evidence of leukemia (NEL)
in 26% of subjects. In addition, MCyR was achieved in 31% of
subjects, including CCyR in 21% of subjects.
Myeloid Blast Phase CML Study
This trial enrolled 74 patients with imatinib resistant (92%) or
intolerant (8%) myeloid-blast-phase CML. Subjects received
treatment for a median of 3.5 months (range: 0.03 to 9.2 months).
Results yielded efficacy in the trial's primary endpoint, with
Sprycel producing MaHR in 32% of subjects, including CHR in 24% of
subjects and NEL in 8% of subjects. In addition, MCyR was achieved
in 30% of subjects, including CCyR in 27% of subjects.
Lymphoid Blast Phase CML/Ph+ ALL Study
This trial enrolled 42 patients with imatinib resistant (92%) or
intolerant (8%) lymphoid-blast-phase CML, and 36 patients with
imatinib resistant (94%) or intolerant (6%) Ph+ ALL. CML subjects
received treatment for a median of 2.8 months (range: 0.1 to 6.4
months), and Ph+ ALL subjects received treatment for a median of
3.2 months (range: 0.2 to 8.1 months). Results yielded efficacy in
the trial's primary endpoint, with Sprycel producing MaHR in
31% of CML subjects and 42% of Ph+ ALL subjects, including CHR in
26% and 31% of subjects and NEL in 5% and 11% of subjects,
respectively. In addition, MCyR was achieved in 50% and 58% of
subjects, including CCyR in 58% and 58% of subjects.
Ongoing Study Commitments
Adverse events associated with the use of Sprycel may include,
but are not limited to, the following:
Myelosuppression was commonly reported, including serious or
severe neutropenia, thrombocytopenia, and anemia. The rate of
myelosuppression was higher in patients with accelerated phase or
myeloid blast phase CML or lymphoid blast phase Ph+ ALL than in
patients with chronic phase CML.
The effectiveness of Sprycel may be affected by concomitant
administration of other drugs:
Sprycel is believed to bind to multiple conformations of ABL
kinase. It has been shown to inhibit multiple tyrosine kinases at
nanomolar concentrations, including BCR-ABL, SRC family (SRC, LCK,
YES, FYN), c-KIT, EPHA2, and PDGFRß.
Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J,
Paquette R, Cortes J, O'Brien S, Nicaise C, Bleickardt E,
Blackwood-Chirchir MA, Iyer V, Chen TT, Huang F, Decillis AP,
Sawyers CL Dasatinib in imatinib-resistant Philadelphia
chromosome-positive leukemias. New England Journal of
Medicine 2006 Jun 15;354(24):2531-41
Bradeen HA, Eide CA, O'hare T, Johnson KJ, Willis
SG, Lee FY, Druker BJ, Deininger MW Comparison of
imatinib, dasatinib (BMS-354825), and nilotinib (AMN107) in an
n-ethyl-n-nitrosourea (ENU)-based mutagenesis screen: high efficacy
of drug combinations. Blood 2006 Jun 13
Tokarski JS, Newitt JA, Chang CY, Cheng JD, Wittekind M,
Kiefer SE, Kish K, Lee FY, Borzillerri R, Lombardo LJ, Xie D, Zhang
Y, Klei HE The structure of Dasatinib (BMS-354825) bound
to activated ABL kinase domain elucidates its inhibitory activity
against imatinib-resistant ABL mutants. Cancer Research
2006 Jun 1;66(11):5790-7
Chen Z, Lee FY, Bhalla KN, Wu J Potent
inhibition of platelet-derived growth factor-induced responses in
vascular smooth muscle cells by BMS-354825 (dasatinib). Mol
Pharmacology 2006 May;69(5):1527-33. Epub 2006 Jan 25
Schittenhelm MM, Shiraga S, Schroeder A, Corbin AS,
Griffith D, Lee FY, Bokemeyer C, Deininger MW, Druker BJ, Heinrich
MC Dasatinib (BMS-354825), a dual SRC/ABL kinase
inhibitor, inhibits the kinase activity of wild-type,
juxtamembrane, and activation loop mutant KIT isoforms associated
with human malignancies. Cancer Research 2006 Jan
For additional information regarding Sprycel or CML and Ph+ ALL,
please visit the Sprycel web page.
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