General Information

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 tolerability.

Clinical Results

FDA Approval
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 disease subclass.

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

• Bristol-Myers Squibb has agreed to submit the complete study report (24 month follow-up) and data from the study, CA-180-015, a phase 2 multicenter study of dasatinib (BMS-354825) in subjects with Lymphoid Blast Phase Chronic Myeloid Leukemia or Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia resistant to high dose Imatinib Mesylate (Gleevec) or who are intolerant of Imatinib Mesylate.
  Protocol Submission: November 2004
  Study Start: January 2005
  Final Report Submission: June 2008
• Bristol-Myers Squibb has agreed to submit the complete study report and data from the study, CA-180-051, a single-dose, pharmacokinetic study of BMS-354825 in subjects with hepatic impairment compared to healthy adult subjects.
  Protocol Submission: May 2006
  Study Start: October 2006
  Final Report Submission: January 2009
• Bristol-Myers Squibb has agreed to submit the complete study report and data from the study, CA-180-021, an open-label, single-sequence study to evaluate the effect of ketoconazole on the pharmacokinetics of BMS-354825 in patients with advanced solid tumors.
  Protocol Submission: March 2005
  Study Start: July 2005
  Final Report Submission: December 2006

Side Effects

Adverse events associated with the use of Sprycel may include, but are not limited to, the following:

• Hemorrhage (including Gastrointestinal Bleeding)
• Fluid Retention (including Pleural Effusion)
• Febrile Neutropenia
• Infection
• Dyspnea
• Pneumonia
• Pyrexia
• Diarrhea
• Headache
• Musculoskeletal Pain

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 metabolized by the liver enzyme CYP3A4. Drugs which inhibit this enzyme (including but not limited to ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, atazanavir, indinavir, nefazodone, nelfinavir, saquinavir, telithromycin) may affect the pharmacokinetics of Sprycel and increase acute drug exposure. Concomitant administration of these medications should be avoided.
• Drugs which induce increased expression of CYP3A4 (including but not limited to dexamethasone, phenytoin, carbamazepine, rifampicin, and phenobarbital) may reduce levels of Sprycel. Alternative therapies and/or dose Sprycel dose adjustment is recommended.
• St. John's wort has been shown to unpredictably decrease Sprycel plasma levels, and should be avoided while on Sprycel therapy.
• Sprycel's solubility is Ph dependent. As such, use of antacids within 2 hours before or after Sprycel administration is not recommended. Use of long term acid reducers such as H2 blockers or proton pump inhibitors (including but not limited to famotidine or omeprazole) is not recommended while on Sprycel.

Mechanism of Action

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.

Literature References

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 1;66(1):473-81

Additional Information

For additional information regarding Sprycel or CML and Ph+ ALL, please visit the Sprycel web page.