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, 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.

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 PDGFRB.

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 two 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.

Dosing/Administration

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 Trial Results

Approval of Sprycel was based on four, single-arm, multicenter studies that 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 percent) or intolerant (32 percent) 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 percent of subjects, including complete cytogenic response (CCyR, defined as 0 percent Ph+ cells detected) in 33 percent of subjects. Further, complete hematologic response (CHR) was achieved in 90 percent of subjects.

Accelerated phase CML study
This trial enrolled 107 patients with imatinib resistant (93 percent) or intolerant (7 percent) 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 percent of subjects, including CHR in 33 percent of subjects and no evidence of leukemia (NEL) in 26 percent of subjects. In addition, MCyR was achieved in 31 percent of subjects, including CCyR in 21 percent of subjects.

Myeloid blast phase CML study
This trial enrolled 74 patients with imatinib resistant (92 percent) or intolerant (8 percent) 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 percent of subjects, including CHR in 24 percent of subjects and NEL in 8 percent of subjects. In addition, MCyR was achieved in 30 percent of subjects, including CCyR in 27 percent of subjects.

Lymphoid blast phase CML/Ph+ ALL study
This trial enrolled 42 patients with imatinib resistant (92 percent) or intolerant (8 percent) lymphoid-blast-phase CML, and 36 patients with imatinib resistant (94 percent) or intolerant (6 percent) 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 percent of CML subjects and 42 percent of Ph+ ALL subjects, including CHR in 26 percent and 31 percent of subjects and NEL in 5 percent and 11 percent of subjects, respectively. In addition, MCyR was achieved in 50 percent and 58 percent of subjects, including CCyR in 58 percent and 58 percent of subjects.