Tasigna (nilotinib hydrochloride monohydrate) is an orally available signal transduction inhibitor of the Bcr-Abl kinase, c-kit and Platelet Derived Growth Factor (PDGF), all of which play a role in cell proliferation, cell migration, and angiogenesis.

Tasigna is specifically indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (CML) in adult patients resistant or intolerant to prior therapy that included imatinib.

Tasigna is supplied as a 400 mg tablet designed for oral administration. The recommended initial dose of the drug is 400 mg orally twice daily, at approximately 12 hour intervals. No food should be consumed at least two hours before and one hour after administration of Tasigna. Dose adjustments or modifications should be followed according to the label for subjects with ECGs with a QTc > 480 msec, for subjects with neutropenia and/or thrombocytopenia and for subjects with selected non-hematologic laboratory abnormalities. The concomitant use of strong CYP3A4 inhibitors and strong CYP3A4 inducers should be avoided.

FDA Approval
FDA approval of Tasigna was based on the results of a clinical trial. This open-label, multi-center trial enrolled subjects with imatinib-resistant or -intolerant CML with separate cohorts for chronic phase (CML-CP) and accelerated phase (CML-AP) disease. Overall 280 CML-CP subjects with a minimum follow-up of 6 months and 105 CML-AP subjects with a minimum follow-up of 4 months were enrolled. The efficacy endpoint in the CML-CP arm was unconfirmed major cytogenetic response (MCyR) which included complete and partial cytogenetic responses. A major cytogenetic response was observed in 40% of the subjects. Complete response was observed in 28% and partial response was observed in 12% of this group. The efficacy endpoint in the CML-AP arm confirmed hematologic response (HR), defined as either a complete hematologic response (CHR) or no evidence of leukemia (NEL). A confirmed hematologic response was observed in 26%, with 18% showing a complete hematologic response and 8% showing no evidence of leukemia. Median duration of response had not been reached at this time for either group. However, based on current data, 59% of the CML-CP subjects with a major cytogenetic response had a duration of response of at least 6 months and 63% of CML-AP subjects with a confirmed hematologic response had a duration of response of at least 6 months.

Ongoing Study Commitments

• Novartis has agreed to submit the complete study report (with at least 24 months follow-up of all patients) and data from study 2101, a phase 2 multicenter study of nilotinib in patients with imatinib resistant or intolerant chronic myeloid leukemia in chronic and accelerated phases respectively (arms 4 & 3, respectively).
  Protocol Submission: Study 2101 filed to IND 69,764 in April 2004
  Study Start: May 2004
  Final Report Submission: by August 2010
• Novartis has agreed to submit the completed study report and datasets for the hepatic impairment study.
  Protocol Submission: Study 2116 filed to IND 69,764 on 10/9/06
  Study Start: October 2006
  Final Report Submission: by June 2008
• Novartis has agreed to conduct a relative bioavailability study (using a liquid formulation as the reference).
  Protocol Submission: by August 2009
  Study Start: by November 2009
  Final Report Submission: by July 2010
• Novartis has agreed to Conduct a clinical study or studies to evaluate whether multiple doses of nilotinib alter the metabolism of a sensitive CYP2C9 substrate (for example, S-warfarin). If a significant interaction is demonstrated, additional clinical studies may be needed to evaluate whether multiple doses of nilotinib alter the metabolism of a sensitive CYP2C8 substrate (for example, repaglinide) and/or a sensitive CYP3A4 substrate (for example, midazolam).
  Protocol Submission: by July 2008
  Study Start: by September 2008
  Final Report Submission: by June 2009
• Novartis has agreed to conduct a clinical study to evaluate if H2 blockers/proton pump inhibitors alter the pharmacokinetics of nilotinib.
  Protocol Submission: by July 2008
  Study Start: by September 2008
  Final Report Submission: by June 2009

Adverse events associated with the use of Tasigna in CML-CP patients may include, but are not limited to, the following:

• Rash
• Pruritis
• Nausea
• Fatigue
• Headache
• Constipation
• Diarrhea
• Vomiting
• Thrombocytopenia
• Neutropenia

Adverse events associated with the use of Tasigna in CML-AP patients may include, but are not limited to, the following:

• Rash
• Pruritus
• Constipation
• Thrombocytopenia
• Neutropenia
• Pneumonia
• Febrile neutropenia
• Leukopenia
• Intracranial hemorrhage
• Elevated lipase
• Pyrexia

Tasigna (nilotinib hydrochloride monohydrate) is an orally available signal transduction inhibitor of the Bcr-Abl kinase, c-kit and Platelet Derived Growth Factor (PDGF). Nilotinib binds to and stabilizes the inactive conformation of the kinase domain of Abl protein. In vitro, nilotinib inhibited Bcr-Abl mediated proliferation of murine leukemic cell lines and human cell lines derived from Ph+ CML patients. In vivo, nilotinib reduced the tumor size in a murine Bcr-Abl xenograft model.

Breccia M, Cannella L, Nanni M, Stefanizzi C, Alimena G Nilotinib can override dasatinib resistance in chronic myeloid leukemia patients with secondary resistance to imatinib first-line therapy. Acta haematologica 2007;118(3):162-4. Epub 2007 Sep 20

Kantarjian HM, Giles F, Gattermann N, Bhalla K, Alimena G, Palandri F, Ossenkoppele GJ, Nicolini FE, O'Brien SG, Litzow M, Bhatia R, Cervantes F, Haque A, Shou Y, Resta DJ, Weitzman A, Hochhaus A, le Coutre P Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood 2007 Nov 15;110(10):3540-6. Epub 2007 Aug 22

Belloc F, Moreau-Gaudry F, Uhalde M, Cazalis L, Jeanneteau M, Lacombe F, Praloran V, Mahon FX. Imatinib and nilotinib induce apoptosis of chronic myeloid leukemia cells through a bim-dependant pathway modulated by cytokines Cancer biology & therapy 2007 Jun;6(6):912-9

Golemovic M, Verstovsek S, Giles F, Cortes J, Manshouri T, Manley PW, Mestan J, Dugan M, Alland L, Griffin JD, Arlinghaus RB, Sun T, Kantarjian H, Beran M AMN107, a novel aminopyrimidine inhibitor of Bcr-Abl, has in vitro activity against imatinib-resistant chronic myeloid leukemia. Clinical cancer research : an official journal of the American Association for Cancer Research 2005 Jul 1;11(13):4941-7

For addiitonal information regarding tasigna or chronic myelogenous leukemia, please visit the Tasigna web page.