Targeted Therapy
Nilotinib- Tasigna
Nilotinib (formerly known as AMN107) is a new molecule that was rationally designed to achieve an improved fit at the ABL binding site. Its molecular structure lessens mutation-induced interference with binding, which was seen in certain patient populations with Glivec resistance (data on file, Novartis Pharma AG, Basel, Switzerland). Nilotinib is a highly selective, orally bioavailable, small-molecule tyrosine kinase inhibitor that binds effectively to BCR-ABL and many BCR-ABL mutants that are resistant to Glivec®. Research studies have shown that nilotinib exhibits 10-50 times greater potency than Glivec in inhibiting the BCR-ABL kinase and has demonstrated antileukaemic activity in several cell lines resistant to Glivec.1 Additionally, preclinical efficacy data show that nilotinib has activity in 32 of 33 Glivec-resistant BCR-ABL mutants.2
In a phase 1 dose-escalation trial, 119 patients with Glivec-resistant CML or Ph+ ALL were assigned to receive nilotinib at 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, or 1200 mg once daily, or 400 mg or 600 mg twice daily. In this trial, preliminary phase 1 efficacy results showed rates of haematological response in CML patients with chronic-phase, accelerated-phase, and blast-crisis disease of 92% (11/12), 72% (33/46), and 39% (13/33), respectively. Rates of MCyR in chronic-phase, accelerated-phase, and blast-crisis disease were 35% (6/12), 20% (9/46), and 18% (6/33), respectively. In these patients, ABL mutations were observed in 45% of patients and response rates were similar in patients with or without these mutations.3
Safety results show that no dose-limiting effects were observed at doses of ≤600 mg/d; the most common AEs included myelosuppression, transient hyperbilirubinaemia, and rashes.3
Indication
Tasigna is indicated for the treatment of adults with chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (CML) with resistance or intolerance to prior therapy including imatinib. Tasigna is a next-generation tyrosine kinase inhibitor for Ph+ CML therapy, designed to meet the needs of patients who fail or become intolerant of imatinib therapy.
References:
1. Weisberg E, Manley PW, Breitenstein W, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell. 2005;7:129-141.
2. Manley PW, Mestan J, Cowan-Jacob S, et al. AMN107: inhibitory profile against non-mutated and mutated forms of the Bcr-Abl tyrosine kinase [abstract]. Paper presented at: Annual Meeting of the American Association for Cancer Research; April 20, 2005; Anaheim, Calif. Abstract 5985.
3. Kantarjian HM, Gattermann N, O’Brien S, et al. A phase II study of AMN107, a novel inhibitor of Bcr-Abl, administered to imatinib resistant and intolerant patients (pts) with chronic myelogenous leukemia (CML) in chronic phase (CP) [abstract]. J Clin Oncol. 2006;24(18S):345s. Abstract 6534.