The Phase II data showed that the use of Nilotinib ( Tasigna ) in patients with Philadelphia chromosome-positive ( Ph+ ) chronic myeloid leukemia ( CML ) reduced or eliminated the presence of this defective chromosome in 51% of Imatinib-resistant patients in chronic phase of this disease and led to normalized white blood cell counts in 74% of these patients.

The study also showed a similar magnitude of elimination or reduction of these defective cells in 55% of intolerant patients.

The open-label study was designed to evaluate the safety and efficacy, as defined by hematologic ( normalization of white blood cell counts ) and cytogenetic ( reduction or elimination of the Ph+ chromosome ) response rates of Nilotinib-administered to Imatinib-resistant or intolerant patients with Ph+ CML in chronic phase and accelerated phase. The 316 chronic-phase patients in the Phase II study were heavily pre-treated for Ph+ CML, with a significant majority ( 72% ) having received at least 600 mg of Imatinib ( Glivec / Gleevec ) as well as having been treated earlier with Interferon ( 65% ) and Hydroxyurea ( 83% ).

Among 279 assessable patients ( i.e., those patients with at least six months of follow up ) with chronic-phase disease, major cytogenetic response was observed in 145 ( 52% ) of which 96 ( 34% ) were complete. Complete hematologic response was reported in 137 ( 74% ) of 185 assessable patients. In patients with at least 10 months follow up, the median time to cytogenetic response was 2.8 months ( range 1 to 11 ), and the median time to complete hematologic response was 1.0 ( range 1 to 8 ) months.

Among 64 patients with accelerated-phase disease, major cytogenetic response was observed after at least eight months follow-up in 23 ( 36% ), of which 14 ( 22% ) were complete. Confirmed hematologic response occurred in 38 ( 59% ), of which 15 ( 23% ) were complete. The median time to cytogenetic response was 2.0 months ( range 1 to 8 ), and the median time to complete hematologic response was 1.0 ( range 1 to 3 ) months.

The Phase II study showed an acceptable tolerability profile with a low incidence of events related to fluid retention such as edema, a side effect common with other tyrosine kinase inhibitors. The most frequent Grade 3 or 4 adverse events were primarily hematological in nature and include neutropenia and thrombocytepenia. Elevations were seen in bilirubin, liver function tests, lipase enzymes and blood sugar, which were mostly transient and resolved over time. These cases were easily managed and rarely led to discontinuation. Pancreatitis was reported in less than 1% of cases.

The study also showed virtually no non-hematologic cross-intolerance between Imatinib and Nilotinib. Causes of non-hematologic intolerance to Imatinib, which occurred in 95 patients, included Grade 3 or 4 rash/skin toxicity, fluid retention, gastrointestinal intolerance, liver toxicity, and myalgia/arthralgia. When treated with Nilotinib, none of these patients experienced severe rash/skin toxicity, fluid retention or myalgia/arthralgia. One patient each experienced severe gastrointestinal intolerance and liver toxicity.

Discovered in the biomedical research facilities of Novartis, Tasigna ( Nilotinib, formerly AMN107 ) entered Phase I clinical studies in 2004 just 21 months after it was first synthesized in August 2002.

Source: American Society of Hematology - Annual Meeting, 2006


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