Nilotinib Responses and Tolerability Confirmed in North American Patients with Chronic Myeloid Leukemia (CML) From ENACT (Expanding Nilotinib Access in Clinical Trials).

Nilotinib is a potent and highly selective BCR-ABL kinase inhibitor, approved for the treatment of patients (pts) with Philadelphia chromosome-positive chronic myelogeneous leukemia (Ph+ CML) in chronic phase (CP) and accelerated phase (AP) who are resistant or intolerant to prior therapy, including imatinib.

The open label, multicenter ENACT study was initiated as a global expanded access program to obtain additional safety information in CML pts in a clinical practice setting outside of a registration study. This report focuses on a subset of patients enrolled in North America.

Adult patients with imatinib resistant or -;intolerant Ph+ CML-CP, AP or BC were admitted to the study. The definition of imatinib resistance and intolerance were the same as the pivotal phase II registration study and pts could have been previously treated with other TKIs in addition to imatinib. Patients with impaired cardiac function, concurrent severe medical conditions or taking prohibited medications were excluded. Pts received nilotinib 400 mg twice daily (BID). Dose escalation was not permitted. Pts who required dose reduction to 400 mg once daily due to toxicity were allowed to have a dose re-escalation to 400 mg BID after resolution of the adverse events (AEs), lack of response, or persistent disease at the investigator's discretion.

A total of 207 North American pts were enrolled in the ENACT study between 01/2006 and 10/2008, including 172 CP pts (83%), 15 AP pts (7%) and 20 BC pts (10%). The median age of all pts was 54 years; 53% were imatinib-resistant, 45% were imatinib-intolerant, and 1.4% were resistant/intolerant. The most common prior anti-neoplastic therapy (other than imatinib) was hydroxyurea (73% of CP pts, 87% of AP pts, and 90% of BC pts), followed by dasatinib (32% of CP pts, 40% of AP pts, and 30% of BC). At study completion, 100 pts (48%) were continuing on nilotinib and 107 pts (52 %) discontinued treatment; 29 (17%) CP pts, 7 (47%) AP pts, and 14 (70%) BC pts discontinued due to disease progression. There were a total of 7 (3.4%) deaths during the study. Patient disposition is summarized in Table 1. Median (range) duration of nilotinib exposure was 227 (1-807) days for CP pts, 78 (15-426) days for AP pts, and 73 (8-571) days for BC pts; median average dose intensity was 766, 785 and 766 mg/day, respectively. Thirty-five CP pts (20%), 3 AP pts (20%) and 6 BC pts (30%) had their dose reduced due to AE, while 75 CP pts (44%), 5 AP pts (33%), and 8 BC pts (40%) had their dose interrupted due to AE. Median duration of dose interruption due to AE was short (8 days for CP and BC pts and 3 days for AP pts). The most common grade 3/4 hematologic AEs suspected of being drug related were thrombocytopenia (12% of CP pts, 20% of AP pts, and 15% of BC pts) followed by neutropenia (9% of CP pts, 27% of AP pts, and 15% of BC pts). The most frequent non hematologic all grades AEs or lab abnormalities included rash, headache, nausea, fatigue and hyperbilirubinaemia, and all were slightly higher in North American patients compared with the overall ENACT population. No patients discontinued treatment due to pleural effusion and there was no incidence of QTcF prolongation > 500 msec. Overall, major cytogenetic responses (MCyR) rates were 49% in CP, 27% in AP and 20% in BC pts, while complete cytogenetic responses (CCyR) rates were 36% in CP, 7% in AP and 20% in BC pts.

ENACT is the largest dataset from a single CML study of the available TKIs that further demonstrates that nilotinib is generally well tolerated in pretreated patients in all phases of CML. The safety profile in this study is similar to that observed the pivotal phase II registration study, as are the cytogenetic response rates, with a maintenance of high dose intensity. This data supports the use of nilotinib at 400 mg BID as the recommended dose in these CML populations.

Powell:Novartis Pharmaceuticals: Research Funding. Khoury:BMS: Honoraria; Wyeth: Honoraria; Novartis Pharmaceuticals: Honoraria; Chemgenex: Honoraria; Genzyme: Honoraria. Rizzieri:Novartis Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau. Williams:Novartis Pharmaceuticals: Employment. Turner:Novartis Pharmaceuticals: Research Funding, Speakers Bureau; BMS: Research Funding, Speakers Bureau; wyeth: Research Funding.