Expanding Nilotinib Access in Clinical Trials (ENACT) Study in Adult Patients (Pts) with Imatinib-Resistant or -Intolerant Chronic Myeloid Leukemia (CML) in Blast Crisis (BC), Accelerated Phase (AP), or Chronic Phase (CP): Preliminary Safety Analysis.

Background: Nilotinib is a novel, oral ATP-competitive inhibitor of BCR-ABL; it is significantly more potent (>30-fold) and selective than imatinib. ENACT is an ongoing multicenter, open-label, expanded-access study for pts with imatinib-resistant/intolerant CML in all phases. The primary objective is to evaluate the safety of nilotinib in these pts.

Methods: Pts with imatinib-resistant or -intolerant CML-CP, -AP, or -BC, who received prior therapies including imatinib and dasatinib were eligible to receive nilotinib 400mg twice daily (BID). Dose escalation was not permitted. Pts who required dose reduction due to toxicity were allowed to have a dose re-escalation to 400mg BID after resolution of the adverse events (AE) to ≤Grade 1, lack of response, or persistent disease at the investigator’s discretion.

Results: To date, 1152 pts have been enrolled. Results for the first 587 pts enrolled between January 2006 and January 2007 are presented, 582 received nilotinib and are included for safety analysis (BC n=73, AP n=62, CP n=447): median time since CML diagnosis 52.8 (2.5–468.6) mos; 68.4% were imatinib-resistant and 31.4% were imatinib-intolerant; median duration of nilotinib exposure was 77 days (overall), 84 days for CP, 71 days for AP, and 48 days for BC. At data cutoff (January 31, 2007), 425(73%) pts were continuing on nilotinib, 10% for ≥6 mos. The main reason for discontinuation was unsatisfactory therapeutic effect (11% overall), which as expected was most frequent in BC pts (n=23, 32%). Discontinuations due to AEs occurred in 7% of pts but did not differ significantly among the CML phases: BC 9 (12%); AP 5 (8%); CP 29 (7%). Of the safety population (N=582), 536 (92%) had AEs reported in the database. The incidence and severity of hematologic AEs were higher in BC or AP. Nonhematologic AEs were overall mostly mild to moderate and included headache, rash, nausea, pyrexia, elevated lipase, vomiting, hyperbilirubinemia and myalgia. Among the 536 pts with AEs reported, 15 (2.8%) deaths occurred, most frequently in pts with BC (n=9, 12.5%), rather than AP (n=3, 5.1%) or CP (n=3, 0.7%). The most frequent causes of death in BC were intracranial hemorrhage (n=4), infectious complications (n=2), CML (n=2), or respiratory failure (n=1). Among pts in AP or CP, deaths were attributed to disease progression (n=2), infectious complications (n=2), CML (n=1), or respiratory failure (n=1).

Conclusion: Preliminary analysis of this large expanded-access study further demonstrates that nilotinib is safe and well-tolerated in heavily pretreated pts with CML. Importantly, the occurrence of nonhematological AEs for CP, AP and BC pts enrolled in the study appear similar. Overall, both hematologic and nonhematologic AEs have been mild to moderate, and preliminary results from this safety study are consistent with previous published clinical experience with nilotinib phase I/II pivotal studies.