Efficacy and Safety of Radotinib in Chronic Phase Chronic Myeloid Leukemia Patients with Resistance or Intolerance to BCR-ABL Tyrosine Kinase Inhibitors: Radotinib Phase 2 Clinical Trial

Radotinib is a novel, selective Bcr-Abl tyrosine kinase inhibitor (TKI) developed by IL-YANG Pharm, South Korea. Radotinib showed a good efficacy and safety profile to chronic myeloid leukemia (CML) in preclinical and phase 1 clinical studies. To investigate the clinical efficacy and safety of radotinib 400 mg twice daily, data from CML patients treated during phase 2 clinical trial are reported.

Philadelphia chromosome (Ph⁺)-positive chronic phase CML (CP-CML) patients who failed or were intolerable to TKIs (imatinib and/or dasatinib and/or nilotinib) were enrolled between July 2009 and November 2011. Patients were treated with radotinib 400 mg twice daily for 12 cycles (1 cycle=4 weeks). The primary end point was an achievement of major cytogenetic response (MCyR, Ph⁺£35%) by 12 months. Safety parameters were also analyzed.

A total of 77 CP CML patients (18 years of age or over) were enrolled from 12 sites in Korea, India, and Thailand. This analysis includes data from last enrolled patient who received at least 3 months of radotinib therapy. The median age of patients was 47 (range; 24–76) years, and 65 (84.4%) were imatinib-resistant and 12 (15.6%) were imatinib-intolerant. Four patients also had intolerance to dasatinib. With a median follow-up of 10.6 months, treatment with radotinib is ongoing in 46 patients (59.7%) and 31 patients (40.3%) discontinued the treatment including two deaths (2.6%). However, there were no CML-related deaths. Median duration of radotinib exposure was 296 (8–798) days. Overall MCyR rate was 63.6%, including 35 patients (45.4%) complete cytogenetic response and 14 patients (18.2%) partial cytogenetic response. The median time to MCyR was 2.8 months (85 days) and the median duration of MCyR was 315 (range; 5–726) days. Of patients achieving complete cytogenetic response, 37% (13/35) achieved major molecular response. Within follow-up durations, 44 patients (57.1%) required dose interruption and 41 patients (53.3%) had dose reduction. Most common grade 3/4 hematologic and laboratory adverse events (AEs) were thrombocytopenia (27.3%), neutropenia (10.4%), anemia (6.5%), and hyperbilirubinemia (31.2%). Common non-hematologic AEs were rash (29.8%), fatigue (14.3%), nausea/vomiting (14.3%), headache (13.0%), and pruritus (11.7%). The majority of AEs were easily manageable with temporal dose interruption and/or reductions. In all patients with CP-CML treated with second-line radotinib, estimated progression-free survival and overall survival rate at 12months was 84.9% (95% CI, 72.7–92.0%) and 97.4% (95% CI, 89.9–99.3% ), respectively.

Radotinib phase 2 trial confirmed the efficacy and safety of radotinib 400 mg twice daily in patients with CP-CML after failure to TKIs. Most of the AEs occurred in the early treatment period, were tolerable, and were easily controlled by dose interruption or reduction.

Off Label Use: Radotinib, new BCR/ABL tyrosine kinase inhibitor, treatment for CML. Lee:IL-YANG Pharm.: Employment. Park:IL-YANG Pharm.: Employment. Woo:IL-YANG Pharm.: Employment. Kim:IL-YANG Pharm.: Employment. Lee:IL-YANG Pharm.: Employment. Cho:IL-YANG Pharm.: Employment. Shin:IL-YANG Pharm.: Employment. Kim:IL-YANG Pharm.: Employment. Kim:IL-YANG Pharm.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.