Philadelphia Chromosome Positive CML Patients Without Optimal Response or Tolerance to Bcr-Abl TKI

This study is a multi-center, open-label, Phase 1/2 clinical trial of Radotinib HCl, a targeted anticancer agent that inhibits the Bcr-Abl oncoprotein. It is aimed at determining the optimal therapeutic dose and confirming safety and efficacy of Radotinib HCl. Phase 1 study began at St. Mary's hospital in Korea and Phase 2 study is ongoing at 9 Korean sites and about 7 sites in China, India and Thailand will take part in Phase 2. After determination of a safe and proper therapeutic dose in Phase 1, Phase 2 began continuously to evaluate efficacy in chronic and accelerated phases. Before the start of the Phase 2 trial, interim or final reports for the Phase 1 trial were reviewed by the Korean Food and Drug Administration.

Inclusion criteria

Phase I

• Age ≥ 18 years old
• Ph+ CML patients who are resistant at chronic, accelerate, and acute phase, or suboptimal responsive, or intolerant to imatinib or resistant or intolerant to at least one second-generation targeted anticancer agent while being resistant, suboptimal responsive, or intolerant to imatinib simultaneously.
• WHO Performance status of ≤2
• Patients must have the following laboratory values With normal liver and renal function
• Patients who have received interferon, other anti cancer drug or radiotherapy > 1 week prior to starting study drug.

Phase II

• Age ≥ 18 years old
• Ph+ CML patients in chronic or accelerated phase who are resistant or intolerant to Imatinib mesylate
• WHO Performance status of ≤2
• Patients must have the following laboratory values With normal liver and renal function
• Patients who have received interferon, other anti cancer drug or radiotherapy > 1 week prior to starting study drug.

Exclusion criteria

Phase I

• CNS infiltration
• Impaired cardiac function, including any one of the followings.

• LVEF <45% as determined by MUGA scan or echocardiogram
• Clinically significant resting bradycardia
• Severe GI disease that may cause drug absorption problem of study drug
• Use of therapeutic Warfarin
• Acute or chronic liver or renal disease
• Other concurrent severe and/or uncontrolled medical conditions
• Treatment with any hematopoietic colony-stimulating growth factors ≤1 week prior to starting study drug.
• Patients who are currently receiving treatment with medications have the potential to prolong the QT interval
• Patients who have received Imatinib, interferon, other anti cancer drug or chemotherapy ≤ 1 week
• Patients who have received Nilotinib and Dasatinib ≤4 weeks prior to starting study drug.
• Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy
• Patients who are pregnant or breast-feeding or adults of reproductive potential not employing an effective method of birth control.
• Patients not to agree using birth control during the study and for up 3 months following study completion.

• HIV infection

Phase II

• Blast phase CML
• CNS infiltration
• Impaired cardiac function, including any one of the following

• LVEF< 45% as determined by MUGA scan or echocardiogram
• Use of Cardiac pacemaker
• ST depression > 1mm in 2 or more leads and/or T wave inversions in 2 or more contiguous leads
• Congenital long QT syndrome
• History of, or presence of significant ventricular or atrial tachyarrhythmias
• Clinically significant resting bradycardia
• QTcF> 480 msec on screening ECG
• Right bundle branch block + left anterior hemiblock, Bifascicular block
• Angina pectoris
• Severe GI disease that may cause drug absorption problem of study
• Use of therapeutic Warfarin
• Acute or chronic liver or renal disease
• Other concurrent severe and/or uncontrolled medical conditions
• Treatment with any hematopoietic colony-stimulating growth factors ≤1 week prior to starting study drug.
• Patients who are currently receiving treatment with medications have the potential to prolong the QT interval
• Patients who have received Imatinib, interferon, other anti cancer drug or chemotherapy ≤ 1 week
• Patients who have received wide field radiotherapy ≤4 weeks prior to starting study drug.
• Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy
• Patients who are pregnant or breast-feeding or adults of reproductive potential not employing an effective method of birth control