A Phase 3 Study for the Efficacy and Safety of Radotinib in CP-CML Patients With Failure or Intolerance to Previous TKIs

A Phase 3 Multinational, Multi-center, Single-arm, Open-label Study for the Efficacy and Safety of Radotinib in Ph+ Chronic Phase Chronic Myeloid Leukemia Patients With Failure or Intolerance to Previous TKIs Therapy Including Imatinib

In a multinational, multicenter, single-arm, open-label and Phase III Radotinib clinical study, chronic phase Ph+ chronic myeloid leukemia patients with failure or intolerance to previous TKIs therapy including Imatinib will be recruited. In this phase 3 study, 173 subjects are expected to be enrolled in a single arm with the administration of Radotinib 400mg twice daily, which includes 10% of dropout rate.

Inclusion Criteria:

1. Male or female patients aged 18 years old

2. Chronic Phase Ph+ Chronic Myeloid Leukemia patients who failed or intolerance the previous TKIs therapy including Imatinib Imatinib

3. ECOG scale 0, 1 or 2

4. Chronic phase is defined as all of the following conditions that subjects meet.

   • Blast in peripheral blood and bone marrow <15%
   • The sum of blast and promyelocyte in peripheral blood and bone marrow <30%
   • Basophil in peripheral blood <20%
   • Platelets count ≥50 × 10^9/L (≥ 50,000/mm3) (But, transient prior therapy related thrombocytopenia [< 50 × 109/L (< 50,000/mm3)] is acceptable
   • No evidence of involvement of extramedullary leukemia other than enlargements of liver and spleen

5. Patients who have adequate organ functions as defined below:

   • Total bilirubin < 1.5 × upper limit of normal (ULN)
   • SGOT and SGPT < 2.5× ULN
   • Creatinine < 1.5 × ULN
   • Serum amylase and lipase ≤ 1.5 × ULN
   • Alkaline Phosphatase ≤ 2.5 × ULN (only if not related to the tumor)

6. Women of childbearing potential should have a negative serum or urine pregnancy test within 14 days of the enrollment.

7. Women of childbearing potential must be using an adequate method of contraception to avoid pregnancy throughout the study and for a period of at least 1 month (4 weeks) after the last dose of investigational product in such a manner that the risk of pregnancy is minimized.

Exclusion Criteria:

1. Patients who have been diagonised accelerated phase and blast crisis CML in previous therapy if only once.

2. Patients with CCyR at the time of screening

3. Any below impaired cardiac function:

   • LVEF <45% or < lower bound of normal limit of study site (whichever higher), confirmed by echocardiogram at the site

   • Patients who cannot have QT intervals measured according to ECG

   • Complete left bundle branch block

   • Patients with cardiac pacemakers

   • Patients with congenital long QT syndrome or the family history of known long QT syndrome

   • History of, or presence of symptomatic ventricular or atrial tachyarrhythmias

   • Clinically significant resting bradycardia (< 50 bpm)

   • The mean QTcF >450msec following three consecutive ECG tests at baseline

     : Screening test will be performed again for QTcF after the adjustment of electrolyte if QTcF >450msec and the electrolyte is not within the normal range.

   • Medical history of clinically confirmed myocardial infarction

   • Medical history of unstable angina (within last 12 months)

   • Other clinically significant cardiac disease

4. Patients with T315I point mutations

5. Patients with central nervous system involvement as cytopathologically confirmed

6. Severe or uncontrolled chronic disease

7. Significant medical history of congenital or acquired bleeding disorders that are not related to leukemia

8. Patients who previously received radiotherapy to at least 25% of the bodies with high portion of bone marrow

9. Patients who received the major surgery within 4 weeks before the initiation of the IP administration or who failed to recover from the surgery that was performed before then.

10. Patients who participated in other clinical study and are receiving any other IP.

11. Patients who cannot give consent to the clinical study.

12. Patients who have concurrently clinically significant primary malignancy

13. Patients currently receiving treatment with a strong CYP3A4 inhibitors or strong CYP3A4 inducers or therapeutic Cumarin derivatives and that can neither stop the administration of these drugs before the start of the IP administration nor switch to other drugs.

14. Patients who are currently receiving treatment with a medication that has the potential to prolong QT intervals and can neither stop the administration of the drugs before the start of the IP administration nor switch to other drugs. If subjects need to start such drug treatments during the study, they should contact the sponsor, IL-YANG PHARM. Co., Ltd.

15. Gastrointestinal disorder or gastrointestinal disease that may result in a significant change in the absorption of the investigational product

16. Medical history of acute or chronic pancreatitis within the past one year

17. Acute or chronic liver, pancreas, or severe kidney disease that are not associated with the disease

18. Patients known seropositive to human immunodeficiency virus (HIV), current acute or chronic hepatitis B (hepatitis B surface-antigen positive), hepatitis C, or cirrhosis. Inactive hepatitis B surface antigen (HBsAg) carriers, treated and stable hepatitis B (HBV DNA < 500 IU/mL or site specific local lab normal range lower limit assessed by investigator), and cured hepatitis C patients can be enrolled.

19. Women patients that meet the following conditions should be excluded from the clinical study.

    • Pregnancy
    • Breastfeeding
    • Pregnancy confirmed at screening pregnancy test
    • Women of childbearing potential who is unwilling to use an appropriate method of contraception during the study

20. Men patients who are unwilling to use and appropriate method of contraception during the study

21. Patients who have hypersensitivity to active ingredient or any of the excipients of this investigational product