Clinical trial NCT01602952: Philadelphia Chromosome Positive CML Patients Without Optimal Response or Tolerance to Bcr-Abl TKI
Official title: A Phase I/II Multicenter Study of IY5511HCl in Philadelphia Chromosome Positive Chronic Myeloid Leukemia Patients Without Optimal Response or Tolerance to Bcr-Abl Tyrosine Kinase Inhibitors (Imatinib and/ or Dasatinib, Nilotinib)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Leukemia
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Philadelphia Chromosome
Hematologic Diseases
Keywords: Radotinib
CML-CP, AP
Lead sponsor: Il-Yang Pharm. Co., Ltd.
Sponsor class: INDUSTRY
First posted: 2012-05-21
Enrollment: 85
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: A Phase I/II multicenter study of IY5511HCl in Philadelphia chromosome positive chronic myeloid leukemia patients without optimal response or tolerance to Bcr-Abl tyrosine kinase inhibitors (Imatinib and/ or Dasatinib, Nilotinib) In this study, The efficacy and safety of CML patients who are resistant or intolerable to imatinib in the Chronic and Accelerated phases.

Phase 1

1. To investigate the Maximum Tolerated Dose (MTD) and the Dose Limiting Toxicity (DLT) of oral Radotinib HCl bid (twice daily) in the Philadelphia chromosome-positive CML subjects who are resistant, 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.

Phase 2

1. To investigate safety of oral Radotinib HCl in CML patients who are resistant or intolerable to imatinib in the chronic and accelerated phases.
2. To evaluate hematologic and cytogenetic efficacy of oral Radotinib HCl in CML patients who are resistant or intolerable to imatinib in the chronic and accelerated phases.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

Phase I

1. Age ≥ 18 years old
2. 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.
3. WHO Performance status of ≤2
4. Patients must have the following laboratory values With normal liver and renal function
5. Patients who have received interferon, other anti cancer drug or radiotherapy \> 1 week prior to starting study drug.

Phase II

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

Exclusion Criteria:

Phase I

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

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

15. HIV infection

Phase II

1. Blast phase CML
2. CNS infiltration
3. 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
4. Severe GI disease that may cause drug absorption problem of study
5. Use of therapeutic Warfarin
6. Acute or chronic liver or renal disease
7. Other concurrent severe and/or uncontrolled medical conditions
8. Treatment with any hematopoietic colony-stimulating growth factors ≤1 week prior to starting study drug.
9. Patients who are currently receiving treatment with medications have the potential to prolong the QT interval
10. Patients who have received Imatinib, interferon, other anti cancer drug or chemotherapy ≤ 1 week
11. Patients who have received wide field radiotherapy ≤4 weeks prior to starting study drug.
12. Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy
13. Patients who are pregnant or breast-feeding or adults of reproductive potential not employing an effective method of birth control

Primary outcomes:
measure: To investigate the Maximum Tolerated Dose(Phase 1)
timeFrame: 12 month
measure: Rate of Complete hematologic response(CHR)(Phase 2)
timeFrame: 12 months
Secondary outcomes:
measure: To investigate the Dose Limiting Toxicity(Phase 1)
timeFrame: 12 months
measure: Rate of complete Cytogenetic Response(CCyR)(Phase 2)
timeFrame: 12 months
measure: Adverse events(Phase 1& Phase 2)
timeFrame: 12 months
measure: Progression-free survival or PFS
timeFrame: 12 months
Other outcomes:
Locations:
city: Mumbai
country: India
facility: Local institution
state: Maharashtra
city: Mumbai
country: India
facility: Local institution
state: Mazagaon
city: Daegu
country: Korea, Republic of
facility: Local institution
state: Buk-gu
city: Jeonju
country: Korea, Republic of
facility: Local institution
state: Deokjin-gu
city: Ulsan
country: Korea, Republic of
facility: Local institution
state: Dong-gu
city: Anyang-si
country: Korea, Republic of
facility: Local institution
state: Dongan-gu
city: Hwasun
country: Korea, Republic of
facility: Local institution
state: Hwasun-eup
city: Seoul
country: Korea, Republic of
facility: Local institution
state: Jongro-ku
city: Busan
country: Korea, Republic of
facility: Local institution
state: Seo-gu
city: Seoul
country: Korea, Republic of
facility: Seoul St. Mary's hospital
state: Seocho-gu
city: Suwon
country: Korea, Republic of
facility: Local institution
state: Yeongtong-gu
city: Bangkok
country: Thailand
facility: Local institution
state: Phyathai
Study officials:
affiliation: IL-YANG Pharmaceutical.Co.,Ltd.
name: IL-yang Pharm
role: STUDY_DIRECTOR
References:
citation: Kim SH, Menon H, Jootar S, Saikia T, Kwak JY, Sohn SK, Park JS, Jeong SH, Kim HJ, Kim YK, Oh SJ, Kim H, Zang DY, Chung JS, Shin HJ, Do YR, Kim JA, Kim DY, Choi CW, Park S, Park HL, Lee GY, Cho DJ, Shin JS, Kim DW. Efficacy and safety of radotinib in chronic phase chronic myeloid leukemia patients with resistance or intolerance to BCR-ABL1 tyrosine kinase inhibitors. Haematologica. 2014 Jul;99(7):1191-6. doi: 10.3324/haematol.2013.096776. Epub 2014 Apr 4.