| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic myelogenous leukemia (CML) |
|
| E.1.1.1 | Medical condition in easily understood language |
| CML is a type of Philadelphia Chromosome positive leukaemia resulting due to changes in chromosones. It is characterized by the uncontrolled growth of white blood cells. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009012 |
| E.1.2 | Term | Chronic myelogenous leukemia |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Compare the rate of complete cytogenetic response (CCyR) at one year in chronic phase subjects receiving bosutinib alone versus chronic phase subjects receiving imatinib alone. |
|
| E.2.2 | Secondary objectives of the trial |
Estimate the major molecular response (MMR) rate at one year.
Estimate the duration of CCyR, CHR, and MMR.
Estimate the time to transformation to accelerated phase (AP) and blast phase (BP).
Assess the population PK of bosutinib.
Assess comparative safety of bosutinib vs. imatinib |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Cytogenetic diagnosis of chronic phase Ph+ CML diagnosed for ≤ 6 months.
2. Diagnosis of chronic phase as defined (prior to any anti-cancer treatment) by all of the following:
a. < 15% blasts in peripheral blood and bone marrow
b. < 20% basophils in peripheral blood and bone marrow
c. < 30% blasts + promyelocytes in peripheral blood and bone marrow
d. Platelets ≥ 100x1000000000/L
e. No extramedullary disease (except liver or spleen)
3. Adequate hepatic and renal function defined as:
a. AST/ALT ≤ 2.5 x upper limit of normal (ULN) or ≤ 5 x ULN if attributable to liver involvement of leukemia.
b. Total bilirubin ≤ 2.0 x ULN (unless associated with Gilbert’s syndrome)
c. Creatinine ≤ 1.5 x ULN
4. Able to take oral tablets.
5. ECOG performance status of 0 or 1.
6. Age ≥ 18 years (≥20 in Japan only).
7. Recovered to ≤ grade 1 or baseline from any toxicities of prior anti-cancer treatment.
8. Negative serum pregnancy test within two weeks of the first dose of test article if the subject is a woman of childbearing potential. A woman of childbearing potential is defined as one who is biologically capable of becoming pregnant. This includes women who are using contraceptives or whose sexual partners are either sterile or using contraceptives.
9. Willingness of all subjects who are not surgically sterile or postmenopausal to agree and commit to the use of a reliable method of birth control for the duration of the study and for 28 days after the last dose of test article. |
|
| E.4 | Principal exclusion criteria |
1. Philadelphia chromosome negative CML.
2. Prior anti-leukemia treatment. Up to six months of prior hydroxyurea or anagrelide treatment is allowed.
3. Identified stem cell donor with transplant planned within 12 months of randomization.
4. Prior stem cell transplant
5. Central nervous system (CNS) leukemia. (Subjects with symptoms of CNS leukemia must have a negative lumbar puncture prior to randomization)
6. Extramedullary disease only
7. History of accelerated or blast phase CML.
8. Major surgery or radiotherapy within 14 days of randomization.
9. Concomitant use of or need for medications known to prolong the QT interval
10. History of clinically significant or uncontrolled cardiac disease including:
• history of or active congestive heart failure
• uncontrolled angina or hypertension within 3 months
• myocardial infarction (within 12 months)
• clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes).
• diagnosed or suspected congenital or acquired prolonged QT syhistory of or prolonged QTc
• unexplained syncope
11. Prolonged QTc (> 0.45; average of triplicate readings at screening)
12. Recent or ongoing clinically significant gastrointestinal disorder.
13. Female subjects who are pregnant or breastfeeding.
14. Known seropositivity to HIV, current acute or chronic hepatitis B (hepatitis B surface antigen positive), hepatitis C, or cirrhosis.
15. History of another malignancy within 5 years with the exception of basal cell carcinoma or cervical carcinoma in situ or stage 1 or 2 cancer that is considered adequately treated and currently in complete remission for at least l2 months.
16. Uncontrolled hypomagnesemia or uncorrected hypokalemia due to potential effects on the QT interval.
17. History of radiation therapy to greater than 25% of bone marrow.
18. Congenital or acquired cytopenia predating CML diagnosis (e.g. congenital neutropenia or immune thrombocytopenia).
19. Unstable or severe uncontrolled medical condition, evidence of serious active infection, significant psychiatric illness, or any important medical illness or abnormal laboratory finding that would, in the investigator’s judgment, increase the risk associated with the subject’s participation in the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is Complete Cytogenetic Response (CCyR) at one year (48 weeks). The CCyR will be assessed for subjects in both arms via cytogenetic analysis conducted by labs local at study sites. To ensure reliable estimation of cytogenetic response, the cytogenetic assessment must have 20 or more metaphases. For post-baseline cytogenetic assessments, if fewer than 20 metaphases are available, then FISH analysis of bone marrow or peripheral blood, for the presence of Bcr-Abl fusion product, will be used if at least 200 cells are analyzed. In this study, a CCyR at 1 year is counted only if the response is demonstrated at the one year visit (week 48); a CCyR gained and lost before the one year visit is deemed a non-response. Further details are outlined in the statistical analysis plan. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Estimate the major molecular response (MMR) rate at one year.
• Estimate the duration of CCyR, CHR, and MMR.
• Estimate the time to transformation to accelerated and blast phases.
• Assess the population PK of bosutinib.
• Assess the comparative safety of bosutinib versus imatinib
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
# 1 year (Estimate the major molecular response (MMR))
# End of Study (Estimate the duration of CCyR, CHR, and MMR)
# End of Study (Estimate the time to transformation to accelerated and blast phases.)
# 3 months(Assess the population PK of bosutinib)
# 1 year and ongoing (Assess the comparative safety of bosutinib versus imatinib) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 65 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Belgium |
| Brazil |
| Canada |
| Chile |
| China |
| Colombia |
| France |
| Germany |
| Hong Kong |
| Hungary |
| India |
| Italy |
| Korea, Republic of |
| Latvia |
| Lithuania |
| Mexico |
| Netherlands |
| Peru |
| Poland |
| Romania |
| Russian Federation |
| Singapore |
| Slovenia |
| South Africa |
| Spain |
| Taiwan |
| Thailand |
| Turkey |
| Ukraine |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of the study is the last visit of the last subject. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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