| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Myeloid Leukemia (CML) |
|
| E.1.1.1 | Medical condition in easily understood language |
| CML is a type of leukemia resulting due to changes in chromosones. It is characterised 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 | 16.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10054352 |
| E.1.2 | Term | Chronic phase chronic myeloid 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 |
| To compare the proportion of patients demonstrating Major Molecular Response (MMR) at 12 months (48 weeks) in the bosutinib arm with that of the imatinib arm in newly diagnosed Philadelphia chromosome positive (Ph+) chronic phase (CP) chronic myelogenous leukemia (CML) patients. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary:
•To evaluate MMR by 18 months in the bosutinib treatment group compared with the imatinib treatment group.
•To evaluate the duration of MMR in the bosutinib treatment group compared with the imatinib treatment group.
To estimate the proportion of patients demonstrating a cytogenic response (CCyR) by 12 months in both treatment groups.
•To evaluate the duration of CCyR in both treatment groups.
•To evaluate event free survival (EFS) in both treatment groups.
•To evaluate overall survival (OS) in both treatment groups.
•To assess the population pharmacokinetics (PK) of bosutinib administered once daily.
•To assess correlations between trough concentrations of bosutinib and key efficacy and safety parameters.
•To evaluate the safety profile of bosutinib and imatinib treatments.
Please see protocol for exploratory endpoints |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Main Inclusion Criteria:
1. Molecular diagnosis of CP CML of ≤ 6 months (from initial diagnosis).
• Diagnosis of CP CML with molecular confirmation by detection of BCR-ABL rearrangement at screening (cytogenetic assessment for Philadelphia chromosome is not required for enrollment); diagnosis of CP CML will be defined as all of the following:
(a) <15% blasts in peripheral blood and bone marrow;
(b) <30% blasts plus promyelocytes in peripheral blood and bone marrow;
(c) <20% basophils in peripheral blood;
(d) ≥100 x 109/L platelets (≥100,000/mm3);
(e) No evidence of extramedullary disease except hepatosplenomegaly; AND
(f) No prior diagnosis of AP or BP CML.
• Philadelphia chromosome status will be identified at screening. Both Philadelphia positive (Ph+) and Philadelphia negative (Ph-) patients may be included.
2. Adequate hepatic, renal and pancreatic function defined as:
• Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT) ≤2.5 x upper limit of normal (ULN) or ≤5 x ULN if attributable to liver involvement of leukemia.
• Total bilirubin ≤2.0 x ULN (unless associated with Gilbert’s syndrome).
• Creatinine ≤1.5 x ULN.
3. Ability to take oral tablets.
4. Eastern Cooperative Oncology Group (ECOG) Performance status of 0 or 1.
5. Age ≥ 18 years.
6. Negative serum pregnancy test within 2 weeks of the first dose of study drug if the patient is a woman of childbearing potential. A woman of childbearing potential is defined as a woman who is biologically capable of becoming pregnant. This includes women who are using contraceptives or whose sexual partners are either sterile or using contraceptives. Patients and patient's partners of childbearing potential (physcially able to have children) and who are sexually active must agree to use birth control consitently and correctly during the study and for at least 28 days after they have stopped taking the study drug.
7. Ability to provide written informed consent prior to any study related screening procedures being performed.
|
|
| E.4 | Principal exclusion criteria |
Main Exclusion Criteria:
1. Any prior medical treatment for CML including tyrosine kinase inhibitors (TKIs) with the exception of hydroxyurea and/or anagrelide treatment.
2. Any past or current CNS involvement, including leptomeningeal leukemia.
3. Hypersensitivity to the active substance or to any of the following excipients: Microcrystalline cellulose (E460), croscarmellose sodium (E468), poloxamer 188, povidone (E1201), magnesium stearate (E470b), polyvinyl alcohol, titanium dioxide (E171), macrogol 3350, Talc (E553b), iron oxide red (E172).
4. Extramedullary disease only.
5. Major surgery or radiotherapy within 14 days of randomization.
6. Concomitant use of or need for medications known to prolong the QT interval.
7. 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 history or prolonged QTc. (QTcF should not exceed 500 msec).
• Unexplained syncope.
8. Known seropositivity to human immunodeficiency virus (HIV), current acute or chronic hepatitis B (hepatitis B surface-antigen positive), hepatitis C, cirrhosis or evidence of decompensated liver disease.
9. Recent or ongoing clinically significant gastrointestinal (GI) disorder e.g. Crohn's Disease, Ulcerative Colitis or prior total or partial gastrectomy.
10. 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 12 months.
11. Uncontrolled hypomagnesemia or uncorrected hypokalemia, due to potential effects on the QT interval.
12. Current, or recent (within 6 months), participation in other clinical trials.
13. Women who are pregnant, planning to become pregnant during the study or are breastfeeding a child, or men who are planning to father a child during their participation in this study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy:
Primary Efficacy Endpoint:
The primary efficacy endpoint is MMR at 12 months (48 weeks). All Ph+ patients harboring either the b2a2 or b3a2 p210 transcript will be assessed and followed-up for MMR as the primary endpoint.
* MMR is defined as BCR-ABL1 ≤0.1% on the international scale (IS) by
real-time quantitative polymerase chain reaction (RQ-PCR).
Safety:
Safety will be assessed on an ongoing basis by physical examination including measurement of vital signs, laboratory assessments, standard safety evaluations (electrocardiograms [ECGs] for monitoring of QTc interval changes and echocardiograms/MUGA scans for monitoring ventricular function) and recording of adverse events (AEs) and serious
adverse events (SAEs). Adverse events will be graded according to the NCI CTC version 4. Discontinuations due to AEs will be considered the main comparative safety endpoint for AEs. In addition standard laboratory assessments will be performed. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
• Hematology including CBC with differential will be conducted weekly for first 4wks, every 2wks during Months 2 and 3, then monthly until 12 Month visit (Wk48). In the follow up phase the Investigator should continue to perform chemistry and hematology testing per standard of care for CML patients and as clinically indicated in line with local guidelines, and at a minimum to reflect the schedule of assessments.
•Bone marrow aspirate and differential will be performed every 3 months for the first year until MMR is achieved; MMR is defined as BCR-ABL1 ≤0.1% BCR-ABL transcript on the international scale (IS) by real-time quantitative polymerase chain reaction (RQ PCR). Once MMR has been achieved, bone marrow aspirates will be performed only if clinically indicated. |
|
| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints:
• MMR by 18 months.
• Duration of MMR.
• CCyR by 12 months .
• Duration of CCyR.
• EFS
• OS
Pharmacokinetic Endpoints
• Population PK of bosutinib.
• Correlations between trough concentrations of bosutinib and key
efficacy and safety parameters. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy data:
•MMR by 3, 6 and 9 months, MMR at 18 months and beyond 12 months.
•Both ≥ 4 and ≥ 4.5 log reduction in BCR-ABL transcripts in bosutinib
treatment group with imatinib at 3, 6, 9, 12 months and beyond 12
months.
Pharmacokinetic Data (bosutinib treatment group only):
A total of 4 PK samples per patient will be drawn. All patients will provide pre-dose blood samples on Day 1, Day 28, Day 56, and Day 84.
|
|
| 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 | No |
| 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 | No |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 81 |
| 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 |
| Belgium |
| Canada |
| Denmark |
| France |
| Ireland |
| Italy |
| Netherlands |
| New Zealand |
| Norway |
| Slovakia |
| Sweden |
| Australia |
| Brazil |
| Czech Republic |
| Finland |
| Germany |
| Hungary |
| Korea, Republic of |
| Spain |
| Israel |
| Mexico |
| Poland |
| Russian Federation |
| Singapore |
| Taiwan |
| Ukraine |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
|
| 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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