| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic phase Philadelphia-Chromosome Positive (Ph+) Chronic Myeloid leukemia (CML) |
|
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this study is to estimate the major cytogenetic response (MCyR) rates of BMS-354825 and imatinib at 800 mg daily at 12 weeks in subjects with chronic phase Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) who have disease that is resistant to imatinib. |
|
| E.2.2 | Secondary objectives of the trial |
1) To estimate the MCyR at any time (prior to crossover) in both treatment arms
2) To assess the durability of major cytogenetic response and time to MCyR prior to
cross over in both treatment arms
3) To estimate complete hematologic response (CHR) rate prior to crossover in both
treatment arms.
4) To assess the durability of CHR and time to CHR prior to crossover in both treatment arms
5) To estimate major molecular response rates by measuring BCR-ABL transcripts in
blood during treatment using quantitative RT-PCR prior to crossover
6) To estimate post-crossover efficacy endpoints in subjects who cross over
7) To assess the health-related quality of life in both treatment arms prior to crossover using the FACT-G
8) To assess further the safety and tolerability of BMS-354825
9) To collect blood samples for pharmacokinetic analysis of BMS-354825 given BID
that will contribute to population pharmacokinetic modeling. |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1- ECOG performance status score 0 - 1 (See Appendix 1)
2- Life expectancy of at least approximately 3 months
3-Subjects with chronic phase Ph+ CML, defined as a myeloproliferative disorder with evidence of a Philadelphia chromosome on cytogenetic analysis. Subjects meeting all of the following criteria will be classified as having chronic phase CML:
• < 15% blasts in peripheral blood and in bone marrow
• < 20% basophils in peripheral blood
• < 30% blasts + promyelocytes in peripheral blood and in bone marrow
• Platelets ≥ 100,000/mm3 unless thrombocytopenia is due to recent therapy
• No extramedullary involvement (other than liver or spleen)
4- Subjects must fulfill all of the following criteria relating to prior treatment with
imatinib:
A. Has not previously been treated with imatinib at a dose greater than 600 mg/day
B. Developed resistance to disease while receiving an imatinib dose 400-600 mg/day
C. Able to tolerate chronic administration of imatinib at the highest dose the subject
has received in the past
5- Adequate hepatic function defined as:
• total bilirubin ≤ 2.0 times the institutional upper limit of normal
• alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times the institutional upper limit of normal
6- Adequate renal function defined as:
• serum creatinine ≤ 1.5 times the institutional upper normal limit
7- Serum potassium and magnesium levels within institutional normal limits. Total
serum calcium or ionized calcium level must be greater than or equal to the lower
limit of normal.
8- Men and women, 18 years of age or older. |
|
| E.4 | Principal exclusion criteria |
1- Women who are pregnant or breastfeeding
2- WOCBP who are unwilling or unable to use an acceptable method to avoid
pregnancy for the entire study period for at least 1 month before and for at least 3
months after completion of the study medication.
3- Prior treatment with imatinib at a dose > 600 mg
4- Subjects who have previously identified BCR-ABL mutation in the following list will
be excluded (L248V, G250E, Q252H/R, Y253H/F, E255K/V, T3151/D, F317L,
H369P/R).
5- Previous diagnosis of accelerated phase or blast crisis CML.
6- Intolerance to imatinib at any dose.
7- Subjects who are eligible and willing to undergo transplantation during the screening period
8- A serious uncontrolled medical disorder or active infection which would impair the
ability of the subject to receive protocol therapy.
9- Uncontrolled or significant cardiovascular disease.
10-Uncontrolled hypertension
11- History of significant bleeding disorder unrelated to CML.
12- Subjects who received
a) imatinib within 7 days
b) interferon or cytarabine within 14 days
c) a targeted small molecule anti-cancer agent within 14 days, any other
investigational or antineoplastic agent other than hydroxyurea within 28 days before starting treatment with BMS-354825
13- Subjects currently taking the drugs that are generally accepted to have a risk of causing Torsade de Pointes
14- Subjects taking medications that irreversibly inhibit platelet function.
15- Prior therapy with BMS-354825.
16- Subjects taking medications known to be potent CYP3A4 inhibitors
or inducers
17-Evidence of organ dysfunction or any clinically significant deviation from normal in
physical examination, vital signs, ECG or clinical laboratory determinations unrelated
to CML that, in the judgment of the Investigator, would jeopardize subject safety
during participation in this study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy
The primary endpoint in this study is MCyR rates, at 12 weeks, to BMS-354825 and to imatinib at 800 mg daily. MCyR rate at 12 weeks is defined as the proportion of all randomized subjects at 12 weeks with best response of complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR).
The secondary efficacy endpoints include MCyR rate at any time prior to cross over, CHR rates, duration of MCyR and CHR, time to MCyR and CHR prior to crossover for both arms.
Safety/Toxicity
Analysis of safety will be performed on the dataset of all treated patients, by arm as
treated for events that have occurred prior to crossover. In addition, safety analyses will be conducted for events that have occurred after crossover on the dataset of subjects that have crossed-over to Imatinib and, separately, on the dataset of subjects that have crossed over to BMS-354825. Descriptive statistics will be employed in the analysis of all safety and laboratory observations in this study.
Other secondary endpoints include pharmacokinetics. |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Exploratory Biomarkers and Outcome Research assessment (Health re. quality of life questionnaire) |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| 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.8.3 |
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.8.5 | The trial involves multiple Member States | Yes |
| 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 | Information not present in EudraCT |
| 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 |
|
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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
|
| Treatment will continue until disease progression, unacceptable toxicity, subject withdrawal or discontinuation of the study. Crossover or dose modification may occur in certain circumstances. Follow-up visits after last dose of study drug will be required at least every 4 weeks until all study related toxicities resolve to baseline or to ≤ CTC Grade 1, stabilize, or are deemed irreversible. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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