E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Subjects with Chronic Phase Philadelphia Chromosome or BCR-ABL Positive Chronic Myelogenous Leukemia who are resistant or intolerant to Imatinib Mesylate |
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MedDRA Classification |
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 efficacy of BMS-354825 as defined by MCyR when administered QD relative to BMS-354825 administered BID in the treatment of CP CML imatinib-resistant subjects. The QD schedule will be considered efficacious if it can be demonstrated that the true 6-month MCyR rate is no more than 15% less than that of the BID schedule.
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E.2.2 | Secondary objectives of the trial |
The main secondary objective is to estimate the difference of MCyR rates between the two TDD levels (MCyRR100 mg TDD minus MCyRR140 mg TDD) in the imatinib-resistant subjects.
Other secondary objectives are: 1) In the imatinib-resistant subjects, by TDD, schedule and arm • To estimate the rate of MCyR and CHR • To estimate the time to, and duration of MCyR and CHR • To evaluate PFS and OS 2) In the imatinib-intolerant subjects • To assess efficacy (MCyR and CHR) 3) In all treated subjects • To assess the safety of BMS-354825 by TDD, schedule and arm • To compare the rates of specific adverse events (e.g. fluid retention, pleural/pericardial effusion, myelosuppression, and dose reduction due to toxicity) between the two schedules and two TDD • To collect PK data and Heath Utility measurements by arm • To describe the spectrum of mutation and to explore the level of expression of the BCR-ABL gene |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Subjects with a myeloproliferative disorder defined as Ph+ (or BCR/ABL+) CP CML whose disease has primary or acquired hematologic resistance to imatinib mesylate or who are intolerant to imatinib mesylate are eligible. Subjects can be pretreated with IFN, standard chemotherapy or high-dose chemotherapy and stem-cell transplantation. Subjects considered to have Ph+ (or BCR/ABL+) CP CML must meet all the following criteria: • < 15% blasts in PB cells or BM • < 30% blasts + promyelocytes in PB cells or BM • < 20% basophils in PB cells • Platelets ≥ 100,000/mm³ (or less if related to prior drug therapy) • No extra-medullar involvement (except liver or spleen)
Subjects with previous history of AP or BP CML and subjects with clonal evolution are not eligible even if they still meet the criteria for CP as defined above. They are considered in cytogenetic AP.
2) ECOG performance status (PS) score 0 - 2 (See Protocol Appendix 1) 3) Adequate hepatic function defined as: • total bilirubin ≤ 2.0 times the institutional ULN • alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times the institutional ULN 4) Adequate renal function defined as: • serum creatinine ≤ 1.5 times the institutional ULN 5) Serum Na, K, Mg, P and total serum Ca or ionized Ca levels must be greater than or equal to the institutional lower limit of normal. Subjects with low K, Mg levels, total serum Ca and/or ionized Ca must be repleted to allow for protocol entry. 6) Men and women, 18 years of age and older |
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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 of at least one month before and for at least 3 months after completion of the study medication. 3) Women with a positive pregnancy test on enrollment or prior to study drug administration. 4) Subjects eligible for immediate autologous or allogeneic stem cell transplantation. 5) A serious uncontrolled medical disorder or active infection that would impair the ability of the subject to receive protocol therapy 6) Uncontrolled or significant cardiovascular disease (see Protocol section 5.2 for details) 7) History of significant bleeding disorder unrelated to CML 8) Clinically significant bleeding from the GI tract within 6 months 9) Concurrent incurable malignancy other than CML 10) Dementia or altered mental status that would prohibit the understanding or rendering of informed consent 11) Evidence of organ dysfunction or digestive dysfunction that would prevent administration of study therapy 12) Subjects who received any of the following: • imatinib mesylate within 7 days • interferon or cytarabine within 7 days • a targeted small molecule anti-cancer agent within 7 days • any other investigational or any antineoplastic agent other than hydroxyurea (HU) within 28 days 13) Subjects currently taking the following drugs that are generally accepted to have a risk of causing Torsades de Pointe (see Protocol section 5.2 for details) 14) Subjects who have discontinued any of these medications must have a wash-out period of at least 5 days or at least 5 half-lives of the drug (whichever is greater) prior to the first dose of BMS-354825. 15) Subjects taking medications that irreversibly inhibit platelet function or anticoagulants. Eligibility criteria for this study have been carefully considered to ensure the safety of the study subjects and to ensure that the results of the study can be used. It is imperative that subjects fully meet all eligibility criteria. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy:
The primary efficacy endpoint is the rate 6-month of MCyR.
Secondary efficacy endpoints include the rate of CHR, time to, and duration of MCyR and CHR, PFS and OS. Definitions of response and progression are detailed in Section 3.3 of the Protocol.
Safety/Toxicity:
Toxic effects will be assessed continuously. Safety and tolerability of BMS-354825 will be reported for all randomized subjects. Adverse events and other symptoms will be graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0.
Other Endpoints:
Additional secondary endpoints include the collection of pharmacokinetics (PK) data and Health Utility measurements, and the exploration of the spectrum of BCR-ABL mutations and of the level of expression of the BCR-ABL gene. |
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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 | 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 | Yes |
E.6.13.1 | Other scope of the trial description |
Health Utility data collection |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
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 | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
two-by-two factorial design |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
QD versus BID dosing regimen |
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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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 61 |
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 |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 7 |
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 | 7 |
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 |