E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Myeloid Blast Phase Chronic Myeloid Leukemia |
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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 and overall hematologic response rates to BMS-354825 in myeloid blast phase CML subjects with primary or acquired resistance to imatinib mesylate. The major hematologic response rate is defined as the proportion of all treated subjects with best response of complete hematologic response (CHR) or no evidence of leukemia (NEL). Overall hematologic response (OHR) rate is defined as the proportion of treated subjects with best response of major or minor hematologic response. |
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E.2.2 | Secondary objectives of the trial |
1) To assess the durability of hematologic response and time to hematologic response (major and overall) in the imatinib resistant group. 2) To assess cytogenetic and molecular responses in the imatinib resistant group. 3) To measure the minor hematologic response rate in the imatinib resistant group. 4) To assess hematologic, cytogenetic and molecular responses in the imatinib intolerant group. Further, durability and time to hematologic response will be assessed. 5) To explore the role of BCR-ABL mRNA expression and point mutations in the BCR-ABL gene as predictors or surrogates of response. 6) To measure health-related quality of life (HRQOL) using the FACT-G. 7) To assess further the safety and tolerability of BMS-354825. 8) To assess the pharmacokinetics of BMS-354825 given every 12 hours on a continuous daily dosing schedule. 9) Population PK will be performed on samples from the initial 60 treated subjects. |
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
1) Subjects with Ph+ (or BCR/ABL+) myeloid blast phase chronic myeloid leukemia whose disease has primary or acquired hematologic resistance to imatinib mesylate or who are intolerant of imatinib mesylate. Subjects are considered to have myeloid blast phase CML if they meet at least one of the following criteria: • ≥ 30% myeloid blasts in peripheral blood or in bone marrow • Extramedullary infiltrates of leukemic cells (other than in spleen or liver) with eripheral blood myeloid blast morphology 2) ECOG performance status score 0 - 2 (See Appendix 1) 3) 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 4) Adequate renal function defined as: • serum creatinine ≤ 1.5 times the institutional upper normal limit 5) 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. 6) Men and women, 18 years of age or 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 1 month before and for at least 3 months after completion of the study medication. 3) Subjects who are eligible and willing to undergo transplantation during the screening period. 4) A serious uncontrolled medical disorder or active infection that would impair the ability of the subject to receive protocol therapy. 5) Uncontrolled or significant cardiovascular disease 6) Subjects who received: - imatinib mesylate within 7 days - interferon or cytarabine within 14 days - 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 7) Subjects currently taking drugs that are generally accepted to have a risk of causing Torsades de Pointes 8) Subjects taking medications that irreversibly inhibit platelet function 9) Prior therapy with BMS-354825. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy
The co-primary endpoints in this study are the major hematologic response rate and the overall hematologic response (OHR) rate in the imatinib resistant group. The major hematologic response rate is defined as the proportion of all treated subjects with best response of major hematologic response. The OHR rate is defined as the proportion of all treated subjects with best response of major or minor hematologic response. The secondary efficacy endpoints include duration of overall hematologic response, duration of major hematologic response, time to overall hematologic response, time to major hematologic response, major cytogenetic response rate, major molecular response rates and quality of life measures. Major cytogenetic response (MCyR) rate is defined as the proportion of all treated subjects with best response of complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). In addition, the minor hematologic response rate in the imatinib resistant group will be computed. Response rates for imatinib intolerant subjects will also be estimated. Results for resistant and intolerant subjects will be presented separately.
Safety/Toxicity
Toxic effects are a secondary study objective and will be assessed continuously. All subjects who receive any study drug will be evaluable for toxicity. Adverse events and other symptoms will be graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. Descriptive statistics will be employed in the analysis of all safety and laboratory observations in this study for each group and pooled.
Other secondary endpoints include pharmacokinetics and Biomarkers analyses. |
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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 | Information not present in EudraCT |
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 |
Exploratory biomarkers and Outcomes research assessment (Health re. quality of life questionnaire) |
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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 | 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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
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) | No |
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 |
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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
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The last visit of the last patient is defined as the last follow-up visit after the last dose of study drug. 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 (≤ CTC Grade 1), stabilize, or are deemed irreversible. |
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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 | 4 |
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 | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |