E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Lympohid blast phase chronic myeloid leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (ALL) |
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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 complete and overall hematologic response rates to BMS-354825 in lymphoid blast phase CML subjects and Ph+ ALL subjects with primary or acquired resistance to imatinib mesylate. Overall hematologic response rate is defined as the proportion of treated subjects with best response of complete hematologic response (CHR) or no evidence of leukemia (NEL) or return to chronic phase (RTC). |
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E.2.2 | Secondary objectives of the trial |
1) To assess the durability of response and time to hematologic response (complete and overall) in the imatinib resistant group. 2) To assess cytogenetic and molecular responses in the imatinib resistant group. 3) To measure the response rates in each category: no evidence of leukemia and return to chronic phase. 4) To assess hematologic, cytogenetic and molecular responses in the imatinib intolerant group. 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. |
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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+) lymphoid 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 lymphoid blast phase CML if they meet at least one of the following criteria: •30% lymphoid blasts in peripheral blood or bone marrow •Extramedullary infiltrates of leukemic cells (other than in spleen or liver) with peripheral blood lymphoid blast morphology. OR Subjects with pH + ALL who experience progression or lack of response after both standard induction or consolidation chemotherapy plus imatinib at a dose of > 600 mg/day ( or 400mg/day to < 600 mg/day if the subject is intolerant of 600 mg/day) after 4 weeks. 2)ECOG performance status score 0 - 2 (See Appendix 1) 3)Adequate hepatic function defined as: •total bilirubin < or equal to 2.0 times the institutional upper limit of normal •alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < or equal to 2.5 times the institutional upper limit of normal 4)Adequate renal function defined as: •serum creatinine < or equal to 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 complete and overall hematologic response rates in the imatinib resistant groups. The complete hematologic response (CHR) rate is defined as the proportion of all treated subjects with best response of CHR. Overall hematologic response (OHR) rate is defined as the proportion of all treated subjects in each of the resistant groups with best response of complete hematologic response (CHR), no evidence of leukemia (NEL), or return to chronic phase (RTC). The secondary efficacy endpoints include duration of overall hematologic response, duration of complete hematological response, time to overall hematologic response, time to complete 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 rates of NEL and RTC will be computed. Response rates for imatinib intolerant subjects will also be estimated. The criteria for hematologic, cytogenetic, and molecular responses are defined in Section 3.3.1.
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 pharmacogenomics. |
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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 |