A Randomized Two-Arm, Multicenter, Open-Label Phase III Study of BMS-354825 Administered Orally at a Dose of 70 mg Twice Daily or 140 mg Once Daily in Subjects with Chronic Myeloid Leukemia in Accelerated Phase or in Myeloid or Lymphoid Blast Phase or with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia who are Resistant or Intolerant to Imatinib Mesylate.Revised Protocol 05, incorporating Administrative Letters 01, 02 and 03 and Amendments 01, 02, 03 and 04 (version 1.0, dated 28-Feb-2008)

Conditions: Subjects with Chronic Myeloid Leukemia (CML) in Accelerated Phase (AP) or in Myeloid (My) or Lymphoid (Ly) Blast Phase (BP) or with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL) who are Resistant or Intolerant to Imatinib Mesylate.

Registration Number: EUCTR2005-001169-32-AT

Lead Sponsor: Bristol-Myers Squibb International Corporation

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 540

Inclusion Criteria

1/ AP CML
Subjects with Ph+ (or BCR/ABL+) AP CML whose disease has primary or acquired hematologic resistance to imatinib mesylate or who are intolerant to imatinib mesylate.
Subjects are considered to have AP CML if they meet at least one of the following criteria:
• At least 15% to < 30% blasts in PB or in BM
• A sum of the percent of blasts and promyelocytes in PB or the BM = 30% (with < 30% blasts alone)
• = 20% basophils in PB or BM
•Platelets < 100,000/mm³ unrelated to prior drug therapy
Subjects may not have extra-medullar infiltrates of leukemic cells other than in spleen or liver.
In addition, the following subjects will be considered to be part of the AP CML population even if they do not reach the above threshold values of % blasts in PB or BM for accelerated phase (i.e. chronic phase by hematologic criteria):
• Subjects with clonal evolution (e.g. +8, +19, +Ph, iso17q, but not -Y only)
• Subjects with prior episode of AP (except those defined by elevated basophil count only) who achieved a hematologic response and subsequently progressed.
2/ BP CML
Subjects with Ph+ (or BCR/ABL+) MyBP or LyBP CML whose disease has primary or acquired hematologic resistance to imatinib mesylate or who are intolerant to imatinib mesylate.
Subjects are considered to have myeloid or lymphoid BP CML if they meet at least one of the following criteria:
• = 30% myeloid or lymphoid blasts in PB or in BM
• Extra-medullar infiltrates of leukemic cells, other than in spleen or liver, with myeloid or lymphoid blast morphology
Subjects with prior episode of BP who achieved a hematologic response and subsequently progressed but do not meet the criteria for BP CML as described above (i.e. in chronic or accelerated phase by hematologic criteria) will be considered to be part of the BP CML population.
Subjects with asymptomatic leptomeningeal leukemia are eligible (see Section 6.2.7).
3/ Ph+ ALL
Subjects with Ph+ (or BCR/ABL+) ALL whose disease has primary or acquired hematologic resistance to imatinib mesylate or who are intolerant to imatinib mesylate.
Subjects must have received at least one prior standard induction +/- consolidation chemotherapy regimen and not be eligible for immediate autologous or allogeneic stem cell transplantation.
Subjects with asymptomatic leptomeningeal leukemia are eligible (see Section 6.2.7).

Subjects characterisctics:
4) ECOG performance status (PS) score 0 - 2 (See Protocol Appendix 1)
5) 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
6) Adequate renal function defined as:
• serum creatinine = 3.0 times the institutional ULN
7) Serum Na, K, Mg, and Phos must be Grade 0-1. Total serum Ca or ionized Ca
levels must be greater than or equal to the institutional lower limit of normal.
8) Men and women, ages 18 and older.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

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. Subjects with active CNS involvement, i.e. resistant to intra-thecal chemotherapy or symptomatic (discuss with Medical Monitor).
6. A serious uncontrolled medical disorder or active infection that would impair the ability of the subject to receive protocol therapy
7. Uncontrolled or significant cardiovascular disease (see Protocol section 5.2 for details)
8. Dementia or altered mental status that would prohibit the understanding or rendering of informed consent
9. History of significant bleeding disorder unrelated to CML (see Protocol section 5.2 for details)
10. Concurrent incurable malignancy other than CML
11. Evidence of organ dysfunction or digestive dysfunction that would prevent administration of study therapy
12. Subjects who received any of the following:
•hydroxyurea within 2 days (unless WBC > 50,000/mm3)
•imatinib, interferon, 6-mercaptopurine or cytarabine within 7 days
•any investigational agent or other antineoplastic agent within 14 days
13. Subjects currently taking drugs that are generally accepted to have a risk of causing Torsades de Pointe (see Protocol section 5.2 for details)
14. Subjects taking medications that irreversibly inhibit platelet function or anticoagulants
15. Prior therapy with BMS-354825