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
Conditions
Interventions
Trade Name: Sprycel
Product Name: BMS-354825-03
Product Code: BMS-354825-03
Pharmaceutical Form: Tablet
INN or Proposed INN: Dasatinib
Sponsors
Bristol-Myers Squibb International Corporation
Eligibility
Sex/Gender
All
Inclusion criteria
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.
Exclusion criteria
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. 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of this study is to compare the efficacy of BMS-354825 when administered to subjects at 140 mg QD relative to BMS-354825 administered at 70 mg BID. The QD schedule will be considered similar (non-inferior) to the BID schedule if the lower bound of the 2-sided 95% CI (equivalently, 1-sided 97.5% CI) of the difference [MHR(QD) - MHR(BID)] is =-12%. ; Secondary Objective: 1)Estimate MHR difference between treatment arms by disease group & imatinib status. 2)Estimate the rates of MHR, overall Hematologic Response (OHR), & major cytogenetic response (MCyR) by treatment arm, disease group, & imatinib status. 3)Assess time and duration of, MHR & OHR by treatment arm, disease group, & imatinib status. 4)Assess progression-free & overall survival by treatment arm, disease group & imatinib status 5)Assess safety of BMS-354825, in particular the incidence of major adverse events, # of dose reductions, interruptions & treatment discontinuations for toxicity by arm 6)Assess population pharmacokinetic data 7)Describe the spectrum of mutations at baseline & at time of PD. 8)Explore the roles of BCR-ABL mRNA expression & point mutations in the BCR-ABL gene as predictors or surrogates of responses 9)Assess Health Utility data previously collected on study by using the EuroQoL (EQ-5D) ; Primary end point(s): Efficacy The primary efficacy endpoint for this study is the rate of MHR in each stratum. The secondary efficacy endpoints include the rates of OHR and CyR, the difference between arms of MHR rates, the time to and duration of MHR, progression-free and overall survival. The spectrum of mutations at baseline and at time of progressive disease will be described. Hea | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Progression free and overall survival;Timepoint(s) of evaluation of this end point: Timeframe: 81 months | — |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Czech Republic, Denmark, Finland, France, Germany, Greece, Hungary, Ireland, Israel, Italy, Korea, Republic of, Mexico, Netherlands, Norway, Peru, Philippines, Poland, Russian Federation, Singapore, South Africa, Spain, Sweden, Switzerland, Taiwan, Thailand, United Kingdom, United States
Contacts
Public ContactEU Study Start Up Unit
Bristol-Myers Squibb International Corporation
Outcome results
None listed