Children and adolescents with CML in chronic, accelerated or blast phase who are resistant or intolerant to imatinib, or in first or subsequent relapse of Ph+ ALL after prior imatinib, or in second or subsequent relapse of other ALL or AML MedDRA version: 19.0 Level: LLT Classification code 10009700 Term: CML System Organ Class: 100000004864
Conditions
Interventions
Product Name: BMS-354825-03
Product Code: BMS-354825-03
Pharmaceutical Form: Tablet
INN or Proposed INN: DASATINIB
CAS Number: 302962-49
Sponsors
Bristol-Myers Squibb International Corporation
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Diagnosis [see §3.2.1 for definitions of resistance and intolerance]: a) Stratum 1: Ph+ chronic myeloid leukemia in chronic phase with resistant or progressive disease during, or intolerance to, imatinib, including: - failure to achieve, or loss of, complete hematologic response after =3 months of imatinib - failure to achieve major cytogenetic response [= 35% Ph+ metaphases] after = 6 months or complete cytogenetic response [0% Ph+ metaphases] after = 12 months of imatinib - recurrence of Ph+ clone with > 35% abnormal metaphases after prior major cytogenetic response to imatinib - increase in BCR-ABL signal by quantitative PCR of = 1 log, confirmed at = 6 week interval [must be discussed with Principal Investigator] [Note: subjects enrolled in Stratum 1 should have an ongoing search for an identical HLA donor while on study] b) Stratum 2/3: i) Ph+ advanced phase CML (accelerated phase (AP), myeloid blast phase (MBP), lymphoid blast phase (LBP)) resistant to imatinib; or ii) Relapsed or refractory Ph+ acute lymphoblastic leukemia (Ph+ALL) after imatinib; iii) Ph+ acute myeloid leukemia (Ph+AML) in second or subsequent relapse (= 25% blasts in bone marrow) after prior imatinib. [Note: For Strata 1 and 2/3: It is not required that imatinib be the most recent treatment. In addition, biopsy-proven isolated extramedullary leukemia, i.e. with negative BM, is permitted for all strata after discussion with Prinicipal Investigator] c) Stratum 4: Ph-negative acute leukemia, any cytopathologic subtype, in second or subsequent relapse [= 25% blasts in bone marrow] or refractory after 2 or more induction regimens and for whom no therapy of greater curative potential is available. 2. Age =1 and 3 weeks 5. Serum Ca2+ levels above institutional lower limit of normal; Na, K, Mg, Phos, AST, ALT, and Bilirubin = Grade 1, and BUN and Creatinine = Grade 2. 6. No organ toxicity = Grade 2 (except alopecia), and recovered from acute toxicity of previous therapy 7. Able to comply with scheduled follow-up at one of the centers involved in this study 8. Women of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to the start of study medication. WOCBP must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 3 months after the study in such a manner that the risk of pregnancy is minimized. 9. Azoospermic males are exempt from contraceptive requirements 10. Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with the study drug dasatinib plus 90 days (duration of sperm turnover) for a total of 90 days post-treatment completion. 11. Written informed consent from subject, or from parents or legal guardians for minor subjects, according to local law and regulation. Are the trial subjects under 18? yes Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. Subjects for whom potentially-curative therapy is available, including electing immediate [i.e. planned 450 ms (Fridericia correction) on baseline electrocardiogram 4. Expected non-compliance or unable to have regular follow-up due to psychological, social, familial or geographic reasons 5. Subjects who have received: a) Any investigational agent or any other anti-cancer agent within 14 days prior to treatment start. Imatinib mesylate may be continued up to 7 days before treatment start, or, in the presence of rising peripheral blast cells, imatinib may be continued up to 2 days before treatment start. If required for control of peripheral blast cells, hydroxyurea, corticosteroids, 6-mercaptopurine or 6-thioguanine may be given up to 2 days before treatment start. For concomitant use of corticosteroids, anagrelide or hydroxyurea, see §6.4.3. b) Any prior therapy with dasatinib 6. Subjects requiring ongoing medications which a) irreversibly inhibit platelet function, or anticoagulants [see Protocol section 6.4.1]. b) have a known risk of causing QTc prolongation [see Protocol section 6.4.1] 7. WOCBP with a positive pregnancy test prior to study drug administration, or who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 3 months after the study, or who are pregnant or breastfeeding 8. Prisoners or subjects who are compulsorily detained
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To establish, by stratum using a dose-finding design, a recommended Phase II dose of dasatinib [BMS-354825] in children and adolescents with relapsed or refractory leukemia ; Secondary Objective: 1. Determine the AEs & identify any dose-limiting toxicities (DLTs) of dasatinib in children a adolescents with CML in CP (Ph+; Stratum 1) or advanced leukemias (Strata 2/3 and 4 aggregated) 2. Estimate, by stratum, the rates of morphologic (major hematologic response, MaHR), cytogenetic (major cytogenetic response, MCyR; strata 1 & 2/3 only), & molecular (qPCR; subjects with MCyR only, 1 and 2/3 only) responses to dasatinib 3. Describe, by stratum, time to response, response duration, progression-free survival, & survival of children & adolescents with relapsed or refractory leukemia treated with dasatinib 4. Estimate, as a function of dasatinib dose, plasma & (if applicable) cerebrospinal fluid (CSF) pharmacokinetic parameters of dasatinib 5. Describe spectrum of mutations in BCR-ABL gene (strata 1 and 2/3) & in FLT3 & KIT genes (stratum 4) at baseline & at end of treatment & explore role of mutations as predictors of response ; Primary end point(s): Safety/Toxicity: Safety and tolerability of dasatinib will be reported for all treated subjects. Adverse events will be assessed continuously and graded according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Safety analyses will include frequency, severity and relatedness of all AEs, abnormal laboratory values, use of concomitant medications, and dose interruptions or reductions. Efficacy: Efficacy will be assessed, by stratum, for all patients with any disease evaluation after treatment start. Hematologic, cytogenetic and molecular responses will be recorded. Other endpoints will include: | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary efficacy endpoints: Best cytogenetic response at any time during study and time to best cytogenetic response (Strata 1 – 3), rates and durations of CCyR and MCyR (Strata 2 & 3), and Best hematologic response at any time during study, duration of CHR, PFS and OS by Stratum (all Strata);Timepoint(s) of evaluation of this end point: end of the study | — |
Countries
Austria, Belgium, Germany, Italy, United Kingdom
Contacts
Public ContactEU Start Up Department
Bristol-Myers Squibb International Corporation
Outcome results
None listed