Phase I study of Src/Abl tyrosine kinase inhibitor dasatinib [BMS-354825] in children and adolescents with relapsed or refractory leukemia, Protocol ITCC 005. Revised protocol #4, incorporating Amendments 01, 02, 03, and 04. - Protocol ITCC 005

• Register: EUCTR
• Last refreshed on: 7 January 2013
• Main ID: EUCTR2005-002882-35-IT
• Date of registration: 21/04/2006
• Prospective Registration: No
• Primary sponsor: BRISTOL-M.SQUIBB
• Public title: Phase I study of Src/Abl tyrosine kinase inhibitor dasatinib [BMS-354825] in children and adolescents with relapsed or refractory leukemia, Protocol ITCC 005. Revised protocol #4, incorporating Amendments 01, 02, 03, and 04. - Protocol ITCC 005
• Scientific title: Phase I study of Src/Abl tyrosine kinase inhibitor dasatinib [BMS-354825] in children and adolescents with relapsed or refractory leukemia, Protocol ITCC 005. Revised protocol #4, incorporating Amendments 01, 02, 03, and 04. - Protocol ITCC 005
• Date of first enrolment: 31/01/2006
• Target sample size: 56
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2005-002882-35
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: no Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: Placebo: Other: Number of treatment arms in the trial: 1

Countries of recruitment

Germany, Italy, United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
Diagnosis (see § 3.2.1 for definitions of resistance and intolerance): Stratum 1: Ph+ chronic myeloid leukemia in chronic phase with resistant or progressive disease during, or intolerance to, imatinib, including: i) failure to achieve, or loss of, complete hematologic response after ≥ 3 months of imatinib ii) failure to achieve major cytogenetic response [minor or equal to 35% Ph+ metaphases] after ≥ 6 months or complete cytogenetic response [0% Ph+ metaphases] after ≥ 12 months of imatinib iii) recurrence of Ph+ clone with ≥ 35% abnormal metaphases after prior major cytogenetic response to imatinib iv) increase in BCR-ABL signal by quantitative PCR of ≥ 1 logs, 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]. 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 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. 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. Age major or equal to 1 and < 21 years. Lansky or Karnofsky scale > 60 (see Appendix 1). Life expectancy > 3 weeks. 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. 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 ITCC-leukemia centers involved in this study. 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. 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: 0
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) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
Subjects for whom potentially-curative therapy is available, including electing immediate stem-cell transplantation 2. Extramedullary leukemia, specifically with a) symptomatic CNS involvement or b) isolated extramedullary disease, with < 5% blasts in marrow 3. Any serious uncontrolled medical disorder that would impair the ability of the subject to receive protocol therapy, including a) Ongoing uncontrolled infection b) Not recovered from acute toxicity of previous therapy c) Clinically-significant disorder of platelet function (e.g. von Willebrand's disease) or ongoing gastrointestinal bleeding d) Clinically-significant cardiovascular disease, congenital long QT syndrome, history of ventricular arrhythmias or heart block, or prolonged QTc interval > 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. Exception: 6-mercaptopurine or 6-thioguanine may be given up to 2 days before entry, if required. For concomitant use of corticosteroids or hydroxyurea, see §6.6. b) Any prior therapy with dasatinib [BMS-354825] 6. Subjects requiring ongoing medications which a) irreversibly inhibit platelet function, or anticoagulants [see §6.4.1]. (Does not apply to low-dose heparin for prophylaxis or to heparin flushes for i.v. lines) b) have a known risk of causing QTc prolongation 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 (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious disease) illness must not be enrolled into this study.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Children and adolescents, 1-20 years, with CML or relapsed Philadelphia positive ALL resistant or intolerant to imatinib or second or subsequent relapse of other ALL or AML
MedDRA version: 14.1 Level: HLGT Classification code 10024324 Term: Leukaemias System Organ Class: 10005329 - Blood and lymphatic system disorders

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Product Name: Dasatinib
Product Code: BMS-354825-03
Pharmaceutical Form: Tablet
INN or Proposed INN: Dasatinib
Concentration unit: mg milligram(s)
Concentration number: 5-

Trade Name: SPRYCEL
Pharmaceutical Form: Tablet
INN or Proposed INN: Dasatinib
Concentration unit: mg milligram(s)
Concentration number: 20-

Trade Name: SPRYCEL
Pharmaceutical Form: Tablet
INN or Proposed INN: Dasatinib
Concentration unit: mg milligram(s)
Concentration number: 50-

Primary Outcome(s)

Secondary Objective: To determine the adverse events and identify any dose-limiting toxicities of dasatinib in children and adolescents with CML in CP (Ph+; Stratum 1) or advanced leukemias (Strata 2/3 e 4 aggregated) 2) To estimate, by stratum, the rates of morphologic (major hematologic response; MaHR), cytogenetic (major cytogenetic response; MCyR; strata 1 e 2/3 only), and molecular (qPCR; subjects with MCyR only, 1 e 2/3 only) response to dasatinib 3) To describe, by stratum, time to response, response duration, progression-free survival, and survival in children and adolescents with relapsed or refractory leukemia treated with dasatinib 4) To estimate, as a function of dasatinib dose, plasma and (if applicable) cerebrospinal fluid pharmacokinetic parameters of dasatinib 5) Describe spectrum of mutations in BCR-ABL gene (strata 1 and 2/3) and in FLT and KIT genes (stratum 4) at baseline and at the end of treatment and explore role of mutations as predictor of response.

Main Objective: To establish, by stratum using a dose-finding design, a recommended dose of dasatinib [BMS-354825] in children and adolescents with relapsed or refractory leukemia

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 analysis will include frequency, severity and relatedness of all AEs, abnormal laboratory values, use of concomitant medications, and dose interruptions of 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.

Secondary ID(s)

2005-002882-35-DE

CA180-018