| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| 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 |
|
| E.1.1.1 | Medical condition in easily understood language |
Children and adolescents with CML in chronic, accelerated or blast
phase. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009700 |
| E.1.2 | Term | CML |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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 |
|
| E.2.2 | Secondary objectives of the trial |
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
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 <21 years
3. Lansky or Karnofsky scale ≥60 (see protocol Appendix 1)
4. Life expectancy >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.
|
|
| E.4 | Principal exclusion criteria |
1. Subjects for whom potentially-curative therapy is available, including electing immediate [i.e. planned < 45 days] stem-cell transplantation. Subjects in Stratum 1 should have an ongoing identical HLA donor search, and may discontinue study if a donor becomes available.
2. In contrast with patients with asymptomatic CNS disease (who are eligible), patients with symptomatic extramedullary leukemia are to be excluded. i.e., patients who have overt clinical symptoms (eg, convulsions) that are due to their CNS disease.
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 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. 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 |
|
| E.5 End points |
| E.5.1 | 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:
- Pharmacokinetic parameters will be evaluated by standard methods.
- Any correlation between Bcr-Abl mutation or expression and response to treatment pharmacodynamic markers of drug effect will be assessed. The spectrum of mutations at baseline and at end of treatmentwill be described.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| May 2011 (final data collection date for primary outcome measure) |
|
| E.5.2 | 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). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| 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 |
| The spectrum of mutations at baseline and at end of treatment will be described. |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| 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) | No |
| 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 | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
