| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Children and Adolescents with Ph+ Leukemia with Resistance or Intolerance to Imatinib |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10034877 |
| E.1.2 | Term | Philadelphia chromosome positive |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10024329 |
| E.1.2 | Term | Leukemia |
|
| 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 |
| The primary objective is to estimate the MCyR rate to dasatinib therapy in children and adolescents with CP-CML, and the CHR rate in children and adolescents with Ph+ ALL, AP- and BP-CML, who are resistant, intolerant to, or relapse after prior imatinib therapy. |
|
| E.2.2 | Secondary objectives of the trial |
• To assess the safety and tolerability of dasatinib in children and adolescents treated with dasatinib for relapsed or refractory Ph+ leukemias
• To evaluate additional measures of efficacy in children and adolescents with relapsed or refractory Ph+ leukemias treated on a given regimen of dasatinib including:
– best cytogenetic and hematological response rates
– time to response and duration of response
– progression-free survival (PFS) and overall survival (OS)
– rates of complete (CMR) and major (MMR) molecular response
• To describe the spectrum of the BCR-ABL mutations at baseline, at progression or
end of treatment, and to explore the role of mutations as predictors of response. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Signed Written Informed Consent
a) Written informed consent from subject, or from parents or legal guardians for
minor subjects, according to local law and regulation.
2) Target Population
a) Diagnosis:
i) Cohort #1: Subjects must have Ph+ CML in CP which is defined by the
presence of all the following criteria:
(a) < 15% blasts in peripheral blood and bone marrow
(b) < 20% basophils in peripheral blood
(c) < 30% blasts + promyelocytes in peripheral blood and bone marrow
(d) ≥ 100 X 109 platelets/L unless thrombocytopenia secondary to recent
treatment
(e) No extramedullary involvement other than liver or spleen
(f) Ph+ or variant must be demonstrated by bone marrow cytogenetics
ii) Cohort #2: Subjects must have Ph+ ALL or Ph+ AP- or BP-CML:
i. Ph+ ALL have to be in first or subsequent relapse [ ≥ 25% blasts in bone
marrow] or fail to achieve remission after imatinib
ii. AP-CML must meet at least one of the following criteria:
(a) ≥ 15% but < 30% blasts in peripheral blood or bone marrow
(b) ≥ 30% blasts + promyelocytes in peripheral blood and in bone marrow
(but percent alone has to be < 30%)
(c) ≥ 20% basophils in peripheral blood or bone marrow
(d) < 10 X 109/L platelets unrelated to therapy
iii. BP-CML has to meet all the following criteria:
(a) ≥ 30% blasts in peripheral blood or bone marrow
(b) Presence of extramedullary blastic disease other than lymph nodes,
liver or spleen
b) Subjects have to be proven resistant or intolerant to imatinib:
i) For both cohorts, intolerance to imatinib is defined as the occurrence of any
toxicity grade ≥ 3 considered at least possibly related to imatinib and that led
to discontinuation of previous imatinib therapy.
ii) For Cohort #1, resistance to imatinib must meet at least one of the following
criteria:
(a) Failure to achieve, or loss of, CHR after ≥ 3 months of imatinib at a
daily dose of 260 mg/m2 or greater;
(b) Failure to achieve MCyR after ≥ 6 months or CCyR after ≥ 12 months
of imatinib therapy at a daily dose of 260 mg/m2 or greater;
(c) Absolute increase of ≥ 30% of the percentage of Ph+ metaphases,
confirmed at ≥ 6 week interval, after prior MCyR to imatinib at a daily
dose of 260 mg/m2 or greater.
iii) For Cohort #2, resistance to imatinib must meet at least one of the following
criteria:
(a) Failure to achieve CHR while on imatinib after a ≥ 4-week treatment
or a ≥ 50% increase in peripheral blood blasts over a 2-week period
(b) Subjects who achieved a CHR subsequently no longer meet the criteria
consistently over a consecutive 2-week period while receiving imatinib
(c) Absolute increase of ≥ 30% of the percentage of Ph+ metaphases,
confirmed at ≥ 6 week interval, after prior MCyR to imatinib.
c) Lansky or Karnofsky scale > 50 (see Appendix 2)
d) Life expectancy ≥ 12 weeks
e) Subjects must have recovered to baseline or Grade 1 (NCI CTCAE, version 3.0)
from the toxicities (except alopecia) resulting from recent therapies, including
chemotherapy, hormonal therapy, immunotherapy, biological therapy or
investigational product and radiation therapy.
f) Serum Na, K, NaHC03, Mg, P and Ca levels within institutional normal limits
and AST, ALT, bilirubin, BUN or urea, creatinine ≤ Grade 2 (NCI CTCAE,
Version 3.0).
3) Age and Sex
a) Men and women, age ≥ 1 to < 21 years
Women of childbearing potential (WOCBP) must be using an adequate method of
contraception to avoid pregnancy throughout the study and for up to 4 weeks after
the last dose of investigational product in such a manner that the risk of pregnancy
is minimized. |
|
| E.4 | Principal exclusion criteria |
1) Sex and Reproductive Status
a) WOCBP who are unwilling or unable to use an acceptable method to avoid
pregnancy for the entire study period and for up to 4 weeks after the last dose of
investigational product.
b) Women who are pregnant or breastfeeding
c) Women with a positive pregnancy test on enrollment or prior to investigational
product administration.
d) Sexually active fertile men not using effective birth control if their partners are
WOCBP who are unwilling or unable to use an acceptable method to avoid
pregnancy for the entire study period and for up to 4 weeks after the last dose of
investigational product.
2) Target Disease Exceptions
a) Subjects for whom potentially-curative therapy is available, including
hematopoietic stem-cell transplantation (HSCT)
b) Symptomatic central nervous system (CNS) involvement (except if signs and
symptoms are from isolated leptomeningeal disease)
c) Isolated extramedullary disease, with < 5% blasts in bone marrow
3) Medical History and Concurrent Diseases
a) Any serious uncontrolled medical disorder that would impair the ability of the
subject to receive protocol therapy, including:
i) Ongoing uncontrolled infection
ii) Clinically-significant disorder of platelet function (e.g. von Willebrand’s
disease) or ongoing gastrointestinal bleeding
iii) 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
b) Expected non-compliance to protocol schedule or unable to have regular followup
due to psychological, social, familial or geographic reasons
4) Prohibited Treatments and/or Therapies
a) Prior therapy with dasatinib.
b) 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.
c) Subjects requiring ongoing medications which may:
i) Have a known risk of causing QTc prolongation - see Section 5.5.3.2
ii) Irreversibly inhibit platelet function, or anticoagulants - see Section 5.5.3.3
(Does not apply to low-dose heparin for prophylaxis or to heparin flushes for
i.v. lines)
5) Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (eg, infectious disease) illness. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary endpoint is MCyR for Cohort #1 and CHR for Cohort #2. Cytogenetic response will be based on the percentage of Ph+ metaphases among ≥ 20 analyzed
metaphases in bone marrow aspirate. CHR will be assessed regularly through serum hematology tests. Molecular responses will also be assessed. Mutation analyses will be reported descriptively.
To assess safety, adverse events will be reported continuously and graded according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Safety will be summarized by cohort, by reporting AEs, laboratory abnormalities, dose interruptions and reductions, treatment discontinuation for toxicity, and use of concomitant medications. |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| 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 | 4 |
| 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 | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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