A Phase II Study of Dasatinib in Children and Adolescents With Newly Diagnosed Chronic Phase CML or With Ph+ Leukemias Resistant or Intolerant to Imatinib

Phase 1

• Conditions: Children and Adolescents with Ph+ Leukemia with Resistance or Intolerance to Imatinib; MedDRA version: 20.1Level: PTClassification code 10034877Term: Philadelphia chromosome positiveSystem Organ Class: 10022891 - Investigations; MedDRA version: 20.1Level: LLTClassification code 10024329Term: LeukemiaSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2008-002260-33-NL
• Lead Sponsor: Bristol Myers Squibb International Corporation

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2009-06-16
• Last Update Posted: 4 December 2018

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 120

Inclusion Criteria

1) Signed Written informed consent from subject, or from parents minor subjects, according to local law and regulation.
2) Target Population
a) Diagnosis:
i) Cohort #1: Subjects must have Ph+ CML in CP which 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 and/or spleen
(f) Ph+ (with 9:22 translocation) must be demonstrated by bone marrow cytogenetics
ii) Cohort #2: Subjects must have Ph+ ALL or Ph+ AP- or Ph+ BP-CML:
(1) Ph+ ALL have to be in first or subsequent relapse [defined as loss of a complete hematologic response as defined in Section 4.3.1.1] or fail to achieve a complete hematological remission [as defined in Section 4.3.1.1].
(2) Ph+ 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) < 100 X 109/L platelets unrelated to therapy
(3) Ph+ BP-CML has to meet either of 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
iii) Cohort #3: Subjects must have been newly diagnosed with 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 and/or spleen
(f) Ph+ (with 9:22 translocation) must be demonstrated by bone marrow cytogenetics
b) Subjects in Cohort #1 or Cohort #2 have to be proven resistant or intolerant to imatinib:
i) Intolerance Definition: Cohort #1 and Cohort #2, 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 (refer to Section 4.3.2 for CHR loss criteria). Capping the dose at 400 mg QD in chronic phase CML subjects with a BSA > 1.5 m2 is accepted.
(b) Failure to achieve MCyR after = 6 months of imatinib therapy at a daily dose of 260 mg/m2 or greater. (refer to Section 4.3.1.2 for cytogenetic response definitions) Capping the dose at 400 mg QD in chronic phase CML subjects with a BSA > 1.5 m2 is accepted;
(c) Failure to achieve CCyR after = 12 months of imatinib therapy at a daily dose of 260 mg/m2 or greater. (refer to Section 4.3.1.2 for cytogenetic response definitions) Capping the dose at 400 mg QD in chronic phase CML subjects with a BSA > 1.5 m2 is accepted;
(d) Absolute increase of = 30% of the percentage of Ph+ metaphases,
confirmed at 2 - 4 weeks, after prior MCyR to imatinib at a daily dose of
260 mg/m2 or greater. Capping the dose at 400 mg QD in chronic phase
CML subjects with a BSA > 1.5 m2 is accepted.
iii) For Cohort #2, resistance to im

Exclusion Criteria

1) Sex and Reproductive Status
a) WOCBP who are unwilling or unable to use a highly effective method
to avoid pregnancy for the entire study period and for up to 1 month after the last
dose of investigational product.
b) Women who are pregnant or breastfeeding or likely to become pregnant
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) at the time when subject
is
assessed for enrollment
b) Subjects with isolated central nervous system disease are excluded
from study.
Subjects with CNS-1 (no detectable blast cells in a sample of
cerebrospinal fluid),
CNS-2 (< 5 leukemic blast cells in a sample with < 10 erythrocytes per
cubic
millimeter) and CNS-3 disease (> 5 leukemic blasts per cubic millimeter
in a
sample with < 10 erythrocytes per cubic millimeter) are eligible for
study,46
provided this is a combined relapse which also involves the bone marrow
in
addition to CNS and they are asymptomatic (no convulsions or other
neurological
symptoms).
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 (eg. 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
iv) Subjects diagnosed with the T315I mutation (mutation testing should
be
performed according to the investigator's standard practice and is not
mandatory at sites without BCR-ABL testing available).
v) Subjects who have experienced hypersensitivity to dasatinib or to any
of the
excipients. Inactive ingredients in dasatinib tablets include: lactose
monohydrate, microcrystalline cellulose, croscarmellose sodium,
hydroxypropyl cellulose, and magnesium stearate. The tablet coating
consists
of hypromellose, titanium dioxide, and polyethylene glycol.
vi) Subjects with hereditary problems of galactose intolerance or Lapp
lactase
deficiency or glucose-galactose malabsorption.
vii)Uncorrected hypokalemia or hypomagnesemia.
b) Expected non-compliance to protocol schedule or unable to have
regular
follow-up 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.
i) 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.
ii) If required for control of peripheral blast cells or WBCs, 6-mercaptopurine or
6-thioguanine may be given up to 2 days before treatment start and
corticosteroids or hydroxyurea can be given during the period

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified