| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Children and Adolescents with Newly Diagnosed Chronic Phase CML or with Ph+ Leukemias Resistant to or Intolerant to Imatinib |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10034877 |
| E.1.2 | Term | Philadelphia chromosome positive |
| E.1.2 | System Organ Class | 10022891 - Investigations |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10024329 |
| E.1.2 | Term | Leukemia |
| 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 |
The primary objective is to estimate:
- The major cytogenetic response (MCyR) rate to dasatinib therapy in children and adolescents with CP-CML subjects who prove resistant to or intolerant to imatinib.
- The complete hematologic response (CHR) rate in children and adolescents with Ph+ ALL, AP-CML and BP-CML, who are resistant, intolerant to, or relapse after prior imatinib therapy.
- The complete cytogenetic response (CCyR) rate to dasatinib therapy in children and adolescents with newly diagnosed CP-CML who are treatment-naive |
|
| 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 assess the safety and tolerability of dasatinib in children and adolescents with newly diagnosed Ph+ CP-CML who are treatment-naive.
To evaluate additional measures of efficacy in children and adolescents with newly diagnosed CP-CML or subjects with relapsed or refractory Ph+ leukemias treated on a given regimen of dasatinib including:
– best cytogenetic rates and hematological response rates
– time to response and duration of response
– disease free survival (DFS)
– 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 | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacokinetic Sub-study approximately 20 subjects included in revised protocol 09 dated 16-Apr-2018.
The objective is to further evaluate the pharmacokinetics of dasatinib
powder for oral suspension (PFOS) at a dose of 90 mg/m2. |
|
| E.3 | Principal 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 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.
(d) For subjects with Ph+ ALL, first or subsequent relapse [≥ 25% bone marrow blasts] or failure to achieve remission after prior imatinib exposure.
c) Lansky or Karnofsky scale > 50
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, HCO3, PO4 and Ca levels ≤ grade 1 and adequate hepatic and renal function defined as AST, ALT, bilirubin and creatinine ≤ Grade 2 (NCI CTCAE, Version 3.0).
3) Age and Sex
a) Men and women, age 0 to 18 years.
b) Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug.
For additional details, refer to the protocol, section 4.2.1 |
|
| E.4 | Principal 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 immediately
prior to treatment start and during the first month of study therapy, these
agents will be discontinued (or tapered in the case of corticosteroids) as soon
as possible.
c) Subjects requiring ongoing medications which may:
i) Have a known risk of causing QTc prolongation - see Section 5.5.1.2
ii) Irreversibly inhibit platelet function, or anticoagulants - see Section 5.5.1.3
(Does not apply to low-dose heparin for prophylaxis or to heparin flushes for
i.v. lines)
d) For Cohort #3: Prior chemotherapy, immunotherapy, or radiotherapy for CML
with the exception of hydroxyurea.
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) |
• Cohort #1: Major Cytogenetic Response (MCyR) rate, defined as the proportion of all
treated subjects who achieve a complete or partial cytogenetic response on study.
• Cohort #2: Complete Hematologic Response (CHR) rate, defined as the proportion of
all treated subjects who achieve a confirmed CHR on study.
• Cohort #3: Complete Cytogenetic Response (CCyR) rate, defined as the proportion of
all treated subjects who achieve a CCyR on study. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Cohort #1: Every 3 months during the first two years. Yearly thereafter and at the end of protocol therapy;
Cohort #2: Every week for the first eight weeks. Then every 3 months during the first two years. Every three months thereafter and at the end of protocol therapy;
Cohort #3: Every 3 months until complete cytogenetic response (CCyR) is achieved and then yearly (or as clinically indicated) once a subject has achieved a CCYR.
|
|
| E.5.2 | Secondary end point(s) |
(1) To assess the safety and tolerability of dasatinib in children and adolescents treated with dasatinib for relapsed or refractory Ph+ leukemias
(2) To assess the safety and tolerability of dasatinib in children and adolescents with newly diagnosed Ph+ CP-CML who are treatment-naive.
(3) To evaluate additional measures of efficacy in children and adolescents with newly diagnosed CP-CML or subjects with relapsed or refractory Ph+ leukemias treated on a given regimen of dasatinib
including: best cytogenetic and hematological response rates (Cohorts 1 & 3);
(4) time to response and duration of response;
(5) disease free survival (DFS);
(6) progression-free survival (PFS) and overall survival (OS);
(7) rates of complete (CMR) and major (MMR) molecular response.
(8) 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.5.2.1 | Timepoint(s) of evaluation of this end point |
(1)/(2)/(4)/(5)/(6) Every week for the first eight weeks. Then every 3 months during the first two years. Every three months thereafter and at the end of protocol therapy.
(3) Best cytogenetic response rates: every 3 months during the first 2 years, then yearly. Hematologic response rates: Cohort 1 and Cohort 3 - Every week for the first eight weeks, monthly until month 6, every 3 months thereafter.
(7) Every 3 months during the first two years. Then every three months thereafter and at the end of protocol therapy
(8) At baseline, every 3 months during the first two years, then at every 6 months, at progression or end of treatment
|
|
| 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 | 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| 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) | 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 | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| 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.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| 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 | No |
| 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 |
| Argentina |
| Australia |
| Brazil |
| Canada |
| France |
| Germany |
| India |
| Italy |
| Korea, Republic of |
| Mexico |
| Netherlands |
| Romania |
| Russian Federation |
| Singapore |
| South Africa |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
| Subjects will be followed yearly for survival for up to 5 years after discontinuation of study therapy. |
|
| 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 | 10 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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