E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
newly diagnosed advanced myelodysplastic syndrome (MDS) or juvenile myelomonocytic leukemia (JMML) prior to hematopoietic stem cell transplantation (HSCT) |
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E.1.1.1 | Medical condition in easily understood language |
JMML is a chronic cancer of blood affecting children whereby liver and spleen enlarges due to abnormal growth of bone marrow.MDS is a disorder whereby bone marrow produces fewer/immature blood cells
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10054439 |
E.1.2 | Term | Juvenile chronic myelomonocytic leukemia |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10028536 |
E.1.2 | Term | Myelodysplastic syndromes |
E.1.2 | System Organ Class | 100000004851 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10023249 |
E.1.2 | Term | Juvenile chronic myelomonocytic leukaemia |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 assess the treatment effect on response rate (MDS: CR, PR, or marrow CR; JMML: either cCR or cPR) at Cycle 3 Day 28 and to compare against standard therapy using a matched-pairs analysis with historical data. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are to further evaluate safety, efficacy, pharmacodynamics (PD), and pharmacokinetics (PK) of azacitidine in this subject population. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
MDS:
1. Patient has newly diagnosed advanced primary or secondary MDS with an amount of immature cells in blood or bone marrow or chromosomal abnormality linked to secondary MDS. Blood or bone marrow samples confirming diagnosis within 14 days prior to ICF as for the MDS.
JMML:
1. Patient has newly diagnosed JMML, with samples from blood and bone marrow confirming diagnosis within the 14 days prior to informed consent/informed assent signature, with specific alteration in genes (which carry the information that determines a person characteristics) in the body
Both MDS and JMML:
2.Patient has a Lansky play score/ Karnofsky performance status at least equal to 60
3.Patient has a normal renal function and a normal liver function.
4.Subjects should be between 1 month to less than 18 years at time of signing ICF/ IAF |
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E.4 | Principal exclusion criteria |
MDS exclusions:
1.Patient has an illness caused by 'genetic defects' (which cause abnormalities in the information that determine a person's characteristics).
2.Patient has inherited disease that cause bone marrow (the soft tissue inside of the bone) failures.
JMML Exclusion:
1.Patient has a specific deviation in so called Germline.
Both:
1.Patient has any other organ dysfunction that will interfere with the administration of the therapy according to this protocol.
2.Hypersensitivity to azacitidine
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E.5 End points |
E.5.1 | Primary end point(s) |
MDS:
Proportion of subjects with CR, PR or marrow CR according to modified criteria based on Table 3 in Cheson 2006, adapted to pediatric reference values at 3 months (Cycle 3, Day 28). Response must be sustained for at least 4 weeks either in the 4-week period preceding or succeeding Cycle 3 Day 28 (ie, sustained over the period Cycle 2 Day 28 to Cycle 3 Day 28, or Cycle 3 Day 28 to Cycle 4 Day 28).
JMML:
Proportion of subjects with sustained cCR or cPR according to the International JMML response criteria in Niemeyer 2015 at 3 months (Cycle 3, Day 28). Response must be sustained for at least 4 weeks either in the 4-week period preceding or succeeding Cycle 3 Day 28 (ie, sustained over the period Cycle 2 Day 28 to Cycle 3 Day 28, or Cycle 3 Day 28 to Cycle 4 Day 28). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
MDS:
Response will be evaluated on Day 1 of Cycles 2 and 3, Day 28 of Cycle 3, if there is a suspected disease progression after Cycle 3 Day 28, Day 28 of Cycle 6 (if applicable), and pre-HSCT (Hematopoietic Stem Cell Transplantation , transplant of cells)
JMML:
Response will be evaluated on Day 1 of Cycles 2 and 3, Day 28 of Cycle 3, if there is a suspected disease progression after Cycle 3 Day 28, Day 28 of Cycle 6 (if applicable), and pre-HSCT (Hematopoietic Stem Cell Transplantation , transplant of cells) |
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E.5.2 | Secondary end point(s) |
1.Cytogenetic Response for MDS subjects
2.Cytogenetic and Molecular Response for JMML subjects
3.Duration of response (DoR)
4. Time to response (TTR)
5.Time to progression (TTP)
6.Leukemia free survival (LFS)
7.Overall survival (OS)
8.Deoxyribonucleic acid methylation status in BM on Days 1 and 15 of Cycle 1, Day 28 of Cycle 3, pre-HSCT, and at the time of relapse/progression
9.Percentage of subjects undergoing HSCT
10.Time to first HSCT
11.Safety defined by frequency and severity of treatment emergent AEs
12.Pharmacokinetics (PK) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1,2.C1D1,C2D1,C3D1,D28 if there is suspected disease progression after C3D28,C6D28 (if applicable)&pre-HSCT(only if >21 days since the last BM aspirate)in order to evaluate response to treatment
3.1st observed response until either disease progression/any cause of death
4.1st study dose day until a response.
5.1st study dose day until either disease progression/death due to progression
6,7,9,10.during follow-up period
8.C1D1,C1D15,C3D28, at time of relapse/disease progression&pre-HSCT for extraction of DNA
11.during the course of study
12.C1D5,D6 Prior to dosing,C1D7 prior to dosing,postdose 5mins(IV use azacitidine application) or 15mins postdose(SC use),postdose 30mins, 1hr, 2hrs, 4hrs, 6hrs IV and SC use. |
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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 | 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 | 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 | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
comparison against a historical control arm using data collected retrospectively from EWOG registry |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 44 |
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 | 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
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End of trial is the date of the last visit of the last subject to complete the study, or the date of receipt of the last data point from the last subject that is required for primary, secondary and/or exploratory analysis, as pre-specified in the protocol and/or the Statistical Analysis Plan (SAP), whichever is the later date. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |