Myelodysplastic SyndromePhase 2NCT02447666
Study With Azacitidine in Pediatric Subjects With Newly Diagnosed Advanced Myelodysplastic Syndrome (MDS) and Juvenile Myelomonocytic Leukemia (JMML)
A Phase 2 study testing Azacitidine in people with Myelodysplastic Syndrome and Leukemia, Myelomonocytic, Juvenile, run by Celgene at 39 sites in 13 countries.
Trial summary
Indication Treatment of pediatric subjects with newly diagnosed advanced myelodysplastic syndrome (MDS) or juvenile myelomonocytic leukemia (JMML) prior to hematopoietic stem cell transplantation (HSCT). Read more about this study
- Who is it for?
- Ages 1 month to 18 years
- Conditions the study is for
- Myelodysplastic Syndrome, Leukemia, Myelomonocytic, Juvenile
- What is being tested?
- Azacitidine
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 28 participants
- Where
- 39 sitesin 13 countries
- Study dates
- 15 Sep 2015to 24 May 2019
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 month to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Myelodysplastic Syndromes (MDS) :
- Understand and voluntarily provide permission (subjects and/or when applicable, parental/legal representative) to the informed consent form/informed assent form (ICF/IAF) prior to conducting any study-related assessments/procedures.
- Able to adhere to the study visit schedule and other protocol requirements.
- Male or female age 1 month to less than 18 years old at the time of informed consent/informed assent.
- Newly diagnosed advanced primary or secondary Myelodysplastic Syndromes (MDS), with latest peripheral blood (PB) and bone marrow (BM) biopsy confirming diagnosis within the 14 days prior to informed consent signature, with one of the following:
- RAEB (Refractory anemia with excess blasts): 2% to 19% blasts in PB or 5% to 19% blasts in BM.
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- RAEB-t (Refractory anemia with excess blasts in transformation): 20% to 29% of blasts in PB or BM.
- Secondary Myelodysplastic Syndromes presenting as chronic myelomonocytic leukemia (CMML) without increase in blasts but with chromosomal abnormality
- Lansky play score at least equal to 60; or Karnofsky performance status at least equal to 60.
- Life expectancy of at least 3 months.
- Normal renal function defined as less than or equal to NCI CTCAE (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE]) v 4.0 Grade 1 (maximum 1.5 x Upper Limit of Normal [ULN]).
- Normal liver function defined as less than or equal to NCI CTCAE v 4.0 Grade 1 (maximum 2.5 x ULN for transaminases and bilirubin).
- Females of childbearing potential and male subjects that have reached puberty and are younger than 18 years of age must agree to undergo physician-approved reproductive education and discuss the side effects of the Investigational Product (IP) on reproduction with parent(s) and/or guardian(s).
- Females of childbearing potential, defined as females who have achieved menarche and/or 8 years or older and have not undergone a hysterectomy or bilateral oophorectomy, must meet the following conditions below. (Note: Amenorrhea following cancer therapy does not rule out childbearing potential):
- Have a negative serum pregnancy test within 72 hours prior to starting IP as verified by the Investigator. Agree to ongoing pregnancy testing during the course of the study
- Female subjects must, as appropriate to age and the discretion of the study physician, either commit to true abstinence1 from heterosexual contact (which must be reviewed on a monthly basis) and/or agree to the use of approved contraceptive method (eg. oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; or vasectomized partner) while on azacitidine; and for 3 months following the last dose.
- Male subjects must, as appropriate to age and the discretion of the study physician:
- Agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential (FCBP) while participating in the study, during dose interruptions, and for at least 3 months following azacitidine discontinuation, even if he has undergone a successful vasectomy.
- Juvenile Myelomonocytic Leukemia Subjects (JMML):
- Understand and voluntarily provide permission (subjects and/or when applicable, parental/legal representative) to the ICF/IAF prior to conducting any study-related assessments/procedures.
- Able to adhere to the study visit schedule and other protocol requirements.
- Male or female age 1 month to less than 18 years old at the time of informed consent/informed assent.
- Newly diagnosed Juvenile Myelomonocytic Leukemia (JMML), with PB and BM confirming diagnosis prior to informed consent signature, with one of the following
- somatic mutation in PTPN11
- somatic mutation in KRAS
- somatic mutation in NRAS and HbF % > 5x normal value for age
- clinical diagnosis of neurofibromatosis Type 1.
- Lansky play score at least equal to 60; or Karnofsky performance status at least equal to 60.
- Life expectancy of at least 3 months.
- Normal renal function defined as less than or equal to NCI CTCAE v 4.0 Grade 1 (maximum 1.5 x ULN).
- Normal liver function defined as less than or equal to NCI CTCAE v 4.0 Grade 1 (maximum 2.5 x ULN for transaminases and bilirubin).
- Females of childbearing potential and male subjects that have reached puberty and are younger than 18 years of age must agree to undergo physician-approved reproductive education and discuss the side effects of the IP on reproduction with parent(s) and/or guardian(s).
- Females of childbearing potential, defined as females who have achieved menarche and/or 8 years or older and have not undergone a hysterectomy or bilateral oophorectomy, must meet the following conditions below.
- Have a negative serum pregnancy test within 72 hours prior to starting IP as verified by the Investigator. Agree to ongoing pregnancy testing during the course of the study
- Female subjects must, as appropriate to age and the discretion of the study physician, either commit to true abstinence2 from heterosexual contact (which must be reviewed on a monthly basis) and/or agree to the use of approved contraceptive method (eg. oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; or vasectomized partner) while on azacitidine; and for 3 months following the last dose.
- Male subjects must, as appropriate to age and the discretion of the study physician:
- Agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential (FCBP) while participating in the study, during dose interruptions, and for at least 3 months following azacitidine discontinuation, even if he has undergone a successful vasectomy.
- SO2 greater than 92% (without additional supply of O2).
- Peripheral blood monocyte count of at least 1.0 x 109/L.
- Blast percentage in PB and BM less than 20%.
- Splenomegaly.
Who cannot join
- Myelodysplastic Syndromes (MDS):
- Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
- Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
- Any condition that confounds the ability to interpret data from the study.
- Treated by any investigational agent in a clinical study within 4 weeks prior to signing of informed consent / informed assent.
- Any central nervous system (CNS) involvement.
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- Isolated extramedullary disease.
- Current uncontrolled infection.
- Cardiac toxicity (shortening fraction below 28%).
- Concurrent treatment with another anticancer therapy.
- Pregnancy or lactation.
- Prior treatment with a demethylating agent.
- Allergy to azacitidine or mannitol.
- Any other organ dysfunction (NCI-CTCAE v 4.0 Grade 4) that will interfere with the administration of the therapy according to this protocol.
- Genetic abnormalities indicative of Core Binding factor AML; t(8;21), inv16, t(16;16), and t(15;17).
- Subjects with inherited BM failure syndromes (ie, Fanconi's anemia, congenital severe neutropenia, Shwachman-Diamond syndrome).
- Juvenile Myelomonocytic Leukemia Subjects:
- Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
- Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
- Any condition that confounds the ability to interpret data from the study.
- Treated by any investigational agent in a clinical study within 4 weeks prior to signing of informed consent / informed assent.
- Any CNS involvement.
- Isolated extramedullary disease.
- Current uncontrolled infection.
- Cardiac toxicity (shortening fraction below 28%).
- Concurrent treatment with another anticancer therapy.
- Pregnancy or lactation.
- Prior treatment with a demethylating agent.
- Allergy to azacitidine or mannitol.
- Any other organ dysfunction (NCI-CTCAE v 4.0 Grade 4) that will interfere with the administration of the therapy according to this protocol.
- Germline molecular aberrations in CBL, PTPN11, NRAS, or KRAS.
Trial locations and contacts
39 sites in 13 countries.
39 sites in 13 countries
Germany15 sites
Klinikum Augsburg
Augsburg, 86156
Charite Berlin
Berlin, 13353
Universitaetsklinikum Carl Gustav Carus
Dresden, 01307
Hematology, Oncology and clinical immunology / Heinrich-Heine-University
Düsseldorf, 40225
Universitatsklinikum Essen
Essen, 45147
Klinikum der Johann Wolfgang Goethe-Universität Frankfurt/Main
Frankfurt am Main, 60596
Universitatsklinik
Freiburg im Breisgau, 79106
University of Hamburg
Hamburg, 20246
Medizinische Hochschule Hannover
Hanover, 30625
Universitatsklinikum
Jena, 7740
Universitatsklinikum Schleswig-Holstein
Kiel, 24105
Klinikum der Universitaet Muenchen
München, 80336
Universitatsklinik Munster
Münster, 48149
Krankenhaus Barmherzige Bruder Regensburg
Regensburg, 93049
Universitatsklinikum
Tübingen, 72076
Italy7 sites
Policlinico Sant'Orsola-Malpighi
Bologna, 40138
IRCCS Gaslini Hospital
Genova Quarto, 16148
Azienda Ospedaliera San Gerardo
Monza, 20900
General Hospital
Padova, 35128
IRCCS Policlinico San Matteo
Pavia, 27100
Ospedale Bambin Gesu
Roma, 00165
Regina Margherita Children's Hospital
Torino, 10126
France3 sites
Centre Hospitalier Universitaire Lyon
Lyon, 69008
Hopital d'Enfants de la Timone
Marseille, 13005
Hopital Robert Debre
Paris, 75935
Spain3 sites
Hospital Sant Joan de Deu
Barcelona, 8950
Hospital Infantil Universitario Nino Jesus
Madrid, 28009
Hospital Universitario Virgen de La Arrixaca
Murcia, 30120
Belgium2 sites
Hopital Universitaire des Enfants
Brussels, 1020
University Hospital Ghent
Ghent, 9000
Sweden2 sites
Queen Silvia Childrens Hospital
Gothenburg, SE-416 85
Karolinska University Hospital
Stockholm, SE-171 76
Austria1 site
St. Anna Kinderkrebsforschung, CHILDREN'S CANCER RESEARCH INSTITUTE
Vienna, 1090
United Kingdom1 site
Royal Manchester Children's Hospital
Manchester, M13 9WL
About this study
Official title: A Phase 2, Multicenter, Open-label Study to Evaluate the Pharmacokinetics, Pharmacodynamics, Safety and Activity of Azacitidine and to Compare Azacitidine to Historical Controls in Pediatric Subjects With Newly Diagnosed Advanced Myelodysplastic Syndrome or Juvenile Myelomonocytic Leukemia Before Hematopoietic Stem Cell Transplantation
Indication Treatment of pediatric subjects with newly diagnosed advanced myelodysplastic syndrome (MDS) or juvenile myelomonocytic leukemia (JMML) prior to hematopoietic stem cell transplantation (HSCT).
Objectives Primary Objective The primary objective is to assess the treatment effect on response rate (MDS: either complete remission [CR], partial remission [PR], or marrow CR; JMML: either clinical complete remission [cCR] or clinical partial remission [cPR]); at Cycle 3 Day 28 (each cycle is 28 days) and to compare against standard therapy using a matched-pairs analysis of historical data.
Read more
Secondary Objective The secondary objective is to further evaluate safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of azacitidine in this subject population.
Study Design This is a prospective, open-label, Phase 2 study consisting of 2 parallel experimental arms, one for each disease group: MDS and JMML. Each arm is designed based on Simon's Optimal 2 stage study design. The sample size has been calculated to allow evaluation of the response rate at 28 day-Cycle 3 Day 28 in each of the 2 disease groups. Each of the experimental arms will also individually be compared against a historical control arm using data retrospectively collected from the European Working Group of MDS in childhood (EWOG-MDS) registry by means of a matched-pairs analysis; matched for predefined subject baseline characteristics defined before any results from this study are known post Stage 1. If matched pair is not viable then other methodologies will be explored to evaluate and compare response rates reported in literature and also in registry database Twenty subjects with MDS and 35 JMML subjects evaluable for the primary endpoint (ie, subjects that receive at least 1 dose of investigational product [IP]) will be enrolled at approximately 45 centers in Europe. Each experimental arm has 1 interim analysis planned (at the end of Stage 1). If, during Stage 1 evaluation, less than 2 subjects are observed with a CR, PR, or marrow CR after 3 months of azacitidine in the first 9 subjects with MDS, then enrollment will be stopped. Similarly, if less than 3 subjects are observed with a cPR or cCR after 3 months of azacitidine in the first 18 subjects with JMML, then enrollment will be stopped.
Read the detailed description
Study Population Pediatric subjects aged 1 month to less than 18 years of age with newly diagnosed conditions of advanced myelodysplastic syndrome (MDS) or juvenile myelomonocytic leukemia (JMML).
Length of Study The enrollment period will last for up to 22 months with subjects being treated for a minimum of 3 months and a maximum of 6 months, until transplantation or disease progression (based on an independent central review of responses). Once investigational product (IP) has been discontinued, subjects will then be followed for 1 year after the last dose of investigational product (IP). The follow-up may not be terminated because of new anticancer treatment or hematopoietic stem cell transplantation (HSCT).
The End of Trial is defined as either 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.
- Being tested
- Azacitidine
- Keywords
- Azacitidine, Myelodysplastic syndrome, Juvenile myelomonocytic leukemia, Hematopoietic stem cell transplantation, Vidaza, Hypomethylating agent
- Medical subject headings
- Myelodysplastic Syndromes, Leukemia, Myelomonocytic, Juvenile
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AzacitidineDrug
Also called Vidaza
| Study group | Role | What they receive |
|---|---|---|
| Azacitidine Myelodysplastic Syndrome (MDS) | Experimental | Azacitidine 75 mg/m2 by Intravenous (IV) or Subcutaneous (SC) administration once daily (QD) on Days 1 to 7 of a 28-day cycle for a minimum of 3 cycles and a maximum of 6 cycles. Receives: Drug: Azacitidine |
| Azacitidine Juvenile Myelomonocytic Leukemia (JMML) | Experimental | Azacitidine 75 mg/m2 by Intravenous (IV) or Subcutaneous (SC) administration once daily (QD) on Days 1 to 7 of a 28-day cycle for a minimum of 3 cycles and a maximum of 6 cycles. Receives: Drug: Azacitidine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Myelodysplastic Syndrome (MDS) response rate at end of third 28-day cycle
Defined as proportion of subjects with complete remission [CR], partial remission [PR] or marrow CR according to modified criteria described by Cheson 2006, adapted to pediatric reference values at 3 months (28 days cycle). Response must be sustained for at least 4 weeks either in the 4-week period preceding or succeeding 3 months (ie, sustained over the period minimum 2 months to end of 3 months, or end of 3 months to end of 4th months).
Measured: Up to 4 Months
Juvenile Myelomonocytic Leukemia (JMML) response rate at end of 3 Months
Defined as proportion of subjects with sustained clinical complete remission [cCR] or clinical partial remission [cPR] according to the International JMML response criteria in Niemeyer 2014 at 3 months (28 days cycles). Response must be sustained for at least 4 weeks either in the 4-week period preceding or succeeding 3 months (ie, sustained over the period minimum 2 months to end of 3 months, or end of 3 monthsto end of 4 months).
Measured: Up to 4 Months
Secondary outcomes (22)
Cytogenetic response for MDS
Cytogenetic response is defined as the number of subjects with complete disappearance of the chromosomal abnormality without appearance of new ones divided by the number of subjects within the analysis population.
Measured: Up to 6 Months
Cytogenetic response for JMML subjects
Cytogenetic response is defined as the number of subjects with complete disappearance of the chromosomal abnormality without appearance of new ones divided by the number of subjects within the analysis population.
Measured: Up to 6 Months
Molecular Response for JMML subjects
Molecular response is defined as the number of subjects with absence of somatic mutations related to JMML divided by the number of subjects within the analysis population.
Measured: Up to 6 Months
Duration of Response (CR, PR or marrow CR) for MDS patients
Duration of response will consist of only the subjects achieving a response (CR, PR or marrow CR) and is defined as the time from first observed response until either disease progression or any cause of death.
Measured: Up to 30 months
Duration of Response (Clinical CR or Clinical PR) for JMML patients
Duration of response will consist of only the subjects achieving a response (cCR or cPR) and is defined as the time from first observed response until either disease progression or any cause of death.
Measured: Up to 18 months
Time to Response (TTR) for MDS patients
TTR is defined as the time from first study dose day until a response of CR, PR or marrow CR, whichever occurs first. Only subjects observed with a response will be included in the analysis with the median TTR across the subjects presented.
Measured: Up to 6 Months
TTR of Clinical CR or Clinical PR for JMML patients
Time to Response (TTR) is defined as the time from first study dose day until a response cCR or cPR, whichever occurs first. Only subjects observed with a response will be included in the analysis with the median TTR across the subjects presented.
Measured: Up to 6 Months
Time to Progression (TTP)
Time to Progression (TTP) is defined as the time from first study dose day until either disease progression or death due to progression.
Measured: Up to 18 months
Leukemia free survival (LFS)
Leukemia free survival (LFS) is defined as the time from HEMATOPOIETIC STEM CELL transplant (HSCT) date until leukemia progression or death for subjects receiving a HSCT only. Subjects alive and leukemia-free at the time of the statistical analysis will be censored at the time of their last disease assessment. Subjects will also be censored at the time of starting a new anticancer therapy if having not previously had a leukemia progression.
Measured: Up to 18 months
Overall survival (OS)
OS is defined as the time from first study dose day until death from any cause. Subjects alive at the time of analysis will be censored at the time they were last known to be alive.
Measured: Up to 18 months
Deoxyribonucleic acid methylation status in (BM)
DNA methylation levels will be assessed across time points by means of a repeated measures analysis of variance (ANOVA) test thereby allowing identification of possible changes in methylation levels over time by treatment arm as well as comparing DNA methylation levels between treatment arms per disease indication
Measured: Up to 18 months
Percentage of subjects undergoing HSCT
Defined as the proportion of subjects undergoing HSCT during the conduct of this study over the total number of subjects enrolled into this study.
Measured: Up to 18 months
Time to first HSCT
The time from first study dose day until HSCT date. Subjects not receiving a HSCT will be censored at the time of the analysis.
Measured: Up to 18 months
Adverse Events (AEs)
All reported adverse events during the duration of the study conduct.
Measured: Up to 7 months
Pharmacokinetic parameters of azacitidine; Cmax
Cmax is defined as the observed maximum plasma concentration
Measured: Up to 28 days
Pharmacokinetic parameters of azacitidine; Tmax
Tmax is defined as the observed time to maximum plasma concentration
Measured: Up to 28 days
Pharmacokinetic parameters of azacitidine; AUCt
Area under the plasma concentration-time curve from time zero to the last quantifiable time point
Measured: Up to 28 days
Pharmacokinetic parameters of azacitidine; area under the plasma concentration-time curve from time zero to infinity (AUC ∞)
The AUC ∞ is defined as area under the plasma concentration-time curve from time zero to infinity
Measured: Up to 28 days
Pharmacokinetic parameters of azacitidine; Terminal Rate λz
Terminal phase rate constant is determined by linear regression of the terminal points of the log-linear plasma concentration-time curve
Measured: Up to 28 days
Pharmacokinetic parameters of azacitidine; terminal phase half-life
The Terminal phase half-life will be calculated according to the following equation: t½ = 0.693/λz
Measured: Up to 28 days
Pharmacokinetic parameters of azacitidine; total clearance (CL)
The total clearance is calculated as Dose/AUC∞
Measured: Up to 28 days
Pharmacokinetic parameters of azacitidine; volume of distribution (Vz)
The volume of distribution will be calculated according to the equation: Vz = (CL)/λz
Measured: Up to 28 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 May 2015 (estimated)
- Study start15 Sep 2015
- Primary completion28 Feb 2018
- Study completion24 May 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Myelodysplastic SyndromeStudies of the same condition, open and under way.
- More trials run by CelgeneThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 28 participants (actual)
Sponsor and investigators
- Lead sponsor
- Celgene
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Bouchra Benettaib, MD, Study director, Celgene Corporation
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02447666
- Sponsor's protocol ID
- AZA-JMML-001
- Status last verified
- Jul 2019
- First submitted
- 14 Apr 2015
- Last updated
- 11 Jul 2019
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Niemeyer CM, Flotho C, Lipka DB, Stary J, Rossig C, Baruchel A, Klingebiel T, Micalizzi C, Michel G, Nysom K, Rives S, Schmugge Liner M, Zecca M, Schonung M, Baumann I, Nollke P, Benettaib B, Biserna N, Poon J, Simcock M, Patturajan M, Menezes D, Gaudy A, van den Heuvel-Eibrink MM, Locatelli F. Response to upfront azacitidine in juvenile myelomonocytic leukemia in the AZA-JMML-001 trial. Blood Adv. 2021 Jul 27;5(14):2901-2908. doi: 10.1182/bloodadvances.2020004144.
PubMed 34297046
Study at a glance
From the registry record, last updated by the sponsor on 11 Jul 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 2, Multicenter, Open-label Study to Evaluate the Pharmacokinetics, Pharmacodynamics, Safety and Activity of Azacitidine and to Compare Azacitidine to Historical Controls in Pediatric Subjects With Newly Diagnosed Advanced Myelodysplastic Syndrome or Juvenile Myelomonocytic Leukemia Before Hematopoietic Stem Cell Transplantation
- ClinicalTrials.gov ID
- NCT02447666
- Acronym / sponsor ID
- AZA-JMML-001
- Keywords
- Azacitidine, Myelodysplastic syndrome, Juvenile myelomonocytic leukemia, Hematopoietic stem cell transplantation, Vidaza, Hypomethylating agent
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 28 participants (actual)
- Lead sponsor
- CelgeneIndustry (pharma, biotech, devices)
- Study start
- 15 Sep 2015 (actual)
- Primary completion
- 28 Feb 2018 (actual)
- Study completion
- 24 May 2019 (actual)
- First posted
- 19 May 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Indication Treatment of pediatric subjects with newly diagnosed advanced myelodysplastic syndrome (MDS) or juvenile myelomonocytic leukemia (JMML) prior to hematopoietic stem cell transplantation (HSCT).
Objectives Primary Objective The primary objective is to assess the treatment effect on response rate (MDS: either complete remission [CR], partial remission [PR], or marrow CR; JMML: either clinical complete remission [cCR] or clinical partial remission [cPR]); at Cycle 3 Day 28 (each cycle is 28 days) and to compare against standard therapy using a matched-pairs analysis of historical data.
Secondary Objective The secondary objective is to further evaluate safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of azacitidine in this subject population.
Study Design This is a prospective, open-label, Phase 2 study consisting of 2 parallel experimental arms, one for each disease group: MDS and JMML. Each arm is designed based on Simon's Optimal 2 stage study design. The sample size has been calculated to allow evaluation of the response rate at 28 day-Cycle 3 Day 28 in each of the 2 disease groups. Each of the experimental arms will also individually be compared against a historical control arm using data retrospectively collected from the European Working Group of MDS in childhood (EWOG-MDS) registry by means of a matched-pairs analysis; matched for predefined subject baseline characteristics defined before any results from this study are known post Stage 1. If matched pair is not viable then other methodologies will be explored to evaluate and compare response rates reported in literature and also in registry database Twenty subjects with MDS and 35 JMML subjects evaluable for the primary endpoint (ie, subjects that receive at least 1 dose of investigational product [IP]) will be enrolled at approximately 45 centers in Europe. Each experimental arm has 1 interim analysis planned (at the end of Stage 1). If, during Stage 1 evaluation, less than 2 subjects are observed with a CR, PR, or marrow CR after 3 months of azacitidine in the first 9 subjects with MDS, then enrollment will be stopped. Similarly, if less than 3 subjects are observed with a cPR or cCR after 3 months of azacitidine in the first 18 subjects with JMML, then enrollment will be stopped.
Detailed description
Study Population Pediatric subjects aged 1 month to less than 18 years of age with newly diagnosed conditions of advanced myelodysplastic syndrome (MDS) or juvenile myelomonocytic leukemia (JMML).
Length of Study The enrollment period will last for up to 22 months with subjects being treated for a minimum of 3 months and a maximum of 6 months, until transplantation or disease progression (based on an independent central review of responses). Once investigational product (IP) has been discontinued, subjects will then be followed for 1 year after the last dose of investigational product (IP). The follow-up may not be terminated because of new anticancer treatment or hematopoietic stem cell transplantation (HSCT).
The End of Trial is defined as either 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Azacitidine Myelodysplastic Syndrome (MDS) | Experimental | Drug: AzacitidineAzacitidine 75 mg/m2 by Intravenous (IV) or Subcutaneous (SC) administration once daily (QD) on Days 1 to 7 of a 28-day cycle for a minimum of 3 cycles and a maximum of 6 cycles. |
| Azacitidine Juvenile Myelomonocytic Leukemia (JMML) | Experimental | Drug: AzacitidineAzacitidine 75 mg/m2 by Intravenous (IV) or Subcutaneous (SC) administration once daily (QD) on Days 1 to 7 of a 28-day cycle for a minimum of 3 cycles and a maximum of 6 cycles. |
Who may qualify
- Ages
- 1 month to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (41 listed)
- Understand and voluntarily provide permission (subjects and/or when applicable, parental/legal representative) to the informed consent form/informed assent form (ICF/IAF) prior to conducting any study-related assessments/procedures.
- Able to adhere to the study visit schedule and other protocol requirements.
- Male or female age 1 month to less than 18 years old at the time of informed consent/informed assent.
- Newly diagnosed advanced primary or secondary Myelodysplastic Syndromes (MDS), with latest peripheral blood (PB) and bone marrow (BM) biopsy confirming diagnosis within the 14 days prior to informed consent signature, with one of the following:
- Lansky play score at least equal to 60; or Karnofsky performance status at least equal to 60.
Key exclusion criteria (31 listed)
- Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
- Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
- Any condition that confounds the ability to interpret data from the study.
- Treated by any investigational agent in a clinical study within 4 weeks prior to signing of informed consent / informed assent.
- Any central nervous system (CNS) involvement.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AzacitidineAlso: Vidaza | Drug | Azacitidine Juvenile Myelomonocytic Leukemia (JMML), Azacitidine Myelodysplastic Syndrome (MDS) |
Primary outcome
Myelodysplastic Syndrome (MDS) response rate at end of third 28-day cycle
Time frame: Up to 4 Months
Defined as proportion of subjects with complete remission [CR], partial remission [PR] or marrow CR according to modified criteria described by Cheson 2006, adapted to pediatric reference values at 3 months (28 days cycle). Response must be sustained for at least 4 weeks either in the 4-week period preceding or succeeding 3 months (ie, sustained over the period minimum 2 months to end of 3 months, or end of 3 months to end of 4th months).
Juvenile Myelomonocytic Leukemia (JMML) response rate at end of 3 Months
Time frame: Up to 4 Months
Defined as proportion of subjects with sustained clinical complete remission [cCR] or clinical partial remission [cPR] according to the International JMML response criteria in Niemeyer 2014 at 3 months (28 days cycles). Response must be sustained for at least 4 weeks either in the 4-week period preceding or succeeding 3 months (ie, sustained over the period minimum 2 months to end of 3 months, or end of 3 monthsto end of 4 months).
22 secondary outcomes
Cytogenetic response for MDS
Time frame: Up to 6 Months
Cytogenetic response for JMML subjects
Time frame: Up to 6 Months
Molecular Response for JMML subjects
Time frame: Up to 6 Months
Duration of Response (CR, PR or marrow CR) for MDS patients
Time frame: Up to 30 months
Duration of Response (Clinical CR or Clinical PR) for JMML patients
Time frame: Up to 18 months
Time to Response (TTR) for MDS patients
Time frame: Up to 6 Months
TTR of Clinical CR or Clinical PR for JMML patients
Time frame: Up to 6 Months
Time to Progression (TTP)
Time frame: Up to 18 months
Leukemia free survival (LFS)
Time frame: Up to 18 months
Overall survival (OS)
Time frame: Up to 18 months
Deoxyribonucleic acid methylation status in (BM)
Time frame: Up to 18 months
Percentage of subjects undergoing HSCT
Time frame: Up to 18 months
Time to first HSCT
Time frame: Up to 18 months
Adverse Events (AEs)
Time frame: Up to 7 months
Pharmacokinetic parameters of azacitidine; Cmax
Time frame: Up to 28 days
Pharmacokinetic parameters of azacitidine; Tmax
Time frame: Up to 28 days
Pharmacokinetic parameters of azacitidine; AUCt
Time frame: Up to 28 days
Pharmacokinetic parameters of azacitidine; area under the plasma concentration-time curve from time zero to infinity (AUC ∞)
Time frame: Up to 28 days
Pharmacokinetic parameters of azacitidine; Terminal Rate λz
Time frame: Up to 28 days
Pharmacokinetic parameters of azacitidine; terminal phase half-life
Time frame: Up to 28 days
Pharmacokinetic parameters of azacitidine; total clearance (CL)
Time frame: Up to 28 days
Pharmacokinetic parameters of azacitidine; volume of distribution (Vz)
Time frame: Up to 28 days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Jul 2019.
- Derived from this study: PubMed 34297046Niemeyer CM, Flotho C, Lipka DB, Stary J, Rossig C, Baruchel A, Klingebiel T, Micalizzi C, Michel G, Nysom K, Rives S, Schmugge Liner M, Zecca M, Schonung M, Baumann I, Nollke P, Benettaib B, Biserna N, Poon J, Simcock M, Patturajan M, Menezes D, Gaudy A, van den Heuvel-Eibrink MM, Locatelli F. Response to upfront azacitidine in juvenile myelomonocytic leukemia in the AZA-JMML-001 trial. Blood Adv. 2021 Jul 27;5(14):2901-2908. doi: 10.1182/bloodadvances.2020004144.
- Expanded Access for CC-486Link provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Bouchra Benettaib, MD study director
Celgene Corporation
39 sites in 13 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Azacitidine in people with Myelodysplastic Syndrome and Leukemia, Myelomonocytic, Juvenile, run by Celgene at 39 sites in 13 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 41 inclusion and 31 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 11 Jul 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 39 sites in Germany, Italy, France, Spain, Belgium and 8 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Myelodysplastic Syndrome (MDS) response rate at end of third 28-day cycle (time frame: Up to 4 Months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02447666, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Jul 2019; AzTrials last refreshed its copy on 26 Oct 2026.