Study With Azacitidine in Pediatric Subjects With Newly Diagnosed Advanced Myelodysplastic Syndrome (MDS) and Juvenile Myelomonocytic Leukemia (JMML)

NCT02447666 | Completed Phase 2 DMC

• 1 other identifier: AZA-JMML-001
• Study Type: interventional
• Target: 28
• Locations: 13 countries
• Sites: 39

Brief 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). 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.

Conditions

Myelodysplastic Syndrome; Leukemia, Myelomonocytic, Juvenile

Keywords

Azacitidine; Myelodysplastic syndrome; Juvenile myelomonocytic leukemia; Hematopoietic stem cell transplantation; Vidaza; Hypomethylating agent

Outcome Measures

Primary Outcomes (2)

• 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).

  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).

  Up to 4 Months

Secondary Outcomes (22)

• Cytogenetic response for MDS

  Up to 6 Months

• Cytogenetic response for JMML subjects

  Up to 6 Months

• Molecular Response for JMML subjects

  Up to 6 Months

• Duration of Response (CR, PR or marrow CR) for MDS patients

  Up to 30 months

• Duration of Response (Clinical CR or Clinical PR) for JMML patients

  Up to 18 months

Study Arms (2)

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.

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.

Drug: Azacitidine

Interventions

Azacitidine DRUG

Also known as: Vidaza

Azacitidine Juvenile Myelomonocytic Leukemia (JMML); Azacitidine Myelodysplastic Syndrome (MDS)

Eligibility Criteria

• Age: 1 Month - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.
• 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

You may not qualify if:

• 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.
• 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).

Sponsors & Collaborators

• Celgene: lead

Study Sites (39)

St. Anna Kinderkrebsforschung, CHILDREN'S CANCER RESEARCH INSTITUTE

Vienna, 1090, Austria

Location

Hopital Universitaire des Enfants

Brussels, 1020, Belgium

Location

University Hospital Ghent

Ghent, 9000, Belgium

Location

University Hospital Motol

Prague, 150 06, Czechia

Location

Rigshospitalet

Copenhagen, DK-2100, Denmark

Location

Centre Hospitalier Universitaire Lyon

Lyon, 69008, France

Location

Hopital d'Enfants de la Timone

Marseille, 13005, France

Location

Hopital Robert Debre

Paris, 75935, France

Location

Klinikum Augsburg

Augsburg, 86156, Germany

Location

Charite Berlin

Berlin, 13353, Germany

Location

Universitaetsklinikum Carl Gustav Carus

Dresden, 01307, Germany

Location

Hematology, Oncology and clinical immunology / Heinrich-Heine-University

Düsseldorf, 40225, Germany

Location

Universitatsklinikum Essen

Essen, 45147, Germany

Location

Klinikum der Johann Wolfgang Goethe-Universität Frankfurt/Main

Frankfurt am Main, 60596, Germany

Location

Universitatsklinik

Freiburg im Breisgau, 79106, Germany

Location

University of Hamburg

Hamburg, 20246, Germany

Location

Medizinische Hochschule Hannover

Hanover, 30625, Germany

Location

Universitatsklinikum

Jena, 7740, Germany

Location

Universitatsklinikum Schleswig-Holstein

Kiel, 24105, Germany

Location

Klinikum der Universitaet Muenchen

München, 80336, Germany

Location

Universitatsklinik Munster

Münster, 48149, Germany

Location

Krankenhaus Barmherzige Bruder Regensburg

Regensburg, 93049, Germany

Location

Universitatsklinikum

Tübingen, 72076, Germany

Location

Our Lady's Hospital for Sick Children

Dublin, Ireland

Location

Policlinico Sant'Orsola-Malpighi

Bologna, 40138, Italy

Location

IRCCS Gaslini Hospital

Genova Quarto, 16148, Italy

Location

Azienda Ospedaliera San Gerardo

Monza, 20900, Italy

Location

General Hospital

Padua, 35128, Italy

Location

IRCCS Policlinico San Matteo

Pavia, 27100, Italy

Location

Ospedale Bambin Gesu

Roma, 00165, Italy

Location

Regina Margherita Children's Hospital

Torino, 10126, Italy

Location

Erasmus University Medical Center

Rotterdam, 3015 GJ, Netherlands

Location

Hospital Sant Joan de Deu

Barcelona, 8950, Spain

Location

Hospital Infantil Universitario Nino Jesus

Madrid, 28009, Spain

Location

Hospital Universitario Virgen de La Arrixaca

Murcia, 30120, Spain

Location

Queen Silvia Childrens Hospital

Gothenburg, SE-416 85, Sweden

Location

Karolinska University Hospital

Stockholm, SE-171 76, Sweden

Location

Universitäts-Kinderklinik

Zurich, 8032, Switzerland

Location

Royal Manchester Children's Hospital

Manchester, M13 9WL, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 34297046 DERIVED

Related Links

• Expanded Access for CC-486

MeSH Terms

Conditions

Myelodysplastic Syndromes; Leukemia, Myelomonocytic, Juvenile

Interventions

Azacitidine

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Myelodysplastic-Myeloproliferative Diseases

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Bouchra Benettaib, MD

  Celgene Corporation

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 14, 2015
• First Posted: May 19, 2015
• Study Start: September 15, 2015
• Primary Completion: February 28, 2018
• Study Completion: May 24, 2019
• Last Updated: July 11, 2019

Record last verified: 2019-07

Locations

ES (3); CZ (1); IT (7); AU (1); IE (1); FR (3); CH (1); GB (1); NL (1); SE (2); DE (15); BE (2); DK (1)