Clinical trial NCT02447666: Study With Azacitidine in Pediatric Subjects With Newly Diagnosed Advanced Myelodysplastic Syndrome (MDS) and Juvenile Myelomonocytic Leukemia (JMML)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Myelodysplastic Syndrome
Leukemia, Myelomonocytic, Juvenile
Keywords: Azacitidine
Myelodysplastic syndrome
Juvenile myelomonocytic leukemia
Hematopoietic stem cell transplantation
Vidaza
Hypomethylating agent
Lead sponsor: Celgene
Sponsor class: INDUSTRY
First posted: 2015-05-19
Enrollment: 28
Sex: ALL
Minimum age (years): 1
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: Inclusion Criteria:

Myelodysplastic Syndromes (MDS) :

1. 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.
2. Able to adhere to the study visit schedule and other protocol requirements.
3. Male or female age 1 month to less than 18 years old at the time of informed consent/informed assent.
4. 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:

   1. RAEB (Refractory anemia with excess blasts): 2% to 19% blasts in PB or 5% to 19% blasts in BM.
   2. RAEB-t (Refractory anemia with excess blasts in transformation): 20% to 29% of blasts in PB or BM.
   3. Secondary Myelodysplastic Syndromes presenting as chronic myelomonocytic leukemia (CMML) without increase in blasts but with chromosomal abnormality
5. Lansky play score at least equal to 60; or Karnofsky performance status at least equal to 60.
6. Life expectancy of at least 3 months.
7. 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 \[ULN\]).
8. 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).
9. 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).
10. 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):

    1. 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
    2. 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.
11. Male subjects must, as appropriate to age and the discretion of the study physician:

    1. 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):

1. 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.
2. Able to adhere to the study visit schedule and other protocol requirements.
3. Male or female age 1 month to less than 18 years old at the time of informed consent/informed assent.
4. Newly diagnosed Juvenile Myelomonocytic Leukemia (JMML), with PB and BM confirming diagnosis prior to informed consent signature, with one of the following

   1. somatic mutation in PTPN11
   2. somatic mutation in KRAS
   3. somatic mutation in NRAS and HbF % \> 5x normal value for age
   4. clinical diagnosis of neurofibromatosis Type 1.
5. Lansky play score at least equal to 60; or Karnofsky performance status at least equal to 60.
6. Life expectancy of at least 3 months.
7. Normal renal function defined as less than or equal to NCI CTCAE v 4.0 Grade 1 (maximum 1.5 x ULN).
8. 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).
9. 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).
10. 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.

    1. 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
    2. 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.
11. Male subjects must, as appropriate to age and the discretion of the study physician:

    a. 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.
12. SO2 greater than 92% (without additional supply of O2).
13. Peripheral blood monocyte count of at least 1.0 x 109/L.
14. Blast percentage in PB and BM less than 20%.
15. Splenomegaly.

Exclusion Criteria:

Myelodysplastic Syndromes (MDS):

1. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
2. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
3. Any condition that confounds the ability to interpret data from the study.
4. Treated by any investigational agent in a clinical study within 4 weeks prior to signing of informed consent / informed assent.
5. Any central nervous system (CNS) involvement.
6. Isolated extramedullary disease.
7. Current uncontrolled infection.
8. Cardiac toxicity (shortening fraction below 28%).
9. Concurrent treatment with another anticancer therapy.
10. Pregnancy or lactation.
11. Prior treatment with a demethylating agent.
12. Allergy to azacitidine or mannitol.
13. Any other organ dysfunction (NCI-CTCAE v 4.0 Grade 4) that will interfere with the administration of the therapy according to this protocol.
14. Genetic abnormalities indicative of Core Binding factor AML; t(8;21), inv16, t(16;16), and t(15;17).
15. Subjects with inherited BM failure syndromes (ie, Fanconi's anemia, congenital severe neutropenia, Shwachman-Diamond syndrome).

Juvenile Myelomonocytic Leukemia Subjects:

1. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
2. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
3. Any condition that confounds the ability to interpret data from the study.
4. Treated by any investigational agent in a clinical study within 4 weeks prior to signing of informed consent / informed assent.
5. Any CNS involvement.
6. Isolated extramedullary disease.
7. Current uncontrolled infection.
8. Cardiac toxicity (shortening fraction below 28%).
9. Concurrent treatment with another anticancer therapy.
10. Pregnancy or lactation.
11. Prior treatment with a demethylating agent.
12. Allergy to azacitidine or mannitol.
13. Any other organ dysfunction (NCI-CTCAE v 4.0 Grade 4) that will interfere with the administration of the therapy according to this protocol.
14. Germline molecular aberrations in CBL, PTPN11, NRAS, or KRAS.

Primary outcomes:
measure: Myelodysplastic Syndrome (MDS) response rate at end of third 28-day cycle
timeFrame: Up to 4 Months
measure: Juvenile Myelomonocytic Leukemia (JMML) response rate at end of 3 Months
timeFrame: Up to 4 Months
Secondary outcomes:
measure: Cytogenetic response for MDS
timeFrame: Up to 6 Months
measure: Cytogenetic response for JMML subjects
timeFrame: Up to 6 Months
measure: Molecular Response for JMML subjects
timeFrame: Up to 6 Months
measure: Duration of Response (CR, PR or marrow CR) for MDS patients
timeFrame: Up to 30 months
measure: Duration of Response (Clinical CR or Clinical PR) for JMML patients
timeFrame: Up to 18 months
measure: Time to Response (TTR) for MDS patients
timeFrame: Up to 6 Months
measure: TTR of Clinical CR or Clinical PR for JMML patients
timeFrame: Up to 6 Months
measure: Time to Progression (TTP)
timeFrame: Up to 18 months
measure: Leukemia free survival (LFS)
timeFrame: Up to 18 months
measure: Overall survival (OS)
timeFrame: Up to 18 months
measure: Deoxyribonucleic acid methylation status in (BM)
timeFrame: Up to 18 months
measure: Percentage of subjects undergoing HSCT
timeFrame: Up to 18 months
measure: Time to first HSCT
timeFrame: Up to 18 months
measure: Adverse Events (AEs)
timeFrame: Up to 7 months
measure: Pharmacokinetic parameters of azacitidine; Cmax
timeFrame: Up to 28 days
measure: Pharmacokinetic parameters of azacitidine; Tmax
timeFrame: Up to 28 days
measure: Pharmacokinetic parameters of azacitidine; AUCt
timeFrame: Up to 28 days
measure: Pharmacokinetic parameters of azacitidine; area under the plasma concentration-time curve from time zero to infinity (AUC ∞)
timeFrame: Up to 28 days
measure: Pharmacokinetic parameters of azacitidine; Terminal Rate λz
timeFrame: Up to 28 days
measure: Pharmacokinetic parameters of azacitidine; terminal phase half-life
timeFrame: Up to 28 days
measure: Pharmacokinetic parameters of azacitidine; total clearance (CL)
timeFrame: Up to 28 days
measure: Pharmacokinetic parameters of azacitidine; volume of distribution (Vz)
timeFrame: Up to 28 days
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: St. Anna Kinderkrebsforschung, CHILDREN'S CANCER RESEARCH INSTITUTE
city: Brussels
country: Belgium
facility: Hopital Universitaire des Enfants
city: Ghent
country: Belgium
facility: University Hospital Ghent
city: Prague 5
country: Czechia
facility: University Hospital Motol
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Lyon
country: France
facility: Centre Hospitalier Universitaire Lyon
city: Marseille Cedex 01
country: France
facility: Hopital d'Enfants de la Timone
city: Paris
country: France
facility: Hopital Robert Debre
city: Augsburg
country: Germany
facility: Klinikum Augsburg
city: Berlin
country: Germany
facility: Charite Berlin
city: Dresden
country: Germany
facility: Universitaetsklinikum Carl Gustav Carus
city: Dusseldorf
country: Germany
facility: Hematology, Oncology and clinical immunology / Heinrich-Heine-University
city: Essen
country: Germany
facility: Universitatsklinikum Essen
city: Frankfurt am Main
country: Germany
facility: Klinikum der Johann Wolfgang Goethe-Universität Frankfurt/Main
city: Freiburg
country: Germany
facility: Universitatsklinik
city: Hamburg
country: Germany
facility: University of Hamburg
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Jena
country: Germany
facility: Universitatsklinikum
city: Kiel
country: Germany
facility: Universitatsklinikum Schleswig-Holstein
city: Munchen
country: Germany
facility: Klinikum der Universitaet Muenchen
city: Münster
country: Germany
facility: Universitatsklinik Munster
city: Regensburg
country: Germany
facility: Krankenhaus Barmherzige Bruder Regensburg
city: Tübingen
country: Germany
facility: Universitatsklinikum
city: Dublin 12
country: Ireland
facility: Our Lady's Hospital for Sick Children
city: Bologna
country: Italy
facility: Policlinico Sant'Orsola-Malpighi
city: Genova Quarto
country: Italy
facility: IRCCS Gaslini Hospital
city: Monza
country: Italy
facility: Azienda Ospedaliera San Gerardo
city: Padova
country: Italy
facility: General Hospital
city: Pavia
country: Italy
facility: IRCCS Policlinico San Matteo
city: Roma
country: Italy
facility: Ospedale Bambin Gesu
city: Torino
country: Italy
facility: Regina Margherita Children's Hospital
city: Rotterdam
country: Netherlands
facility: Erasmus University Medical Center
city: Barcelona
country: Spain
facility: Hospital Sant Joan de Deu
city: Madrid
country: Spain
facility: Hospital Infantil Universitario Nino Jesus
city: Murcia
country: Spain
facility: Hospital Universitario Virgen de La Arrixaca
city: Gothenburg
country: Sweden
facility: Queen Silvia Childrens Hospital
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
city: Zurich
country: Switzerland
facility: Universitäts-Kinderklinik
city: Manchester
country: United Kingdom
facility: Royal Manchester Children's Hospital
Study officials:
affiliation: Celgene Corporation
name: Bouchra Benettaib, MD
role: STUDY_DIRECTOR
References:
citation: 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.