Study With Azacitidine in Pediatric Subjects With Newly Diagnosed Advanced Myelodysplastic Syndrome (MDS) and Juvenile Myelomonocytic Leukemia (JMML)
Information source: Celgene Corporation
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Myelodysplastic Syndrome; Leukemia, Myelomonocytic, Juvenile
Intervention: Azacitidine (Drug)
Phase: Phase 2
Status: Not yet recruiting
Sponsored by: Celgene Corporation Official(s) and/or principal investigator(s): Bouchra Benettaib, MD, Study Director, Affiliation: Celgene Corporation
Overall contact: Associate Director Clinical Trial Disclosure, Phone: 1-888-260-1599, Email: clinicaltrialdisclosure@celgene.com
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.
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. 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.
Clinical Details
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 design: Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Myelodysplastic Syndrome (MDS) response rate at end of third 28-day cycleJuvenile Myelomonocytic Leukemia (JMML) response rate at end of 3 Months
Secondary outcome: Cytogenetic response for MDSCytogenetic response for JMML subjects Molecular Response for JMML subjects Duration of Response (CR, PR or marrow CR) for MDS patients Duration of Response (Clinical CR or Clinical PR) for JMML patients Time to Response (TTR) for MDS patients TTR of Clinical CR or Clinical PR for JMML patients Time to Progression (TTP) Leukemia free survival (LFS) Overall survival (OS) Deoxyribonucleic acid methylation status in BM Percentage of subjects undergoing HSCT Time to first HSCT Adverse Events (AEs) Pharmacokinetic parameters of azacitidine; Cmax Pharmacokinetic parameters of azacitidine; Tmax Pharmacokinetic parameters of azacitidine; AUCt Pharmacokinetic parameters of azacitidine; area under the plasma concentration-time curve from time zero to infinity (AUC ∞) Pharmacokinetic parameters of azacitidine; Terminal Rate λz Pharmacokinetic parameters of azacitidine; terminal phase half-life Pharmacokinetic parameters of azacitidine; total clearance (CL) Pharmacokinetic parameters of azacitidine; volume of distribution (Vz)
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 2
years 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
Minimum age: 1 Month.
Maximum age: 18 Years.
Gender(s): Both.
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 (oral, injectable, or implantable hormonal contraceptive;
tubal ligation; intra-uterine device; barrier contraceptive with spermicide; 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 (oral, injectable, or implantable hormonal contraceptive;
tubal ligation; intra-uterine device; barrier contraceptive with spermicide; 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.
Locations and Contacts
Associate Director Clinical Trial Disclosure, Phone: 1-888-260-1599, Email: clinicaltrialdisclosure@celgene.com
St. Anna Kinderkrebsforschung, CHILDREN'S CANCER RESEARCH INSTITUTE, Vienna 1090, Austria; Not yet recruiting
Hopital Universitaire des Enfants, Brussels 1020, Belgium; Not yet recruiting
University Hospital Ghent, Ghent 9000, Belgium; Not yet recruiting
University Hospital Motol, Prague 5 150 06, Czech Republic; Not yet recruiting
Rigshospitalet, Copenhagen DK-2100, Denmark; Not yet recruiting
Klinikum Augsburg, Augsburg 86156, Germany; Not yet recruiting
Charité Berlin, Berlin 13353, Germany; Not yet recruiting
Universitaetsklinikum Carl Gustav Carus, Dresden 01307, Germany; Not yet recruiting
Hematology, Oncology and clinical immunology / Heinrich-Heine-University, Dusseldorf 40225, Germany; Not yet recruiting
Universitätsklinikum Essen, Essen 45147, Germany; Not yet recruiting
Klinikum der Johann Wolfgang Goethe-Universität Frankfurt/Main, Frankfurt am Main 60596, Germany; Not yet recruiting
Universitätsklinik, Freiburg 79106, Germany; Not yet recruiting
University of Hamburg, Hamburg 20246, Germany; Not yet recruiting
Medizinische Hochschule Hannover, Hannover 30625, Germany; Not yet recruiting
Universitätsklinikum, Jena 7740, Germany; Recruiting
Universitätsklinikum Schleswig-Holstein, Kiel 24105, Germany; Not yet recruiting
Klinikum der Universitaet Muenchen, Munchen 80336, Germany; Not yet recruiting
Universitätsklinik Münster, Münster 48149, Germany; Not yet recruiting
Krankenhaus Barmherzige Brüder Regensburg, Regensburg 93049, Germany; Not yet recruiting
Universitätsklinikum, Tübingen 72076, Germany; Not yet recruiting
Our Lady's Hospital for Sick Children, Dublin 12, Ireland; Not yet recruiting
Policlinico Sant'Orsola-Malpighi, Bologna 40138, Italy; Not yet recruiting
IRCCS Gaslini Hospital, Genova Quarto 16148, Italy; Not yet recruiting
Ospedale S. Gerardo, Monza 20052, Italy; Not yet recruiting
Ospedale "Bambin Gesù", Roma 00165, Italy; Not yet recruiting
Regina Margherita Children's Hospital, Torino 10126, Italy; Not yet recruiting
Erasmus MC, Rotterdam 3015 GJ, Netherlands; Not yet recruiting
Hospital Sant Joan de Deu, Barcelona 8950, Spain; Not yet recruiting
Hospital Infantil Universitario Niño Jesus, Madrid 28009, Spain; Not yet recruiting
Hospital Universitario Virgen de La Arrixaca, Murcia 30120, Spain; Not yet recruiting
Queen Silvia Childrens Hospital, Gothenburg SE-416 85, Sweden; Not yet recruiting
Karolinska University Hospital, Stockholm SE-171 76, Sweden; Not yet recruiting
Great Ormond Street Hospital, London WC1N 3JH, United Kingdom; Not yet recruiting
Royal Manchester Children's Hospital, Manchester M13 9WL, United Kingdom; Not yet recruiting
Additional Information
Starting date: December 2015
Last updated: August 18, 2015
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