Symptoms and General Pathology

All Conditions

Neoplasms

Blood and Lymph Conditions

Rare Diseases

Syndrome

Leukemia

Preleukemia

Myelodysplastic Syndromes

Leukemia, Myelomonocytic, Juvenile

Neoplasms by Histologic Type

Hematologic Diseases

Bone Marrow Diseases

Precancerous Conditions

Leukemia, Myeloid

Myeloproliferative Disorders

Myelodysplastic-Myeloproliferative Diseases

Chronic Myelomonocytic Leukemia

Juvenile Myelomonocytic Leukemia

Chronic Myeloproliferative Disorders

Myelodysplastic/myeloproliferative Disease

Antineoplastic Agents

All Drugs and Chemicals

Azacitidine

Antimetabolites

Enzyme Inhibitors

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.

Bouchra Benettaib, MD

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.

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

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

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).

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).

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.

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.

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.

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.

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.

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.

Time to Progression (TTP) is defined as the time from first study dose day until either disease progression or death due to progression.

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.

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.

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

Defined as the proportion of subjects undergoing HSCT during the conduct of this study over the total number of subjects enrolled into this study.

The time from first study dose day until HSCT date. Subjects not receiving a HSCT will be censored at the time of the analysis.

All reported adverse events during the duration of the study conduct.

Cmax is defined as the observed maximum plasma concentration

Tmax is defined as the observed time to maximum plasma concentration

Area under the plasma concentration-time curve from time zero to the last quantifiable time point

The AUC ∞ is defined as area under the plasma concentration-time curve from time zero to infinity

Terminal phase rate constant is determined by linear regression of the terminal points of the log-linear plasma concentration-time curve

The Terminal phase half-life will be calculated according to the following equation: t½ = 0.693/λz

The total clearance is calculated as Dose/AUC∞

The volume of distribution will be calculated according to the equation: Vz = (CL)/λz

Celgene

Immune System Diseases

Heart and Blood Diseases

Skin and Connective Tissue Diseases

Mastocytosis

Polycythemia Vera

Polycythemia

Primary Myelofibrosis

Thrombocytosis

Thrombocythemia, Essential

Leukemia, Myelomonocytic, Chronic

Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Hypereosinophilic Syndrome

Bone Marrow Neoplasms

Hematologic Neoplasms

Blood Platelet Disorders

Hemostatic Disorders

Blood Coagulation Disorders

Hemorrhagic Disorders

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Mast Cell Activation Disorders

Eosinophilia

Leukocyte Disorders

Chronic Disease

Disease Attributes

Chronic Graft Versus Host Disease

Essential Thrombocythemia

Patients with a myeloproliferative neoplasm (MPN) diagnosis:

Atypical chronic myeloid leukemia (aCML), chronic eosinophilic leukemia-not otherwise specified (CEL NOS), chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia (CNL), polycythemia vera (PV), essential thrombocythemia (ET), JMML, mastocytosis, MPN unclassifiable, myeloproliferative neoplasm/myelodysplastic syndrome unclassifiable (MPN/MDS unclassifiable), primary myelofibrosis (PMF), post-ET MF, post-PV MF, or (refractory anemia with ringed sideroblasts associated with marked thrombocytosis) RARS-T

Observational

Vikas Gupta, MD

Jaime O. Claudio, PhD

The mandate of this MPN registry is to collect clinical information, including molecular results, from consenting patients with a variety of MPNs at different time points during the course of their disease.

The myeloproliferative neoplasms (MPNs) are a group of rare hematological malignancies in which the bone marrow cells that produce the body's blood cells develop and function abnormally.

Despite the gains that have already been made in understanding and treatment of MPNs there is much that can still be learned. This registry will establish a clinical annotation database would help to better understand this group of diseases and to more effectively assign individual patients to the optimal therapy and so, improve their outcomes. This project will provide new insights on the molecular profiling of patients with MPN. It will be used as future resource for observational studies related to MPN.

The registry involves the collection of clinical information from patients with diagnosis of MPN at different time points during the course of their disease. The clinical data is collected following written informed consent from the Hematologic Malignancy tissue bank (UHN REB 01-0573C).

Data collected includes: a range of clinical measures, disease-associated factors, details of treatment and its results, complications during treatment, molecular and cytogenetic data, symptom assessment and survival outcome (up to 10 years).

Data will be collected prospectively and retrospectively, in both cases after obtaining written informed consent as per the study standard operating procedure (SOP).

Myeloproliferative Neoplasms (MPNs) Patient Registry

Clinical and Molecular Epidemiology of Myeloproliferative Neoplasms (MPNs)

De-identified participant data may be shared for REB approved research studies. Only the data necessary to achieve the study's aims will be shared and all data will be de-identified prior to sharing.

Type and phase of MPN, previous cancer history, age, sex

Risk stratification (IPSS, DIPSS and DIPSS)

o Details of transformation to accelerated/phase phase disease

Physical examination: Splenomegaly and hepatomegaly, ascites, EMS, ECOG

CBC, INR, PT, APTT, fibrinogen, creatinine, ALP, ALT, AST, GGT, total bilirubin, LDH, urate, CRP, erythropoietin, hepatitis B and HIV

Details of recipient (CMV status, ABO blood group)

* Details of donor (gender, CMV status, ABO blood group)
* Disease status at time of transplant (blood work disease status)
* Transplant details (stem cell source, HLA matching, conditioning intensity \& regimen, serotherapy, GVHD prophylaxis)

Toxicities, engraftment and chimerism, GVHD, significant infections in the first 100 days

Presence and details of ascites, GIT bleeding, esophageal \& gastric varices, cirrhosis and portal hypertensive gastropathy

o Endoscopy results

WHO classification, echocardiogram results, CNP, troponin, pulmonary function tests, 6 minute walk test distance, blood gas, treatment, complications

Details of thrombosis (type, site)

o Treatment of thrombosis (type, duration)

Relative affected (e.g. daughter, uncle, mother), details of MPN (type, phase, treatment received)

Risk stratification (IPSS, DIPSS and DIPSS)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study With Azacitidine in Pediatric Subjects With Newly Diagnosed Advanced Myelodysplastic Syndrome (MDS) and Juvenile Myelomonocytic Leukemia (JMML)	NCT02447666	Myelodysplastic... Leukemia, Myelo...	Azacitidine	1 Month - 18 Years	Celgene
Myeloproliferative Neoplasms (MPNs) Patient Registry	NCT02760238	Primary Myelofi... Polycythemia Ve... Essential Throm... Mastocytosis Leukemia, Myelo... Leukemia, Myelo... Chronic Eosinop... Myelodysplastic... Neoplasms Leukemia, Myelo...	Observational	-	University Health Network, Toronto
Myeloproliferative Neoplasms (MPNs) Patient Registry	NCT02760238	Primary Myelofi... Polycythemia Ve... Essential Throm... Mastocytosis Leukemia, Myelo... Leukemia, Myelo... Chronic Eosinop... Myelodysplastic... Neoplasms Leukemia, Myelo...	Observational	-	University Health Network, Toronto
Myeloproliferative Neoplasms (MPNs) Patient Registry	NCT02760238	Primary Myelofi... Polycythemia Ve... Essential Throm... Mastocytosis Leukemia, Myelo... Leukemia, Myelo... Chronic Eosinop... Myelodysplastic... Neoplasms Leukemia, Myelo...	Observational	-	University Health Network, Toronto

Spots Global Cancer Trial Database for leukemia, myelomonocytic, juvenile