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

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

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

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.

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

Detailed Summary:

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.

Current 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).

Original 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).

Current Secondary Outcome:

• Cytogenetic response for MDS [ Time Frame: Up to 6 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.
• Cytogenetic response for JMML subjects [ Time Frame: Up to 6 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 for JMML subjects [ Time Frame: Up to 6 Months ]
  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 (CR, PR or marrow CR) for MDS patients [ Time Frame: Up to 30 months ]
  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 (Clinical CR or Clinical PR) for JMML patients [ Time Frame: Up to 30 months ]
  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.
• Time to Response (TTR) for MDS patients [ Time Frame: Up to 6 Months ]
  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.
• TTR of Clinical CR or Clinical PR for JMML patients [ Time Frame: Up to 6 Months ]
  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) [ Time Frame: Up to 30 months ]
  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) [ Time Frame: Up to 30 months ]
  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.
• Overall survival (OS) [ Time Frame: Up to 30 months ]
  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.
• Deoxyribonucleic acid methylation status in BM [ Time Frame: Up to 30 months ]
  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
• Percentage of subjects undergoing HSCT [ Time Frame: Up to 30 months ]
  Defined as the proportion of subjects undergoing HSCT during the conduct of this study over the total number of subjects enrolled into this study.
• Time to first HSCT [ Time Frame: Up to 30 months ]
  The time from first study dose day until HSCT date. Subjects not receiving a HSCT will be censored at the time of the analysis.
• Adverse Events (AEs) [ Time Frame: Up to 7 months ]
  All reported adverse events during the duration of the study conduct.
• Pharmacokinetic parameters of azacitidine; Cmax [ Time Frame: Up to 28 days ]
  Cmax is defined as the observed maximum plasma concentration
• Pharmacokinetic parameters of azacitidine; Tmax [ Time Frame: Up to 28 days ]
  Tmax is defined as the observed time to maximum plasma concentration
• Pharmacokinetic parameters of azacitidine; AUCt [ Time Frame: Up t
  
  

  Original Secondary Outcome: Same as current
  
  Information By: Celgene
  

  Dates:
  Date Received: April 14, 2015
  Date Started: September 15, 2015
  Date Completion: September 27, 2022
  Last Updated: February 28, 2017
  Last Verified: February 2017