A Study of Safety, Efficacy and Pharmacodynamics of Azacitidine in Children and Young Adults With Acute Myeloid Leukemia.
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|ClinicalTrials.gov Identifier: NCT02450877|
Recruitment Status : Recruiting
First Posted : May 21, 2015
Last Update Posted : April 2, 2018
This study is a randomized, multicenter, open-label, Phase 2 study that will be run in 2 parts: a safety run-in part to determine the dose of azacitidine and then a second part to determine the efficacy of that dose in children and young adults with acute myeloid leukemia in molecular relapse after their first complete remission.
Indication Treatment of children and young adults with molecular relapse of acute myeloid leukemia (AML) after first complete remission (CR1).
Objectives Primary Objectives Safety Run-in Part To establish a safe and tolerable dose of azacitidine to be used in the randomized part of the study.
Randomized Part To evaluate the effect of azacitidine treatment in AML subjects at molecular relapse after CR1 when compared to no treatment with regard to the progression-free rate (PFR) at Day 84 (±4 days) post randomization.
Secondary Objectives Safety Run-in Part To establish azacitidine plasma pharmacokinetic (PK) parameters in subjects with molecular relapse AML after CR1 and to assess efficacy.
Randomized Part To evaluate the safety, pharmacodynamics (PD), and efficacy of azacitidine treatment in subjects with molecular relapse AML after CR1.
Study Design The population of this trial consists of children and young adults with AML who achieved a complete response (CR) with molecular remission, defined as Minimal Residual Disease (MRD) less than 5 x 10-4, following their initial induction therapy and who subsequently have a molecular relapse (defined as increase in MRD level by at least 1 log [10-fold] to a level greater than or equal to 5 x 10-4 despite a normal percentage [<5%] of myeloblasts in the bone marrow [BM] aspirate and peripheral blood [PB], and in the absence of proven histological extramedullary relapse). Eligible subjects have a documented diagnosis of AML with at least one of the following molecular aberrations t(8;21), RUNX1-RUNX1T1, inv(16), CBFb/MYH11, t(9;11), MLL-AF9, NPM1 mutation, or FLT3-ITD mutation. Enrolled/randomized pediatric subjects will be followed with regular MRD testing in order to detect a molecular relapse.
In the safety run-in part, up to 12 subjects aged 3 months to less than 18 years will be enrolled. Six subjects will be enrolled in the first cohort of 100 mg/m2 azacitidine administered intravenously (IV) on Days 1 to 7 of a 28-day cycle. Six additional subjects could be enrolled into a second cohort of 75 mg/m2 azacitidine administered IV on Days 1 to 7 of a 28-day cycle depending on the safety and tolerability results of the 100 mg/m2 cohort.
In the randomized part of the study at least 68 subjects will be randomized (or more depending on whether at least 64 subjects are evaluable for the primary endpoint), with at least 60 of the subjects being less than 18 years of age.
Both parts of the study, the safety run-in part and the randomized part, will contain 3 periods: the screening period, the treatment period and the follow-up period. The screening period will last no more than 10 days in the safety run-in part after which the subjects may be enrolled and treated. In the randomized part, the screening period will last an indefinite amount of time until detection of a molecular relapse in the PB followed by confirmation of the relapse in both PB and BM aspirate, at which point the subject may then be randomized. Subjects will be treated with azacitidine (safety run-in part) or in accordance to their assigned treatment arm (randomized part). Upon discontinuation from the treatment period, subjects will enter into the follow-up period which will last up to 2 years from last patient enrolled/randomized.
|Condition or disease||Intervention/treatment||Phase|
|Leukemia, Myeloid, Acute||Drug: Azacitidine Other: Control Arm||Phase 2|
Show Detailed Description
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||80 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Randomized, Multicenter, Open-label, Phase 2 Study, With a Safety Run-in Part to Evaluate Safety, Pharmacodynamics and Efficacy of Azacitidine Compared to No Anticancer Treatment in Children and Young Adults With Acute Myeloid Leukemia in Molecular Relapse After First Complete Remission|
|Actual Study Start Date :||August 12, 2015|
|Estimated Primary Completion Date :||November 2, 2018|
|Estimated Study Completion Date :||October 28, 2019|
Experimental: Azacitidine Treatment
: Subjects randomized to the experimental arm will receive up to 3 cycles of IV azacitidine on Days 1 through 7 at the dose selected from the safety run-in part.
Control Arm: 'Watch and Wait'
Subjects randomized to the control arm will undergo 'watch and wait' until clinical relapse (defined as at least 5% blasts in PB (peripheral blood) and/or BM (bone marrow) and/or proven histological extramedullary relapse).
|Other: Control Arm|
- Adverse Events (AEs) [ Time Frame: Up to Day 28 ]All reported adverse events during the first treatment cycle
- Dose-limiting toxicities (DLTs) [ Time Frame: up to Day 28 ]
Number of participant with DLT
The rate of the following treatment-related DLTs as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAEs) version 4.0, occurring during Cycle 1 only will be considered in determining the tolerability of the 100 mg/m2 dose of azacitidine:
- Grade 4 nonhematologic toxicity (excluding transient transaminase elevation)
- Grade 3 nonhematological toxicity lasting more than 7 days despite optimal treatment with standard supportive measures
- Grade 3 or 4 hematologic toxicity requiring treatment delay greater than 21 days (disease-related Grade 3 or 4 hematologic toxicity will not be counted as a DLT)
- Progression-free rate at Day 84 post randomization [ Time Frame: up to Day 84 ]Proportion of subjects free from clinical progression (clinical relapse and death from any cause) and from molecular progression (defined as lack of stabilization or lack of decrease in molecular aberrations concerning FLT3-ITD mutated, CBF leukemias (eg, t(8;21) and/or inv(16)), MLL-gene rearrangements or NPM1-mutations using central assessment of BM samples by the central laboratories identified for the study, obtained at time points identically prespecified in both randomization arms) at Day 84 (±4 days) post randomization.
- Pharmacokinetics ‐ Cmax [ Time Frame: Up to Day 7 ]Maximum observed concentration in plasma
- Pharmacokinetics - Tmax [ Time Frame: Up to Day 7 ]Observed time to maximum plasma concentration
- Pharmacokinetics - AUCt [ Time Frame: Up to Day 7 ]Area under the plasma concentration-time curve from time zero to the last quantifiable time point
- Pharmacokinetics - AUC∞ [ Time Frame: Up to Day 7 ]Area under the plasma concentration-time curve from time zero to infinity
- Pharmacokinetics - λz [ Time Frame: Up to Day 7 ]Terminal phase rate constant, determined by linear regression of the terminal points of the log-linear plasma concentration-time curve
- Pharmacokinetics - t½ [ Time Frame: Up to Day 7 ]Terminal phase half-life, will be calculated according to the following equation:t½ = 0.693/λz
- Pharmacokinetics - CL [ Time Frame: Up to Day 7 ]Total clearance, calculated as Dose/AUC∞
- Pharmacokinetics - Vz [ Time Frame: Up to Day 7 ]volume of distribution will be calculated according to the equation: Vz = (CL)/λz
- Changes in DNA methylation (assessments of BM samples using Nano-HELP assay) [ Time Frame: up to Day 60 ]Descriptive analyses if the level of DNA methylation at certain CpG loci may predict the response or resistance to azacitidine with regard to the following efficacy endpoints: response, LFS, and OS.
- Leukemia-free survival (LFS) [ Time Frame: Up to 9 years ]Leukemia-free survival is defined as the time from study enrollment (safety run-in part) or randomization (randomized part) until transition to leukemia progression or death.
- Minimal residual disease pre-, and 3 and 6 months post-HSCT [ Time Frame: up to 9 years ]Minimal residual disease levels will be assessed across time points
- Overall survival [ Time Frame: up to 9 years ]Overall survival is the time from study enrollment (safety run-in part) or randomization (randomized part) until death from any cause.
- Proportion treated with HSCT [ Time Frame: Up to 9 years ]The proportion of subjects undergoing HSCT during the conduct of this study over the total number of subjects enrolled into this study.
- Molecular response [ Time Frame: up to Day 84 ]Molecular response is the number of subjects with molecular response (1 log or more decrease in defined MRD molecular markers from baseline) divided by the number of subjects within the analysis population.
- Treatment-related mortality/morbidity [ Time Frame: up to 9 years ]All reported SAEs and Deaths during the duration of the study conduct.
- Toxicity after HSCT [ Time Frame: up to 9 years ]All reported SAEs and deaths post HSCT during the duration of the study conduct
- Adverse Events (AEs) [ Time Frame: up to 9 years ]All reported adverse events during the duration of the study conduct
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02450877
|Contact: Associate Director Clinical Trial Disclosureemail@example.com|
|Copenhagen, Denmark, DK-2100|
|Berlin, Germany, 13353|
|Essen, Germany, 45147|
|Klinikum der Johann Wolfgang Goethe-Universität Frankfurt/Main||Recruiting|
|Frankfurt am Main, Germany, 60596|
|Freiburg, Germany, 79106|
|Medical School of Hannover||Recruiting|
|Hannover, Germany, 30625|
|VU University Medical Center||Recruiting|
|Amsterdam, Netherlands, 1081 HV|
|Rotterdam, Netherlands, 3015 GJ|
|Study Director:||Bouchra Benettaib, MD||Celgene Corporation|