Last updated on February 2018

A Study of Safety Efficacy and Pharmacodynamics of Azacitidine in Children and Young Adults With Acute Myeloid Leukemia.

Brief description of study

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.

Detailed Study Description

Study Population Subjects with AML in molecular relapse after CR1, aged 3 months to less than 18 years of age for the safety run-in part, and 3 months to less than 21 years of age for the randomized part.

Length of Study Study duration is estimated to last up to approximately 9 years from the time of the first subject enrollment until completion of the follow-up period for all subjects enrolled/randomized. Estimated duration is based on expected duration of the study treatment/'watch and wait' period (3 months) and completion of the follow-up period (2 years from randomization of last subject).

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, whichever is the later date.

Study Treatments Safety Run-in Part Intravenous azacitidine 100 mg/m2 with a possible decrease to a cohort of 75 mg/m2, Days 1 to 7 of a 28-day cycle for a maximum of 3 cycles.

Randomized Part Intravenous azacitidine dose established during the safety run-in part on Days 1 to 7 of a 28-day cycle for a maximum of 3 cycles (for subjects randomized to the azacitidine arm).

Overview of Efficacy Assessments The primary endpoint of the randomized part, PFR at Day 84 (4 days) post randomization, will be assessed at Day 80 to 88 (approximately end of Cycle 3 of active treatment) post randomization for both the control and the experimental arm. In case of clinical relapse, the investigator will be asked to document it and to evaluate the morphology and immunophenotyping in BM aspirate and PB. This must be done according to standardized diagnostic procedures contained in the AML BFM 2012 guidelines (Creutzig, 2012).

Overview of Safety Assessments Subject safety will be assessed at each visit during the study. Any AE will be reported and recorded in an AE electronic case report form (eCRF). For serious adverse events (SAEs) an expedited reporting procedure will be used in addition to an AE eCRF. The rate of AEs and SAEs, including second malignancies and cardiovascular events which are events of special interest for this study, and abnormal laboratory values and vital signs (NCI CTC Criteria version 4.0 to be used to grade AEs) will be collected while the subject is on study therapy and during the 'watch and wait' period. Once the subject starts the next-line therapy or has a HSCT, only SAEs related to study treatment (experimental arm) or HSCT will be collected for the safety analysis.

Overview of Statistical Methods Subjects from both the safety run-in part and randomization part shall be used for analysis of the safety and efficacy endpoints which are common to both parts of the study. In addition, a PK analysis will be performed on subjects from the safety run-in part, and analysis of the PFR endpoint and all other endpoints unique to the randomized part will only be performed on randomized subjects.

One interim analysis for futility of the primary endpoint is planned during the randomization part of the study once the first 32 (50% of 64) randomized subjects become evaluable for the primaryendpoint analysis. The study will be stopped if the criteria for futility is met.

Subject demographic and baseline characteristics, disposition, and safety data will be presented by study part as well as treatment dose (safety run-in part) and study arm (randomized part) as well as in aggregate for all subjects receiving azacitidine regardless of study part. All efficacy based endpoints will be presented by treatment arm.

First data analysis and reporting of the safety run-in part will be conducted once the final dose assessment SMC meeting has been held (final safety run-in SMC date = data cut-off of initial analysis of safety run-in part). This analysis will consist of the safety run-in primary endpoint and the PK secondary endpoint only. All other safety run-in part secondary endpoints will be analyzed at the time of analysis and reporting of data from the randomized part.

In addition to PK data analysis, all other secondary endpoints can only be analyzed and reported as and when required based on subjects who have had at least 6 months from enrollment (safety run-in part) or randomization (randomization part).

Clinical Study Identifier: NCT02450877

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Associate Director Clinical Trial Disclosure

Universitatsklinikum Essen
Essen, Germany
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Associate Director Clinical Trial Disclosure

Klinikum der Johann Wolfgang Goethe-Universit t Frankfurt/Main
Frankfurt am Main, Germany
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Associate Director Clinical Trial Disclosure

Medical School of Hannover
Hannover, Germany
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Associate Director Clinical Trial Disclosure

VU University Medical Center
Amsterdam, Netherlands
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