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

NCT02450877 | Completed Phase 2 DMC

• 1 other identifier: AZA-AML-004
• Study Type: interventional
• Target: 7
• Locations: 3 countries
• Sites: 8

Brief Summary

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.

Conditions

Leukemia, Myeloid, Acute

Keywords

Children; Young Adults; Azacitidine; Acute Myeloid Leukemia; Molecular Relapse; Vidaza; AZA-AML-004

Outcome Measures

Primary Outcomes (3)

• Adverse Events (AEs)

  All reported adverse events during the first treatment cycle

  Up to Day 28

• Dose-limiting toxicities (DLTs)

  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)

  up to Day 28

• Progression-free rate at Day 84 post randomization

  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.

  up to Day 84

Secondary Outcomes (17)

• Pharmacokinetics - Cmax

  Up to Day 7

• Pharmacokinetics - Tmax

  Up to Day 7

• Pharmacokinetics - AUCt

  Up to Day 7

• Pharmacokinetics - AUC∞

  Up to Day 7

• Pharmacokinetics - λz

  Up to Day 7

Study Arms (2)

Azacitidine Treatment

EXPERIMENTAL

: 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.

Drug: Azacitidine

Control Arm: 'Watch and Wait'

OTHER

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

Interventions

Azacitidine DRUG

Azacitidine Treatment

Control Arm OTHER

Control Arm: 'Watch and Wait'

Eligibility Criteria

• Age: 3 Months - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Safety Run-in Part:
• Understand and voluntarily provide permission (subjects and when applicable, parental/legal representative(s)) to the informed consent/assent form (ICF/IAF) prior to conducting any study related assessments/procedures.
• Able to adhere to the study visit schedule and other protocol requirements.
• Male or Female subjects aged 3 months to less than 18 years old at the time of informed consent/assent.
• Documented diagnosis of Acute myeloid leukemia (AML) according to World Health Organization (WHO) classification with at least one of the following molecular aberrations below:
• t(8;21), RUNX1-RUNX1T1
• inv(16), CBFb/MYH11
• t(9;11), MLL-AF9
• NPM1 mutation
• FLT3-ITD mutation.
• Documentation of molecular remission (MRD less than 5 x 10-4) confirmed at the start of last consolidation course or within 1 month after completion of consolidation treatment.
• Detection of molecular relapse in the Peripheral Blood (PB) by real-time quantitative polymerase chain reaction (RQ-PCR) within the 7 days prior to signing informed consent/assent form and confirmation of relapse during the screening period. Molecular relapse is defined as an increase in molecular remission (MRD) level of a subject-specific fusion gene or aberration by at least 1 log (10-fold) to a level of at least 5 x 10-4. For subjects who are MRD negative, the rise should be at least 1 log (10-fold) greater than previous sensitivity to a level of 5 x 10-4 or above. An increase in PB must be confirmed in PB and bone marrow (BM) aspirate by RQ-PCR. Confirmation of a molecular relapse is given if the MRD positivity is at the same level or higher in the PB and BM sample compared to the PB MRD levels at the detection of the relapse and in the absence of clinical relapse (defined as at least 5% blasts in PB and/or BM and/or proven histological extramedullary relapse).
• Lansky play score at least equal to 50; or Karnofsky performance status at least equal to 50, whichever is applicable.
• 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 study therapy on reproduction with parent/parents and/or guardian/guardians.
• 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.

You may not qualify if:

• Safety Run-in Part (criteria must be checked at Screening and re-checked on Cycle 1 Day
• The presence of any of the following will exclude a subject from enrollment:
• Concomitant Treatment
• Concomitant treatment with any other anticancer therapy except those specified in protocol.
• Received maintenance therapy after end of consolidation therapy and CR1.
• Prior Treatment
• HSCT (hematopoietic stem cell transplantation) within previous 3 months.
• Treated by any investigational agent in a clinical study within previous 4 weeks.
• Medical Condition/Laboratory
• Pregnant or lactating.
• Symptomatic central nervous system (CNS)-involvement or isolated extramedullary disease at initial diagnosis.
• FAB (French-American-British) type M3 leukemia (acute promyelocytic leukemia)
• Therapy-related AML
• AML of Down syndrome or other congenital syndromes giving rise to leukemia or treatment complications.
• Symptomatic cardiac disorders (CTCAE (Common Terminology Criteris for Adverse Events) Grade 3 or 4).

Sponsors & Collaborators

• Celgene: lead

Study Sites (8)

Rigshospitalet

Copenhagen, DK-2100, Denmark

Location

Charite Berlin

Berlin, 13353, Germany

Location

Universitatsklinikum Essen

Essen, 45147, Germany

Location

Klinikum der Johann Wolfgang Goethe-Universität Frankfurt/Main

Frankfurt am Main, 60596, Germany

Location

Universitatsklinik

Freiburg im Breisgau, 79106, Germany

Location

Medical School of Hannover

Hanover, 30625, Germany

Location

VU University Medical Center

Amsterdam, 1081 HV, Netherlands

Location

Erasmus University Medical Center

Rotterdam, 3015 GJ, Netherlands

Location

Related Links

• Expanded Access for CC-486

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

Azacitidine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Bouchra Benettaib, MD

  Celgene Corporation

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 19, 2015
• First Posted: May 21, 2015
• Study Start: August 12, 2015
• Primary Completion: October 10, 2018
• Study Completion: October 8, 2019
• Last Updated: December 20, 2019

Record last verified: 2019-12

Locations

DE (5); DK (1); NL (2)