Epigenetic Reprogramming in Relapse/Refractory AML
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|ClinicalTrials.gov Identifier: NCT03263936|
Recruitment Status : Active, not recruiting
First Posted : August 28, 2017
Last Update Posted : September 8, 2021
|Condition or disease||Intervention/treatment||Phase|
|Acute Myelogenous Leukemia||Drug: Decitabine Drug: Vorinostat Drug: Filgrastim (G-CSF) Drug: Fludarabine Drug: Cytarabine||Phase 1|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||24 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Epigenetic Reprogramming in Relapse AML: A Phase 1 Study of Decitabine and Vorinostat Followed by Fludarabine, Cytarabine and G-CSF (FLAG) in Children and Young Adults With Relapsed/Refractory AML|
|Actual Study Start Date :||July 11, 2017|
|Actual Primary Completion Date :||July 9, 2020|
|Estimated Study Completion Date :||December 2021|
decitabine, vorinostat, fludarabine, high dose cytarabine, filgrastim (G-CSF)
Dose Level #0: 5 mg/m2 Dose Level #1: 7.5 mg/m2 Dose Level #2: 10 mg/m2 Dose Level #3: 15 mg/m2 Dose Level #4: 20 mg/m2 given IV over __ hour on days 1 through 5
Other Name: Dacogen
Age <18: 180 mg/m2/day once daily PO. Age≥18: 200 mg twice daily PO.
Other Name: Zolinza, SAHA, suberoylanilide acid
Drug: Filgrastim (G-CSF)
Given on days 5 until evidence of ANC recovery (>500/µL)5µg/kg/dose IV or SQ (starting at hour 0)
Other Name: G-CSF, neupogen
30 mg/m2/day IV over 30 minutes (starting at Hour 0 - Immediately after G-CSF)
Other Name: Fludara
2000 mg/m2/day (Starting at Hour 0.5),IV over 3 hours, days 6-10
Other Name: Cytosine arabinoside, Ara-C, Cytosar
- The dose of decitabine that can be safely given with vorinostat, fludarabine, high dose cytarabine and G-CSF (FLAG) [ Time Frame: during course 1, approx 5 weeks ]The incidence of dose limiting toxicity (DLT) will be measured. The maximum tolerated dose will be the highest study dose at which 1 or fewer of six patients experience DLT during cycle 1 of therapy
- To examine peripheral blood mononuclear cells for immunophenotypic changes. [ Time Frame: approx 8 weeks ]To examine peripheral blood mononuclear cells for immunophenotypic changes using peripheral blood samples
- To analyze plasma for cytokine content. [ Time Frame: approx 8 weeks ]To analyze plasma for cytokine content using plasma samples.
- To analyze the correlation between biological changes and clinical response. [ Time Frame: approx 8 weeks ]To analyze the correlation between biological changes and clinical response using standard statistical methods
- To establish the extent of hypomethylation of peripheral blood (PB) and bone marrow (BM) pre- and post- decitabine and vorinostat treatment: [ Time Frame: approx 8 weeks ]Reduced representation bisulfite sequencing (RRBS) will be used to analyze the genome-wide methylation profiles on a single nucleotide level; To quantitatively assess global changes in DNA methylation, a LINE-methylation assay will be utilized and specific genes monitored through advanced Infinium MethylationEPIC BeadChip from Illumina. Chromatin immunoprecipitation (ChIP) with antibodies specific for histone modifications associated with transcriptional activation (H3K4me3 and H3K27ac) and repression (H3K9me3 and H3K27me3) and isotype controls, followed by DNA sequencing (ChIP-seq); RNA sequencing analysis will be used to measure global transcriptome changes. Profiles of CD33+ umbilical cord blood cells, whole bone marrow, or Peripheral Blood Stem Cells (PBSCs) will be used as normal controls for each sample.
- To analyze the correlation between DNA methylation and gene expression pre- and post-treatment with decitabine and vorinostat. [ Time Frame: approx 8 weeks ]Assessment of the in vivo effects of combined DNMTi/HDACi on the functional epigenetic profile by comparing the following in paired pre- (Day 0) and post-exposure (Day 5, Day 14 and Day 35) leukemic blasts: Reversal of DNA promoter hypermethylation of "repressed" genes of interest using RRBS, validated with Pyrosequencing-based methylation assay; Increase in H3K9/14 acetylation in association with "repressed" genes of interest using H3K9/14 ChIP-seq, validated with ChIP-qPCR; Reversal of transcriptional silencing of "repressed" genes of interest using RNA seq, validated by qRT-PCR. Since significant acute cell kill is unlikely during the 5-day "window" of DNMTi/HDACi, we will have a unique opportunity to assess the in vivo effects of epigenetic therapy with the Day 5 sample. The Day 14 peripheral blood and Day 35 marrow samples will also contribute in patients whose leukemic blasts persist at these time points.
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Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03263936