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Epigenetic Reprogramming in Relapse/Refractory AML

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03263936
Recruitment Status : Completed
First Posted : August 28, 2017
Last Update Posted : June 24, 2022
Information provided by (Responsible Party):
Therapeutic Advances in Childhood Leukemia Consortium

Brief Summary:
This is a pilot study using decitabine and vorinostat before and during chemotherapy with fludarabine, cytarabine and G-CSF (FLAG).

Condition or disease Intervention/treatment Phase
Acute Myelogenous Leukemia Drug: Decitabine Drug: Vorinostat Drug: Filgrastim (G-CSF) Drug: Fludarabine Drug: Cytarabine Phase 1

Detailed Description:
Decitabine is a demethylating agent and vorinostat is a HDAC inhibitor. The use of demethylating agents and HDAC inhibitors in combination have been previously shown to have synergistic effects in altering neoplastic pathways of cancer cells and be well tolerated in human clinical studies. With the ability of decitabine and vorinostat to alter the abnormal cellular pathways of leukemic blasts and essentially turn off anti-apoptotic proteins, the leukemia cells have become primed for cytotoxic cell kill via chemotherapeutic agents. This study will ask the question as to whether or not the combination of decitabine and vorinostat followed by chemotherapy is feasible and whether it can positively impact outcome in patients with relapsed or refractory acute myelogenous leukemia.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 37 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Completion Date : February 10, 2022

Arm Intervention/treatment
decitabine, vorinostat, fludarabine, high dose cytarabine, filgrastim (G-CSF)
Drug: Decitabine
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

Drug: Vorinostat
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

Drug: Fludarabine
30 mg/m2/day IV over 30 minutes (starting at Hour 0 - Immediately after G-CSF)
Other Name: Fludara

Drug: Cytarabine
2000 mg/m2/day (Starting at Hour 0.5),IV over 3 hours, days 6-10
Other Name: Cytosine arabinoside, Ara-C, Cytosar

Primary Outcome Measures :
  1. 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

Secondary Outcome Measures :
  1. 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

  2. To analyze plasma for cytokine content. [ Time Frame: approx 8 weeks ]
    To analyze plasma for cytokine content using plasma samples.

  3. 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

  4. 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.

  5. 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.

Information from the National Library of Medicine

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Ages Eligible for Study:   1 Year to 25 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

- Patients must be ≥ 1 and ≤25 years of age.

Diagnosis: Patients with relapse or refractory AML must have measurable disease ( >M1 marrow)

  • 1st or greater relapse, OR
  • Failed to go into remission after 1st or greater relapse, OR
  • Failed to go into remission from original diagnosis after 2 or more induction attempts

Eligibility for patients with an M1 marrow; defined as >0.1% by flow or molecular testing (e.g. PCR).

  • must include two serial marrows (at least 1-week apart) demonstrating stable or rising minimal residual disease (MRD) (i.e. not declining).
  • Patients may have CNS or other sites of extramedullary disease. No cranial irradiation is allowed during the protocol therapy.
  • Patients with secondary AML are eligible.
  • Patients with Down syndrome are eligible.
  • Patients with DNA fragility syndromes (such as Fanconi anemia, Bloom syndrome) are excluded.

Performance Level:

- Karnofsky >50% for patients >16 years of age and Lansky > 50% for patients ≤ 16 years of age (See Appendix II for Performance Scales)

Prior therapy - Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

  1. Cytoreduction with hydroxyurea: hydroxyurea can be initiated and continued for up to 24 hours prior to the start of decitabine/vorinostat. It is recommended to use hydroxyurea in patients with significant leukocytosis (WBC >50,000/L) to control blast count before initiation of systemic protocol therapy.
  2. Patients who relapsed while they are receiving cytotoxic therapy: at least 14 days must have elapsed since the completion of the cytotoxic therapy, except Intrathecal chemotherapy.

Hematopoietic stem cell transplant (HSCT):

- Patients who have experienced their relapse after a HSCT are eligible, provided they have no evidence of acute or chronic Graft-versus-Host Disease (GVHD) and are off all transplant immune suppression therapy for at least 7-days (e.g. steroids, cyclosporine, tacrolimus). Steroid therapy for non-GVHD and/or non-leukemia therapy is acceptable.

Hematopoietic growth factors:

- It must have been at least 7 days since the completion of therapy with GCSF or other growth factors at the time of enrollment. It must have been at least 14 days since the completion of therapy with pegfilgrastim (Neulasta ®)

Biologic (anti-neoplastic agent):

-At least 7 days after the last dose of a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair.

Monoclonal antibodies: At least 3 half-lives of the antibody must have elapsed after the last dose of monoclonal antibody (i.e. Gemtuzumab = 36 days)

Immunotherapy: At least 42 days after the completion of any time of immunotherapy, e.g. tumor vaccines or CAR T-cell therapy.

XRT: Cranio or craniospinal XRT is prohibited during protocol therapy. No washout period is necessary for radiation given to non-CNS chloromas; >90 days must have elapsed if prior TBI, cranio or craniospinal XRT.

Prior Demethylating and/or HDAC Inhibitor Therapy: Patients who have received prior DNMTi (e.g. decitabine) and/or HDACi (e.g. vorinostat) therapy are eligible to participate in this Phase 1 study. At least 7 days must have passed from prior DNMTi or HDACi as a washout period.

Renal and hepatic function: Patients must have adequate renal and hepatic functions as indicated by the following laboratory values:

A. Adequate renal function defined as: Patient must have a calculated creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73m2 OR a normal serum creatinine based on age/gender.

B. Adequate Liver Function Defined as: Direct bilirubin < 1.5 x upper limit of normal (ULN) for age or normal, AND alanine transaminase (ALT) < 5 x ULN for age. The hepatic requirements are waived for patients with known or suspected liver involvement by leukemia. This must be reviewed by and approved by the study chair or vice chair.

Adequate Cardiac Function Defined as: Shortening fraction of ≥ 27% by echocardiogram, OR ejection fraction of ≥ 50% by radionuclide angiogram (MUGA).

Reproductive Function A. Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed within 1 week prior to enrollment.

B. Female patients with infants must agree not to breastfeed their infants while on this study.

C. Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study and for a minimum of 6 months after study treatment.

Exclusion Criteria:

  • No NG or G-Tube administration of Vorinostat is allowed. Capsule must be swallowed whole or given as oral suspension.
  • They are currently receiving other investigational drugs.
  • There is a plan to administer non-protocol chemotherapy, radiation therapy, or immunotherapy during the study period.
  • They have significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results.
  • They have a known allergy to any of the drugs used in the study.
  • Patients with DNA fragility syndromes are excluded (e.g. Fanconi Anemia, Bloom Syndrome)
  • They are receiving valproic acid (VPA) therapy.
  • Patients with Acute Promyelocytic Leukemia (APL, APML) are excluded
  • Patients with documented active and uncontrolled infection at the time of study entry are not eligible

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03263936

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Sponsors and Collaborators
Therapeutic Advances in Childhood Leukemia Consortium
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Responsible Party: Therapeutic Advances in Childhood Leukemia Consortium
ClinicalTrials.gov Identifier: NCT03263936    
Other Study ID Numbers: T2016-003
First Posted: August 28, 2017    Key Record Dates
Last Update Posted: June 24, 2022
Last Verified: September 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Therapeutic Advances in Childhood Leukemia Consortium:
Additional relevant MeSH terms:
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Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Disease Attributes
Pathologic Processes
Antineoplastic Agents
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Histone Deacetylase Inhibitors