Epigenetic Reprogramming in Relapse/Refractory AML
- Conditions
- Acute Myelogenous Leukemia
- Interventions
- Registration Number
- NCT03263936
- Lead Sponsor
- 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).
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 37
- 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.
- 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.
- 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.
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Other Filgrastim (G-CSF) decitabine, vorinostat, fludarabine, high dose cytarabine, filgrastim (G-CSF) Other Decitabine decitabine, vorinostat, fludarabine, high dose cytarabine, filgrastim (G-CSF) Other Fludarabine decitabine, vorinostat, fludarabine, high dose cytarabine, filgrastim (G-CSF) Other Vorinostat decitabine, vorinostat, fludarabine, high dose cytarabine, filgrastim (G-CSF) Other Cytarabine decitabine, vorinostat, fludarabine, high dose cytarabine, filgrastim (G-CSF)
- Primary Outcome Measures
Name Time Method The dose of decitabine that can be safely given with vorinostat, fludarabine, high dose cytarabine and G-CSF (FLAG) 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
Name Time Method To analyze the correlation between biological changes and clinical response. 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: 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. 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.
To examine peripheral blood mononuclear cells for immunophenotypic changes. approx 8 weeks To examine peripheral blood mononuclear cells for immunophenotypic changes using peripheral blood samples
To analyze plasma for cytokine content. approx 8 weeks To analyze plasma for cytokine content using plasma samples.
Trial Locations
- Locations (33)
National Cancer Institute, Pediatric Oncology Branch
🇺🇸Bethesda, Maryland, United States
Children's Hospital Orange County
🇺🇸Orange, California, United States
UCSF School of Medicine
🇺🇸San Francisco, California, United States
Primary Children's Hospital
🇺🇸Salt Lake City, Utah, United States
Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
The Children's Hospital, University of Colorado
🇺🇸Aurora, Colorado, United States
Oregon Health and Science University
🇺🇸Portland, Oregon, United States
Cook Children's Medical Center
🇺🇸Fort Worth, Texas, United States
Sydney Children's Hospital
🇦🇺Randwick, New South Wales, Australia
Hospital for Sick Children
🇨🇦Toronto, Ontario, Canada
Children's Hospital Los Angeles
🇺🇸Los Angeles, California, United States
Children's Healthcare of Atlanta, Emory University
🇺🇸Atlanta, Georgia, United States
Sidney Kimmel Cancer Center at Johns Hopkins
🇺🇸Baltimore, Maryland, United States
Dana-Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Texas Children's Cancer Center, Baylor
🇺🇸Houston, Texas, United States
Seattle Children's Hospital
🇺🇸Seattle, Washington, United States
Sainte Justine University Hospital
🇨🇦Montreal, Quebec, Canada
All Children's Hospital
🇺🇸Saint Petersburg, Florida, United States
University of Miami
🇺🇸Miami, Florida, United States
Lurie Children's Hospital of Chicago
🇺🇸Chicago, Illinois, United States
Johns Hopkins University
🇺🇸Baltimore, Maryland, United States
CS Mott Children's Hospital, Ann Arbor
🇺🇸Ann Arbor, Michigan, United States
C.S. Mott Children's Hospital
🇺🇸Ann Arbor, Michigan, United States
Levine Children's Hospital
🇺🇸Charlotte, North Carolina, United States
Cincinnati Children's Hospital
🇺🇸Cincinnati, Ohio, United States
New York University Medical Center
🇺🇸New York, New York, United States
Children's Hospital New York-Presbyterian
🇺🇸New York, New York, United States
Nationwide Children's Hospital
🇺🇸Columbus, Ohio, United States
British Columbia Children's Hospital
🇨🇦Vancouver, British Columbia, Canada
Children's Hospitals and Clinics of Minnesota
🇺🇸Minneapolis, Minnesota, United States
Children's National Medical Center
🇺🇸Washington, District of Columbia, United States
Children's Hospital at Westmead
🇦🇺Westmead, Australia
Medical College of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States