Epigenetic Reprogramming in Relapse/Refractory AML

  • days left to enroll
  • participants needed
  • sponsor
    Therapeutic Advances in Childhood Leukemia Consortium
Updated on 8 October 2020
Ellynore Florendo
Primary Contact
Children's National Medical Center (5.4 mi away) Contact
+33 other location
graft versus host disease
granulocyte colony stimulating factor
direct bilirubin
residual tumor
refractory acute myeloid leukemia (aml)
secondary acute myeloid leukemia
hematopoietic growth factors


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


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.

Treatment cytarabine, Fludarabine, Decitabine, Vorinostat, Filgrastim (G-CSF)
Clinical Study IdentifierNCT03263936
SponsorTherapeutic Advances in Childhood Leukemia Consortium
Last Modified on8 October 2020

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Inclusion Criteria

Is your age between 1 yrs and 25 yrs?
Gender: Male or Female
Do you have any of these conditions: Acute myeloid leukemia or Acute Myelogenous Leukemia (AML)?
Patients must be 1 and 25 years of age
Diagnosis: Patients with relapse or refractory AML must have measurable
disease ( >M1 marrow)
st 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
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
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
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
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