Acute Myelogenous LeukemiaPhase 1NCT03263936
Epigenetic Reprogramming in Relapse/Refractory AML
A Phase 1 study testing Decitabine, Vorinostat and Filgrastim (G-CSF) in people with Acute Myelogenous Leukemia, run by Therapeutic Advances in Childhood Leukemia Consortium at 33 sites in 3 countries.
Trial summary
This is a pilot study using decitabine and vorinostat before and during chemotherapy with fludarabine, cytarabine and G-CSF (FLAG). Read more about this study
- Who is it for?
- Ages 1 year to 25 years
- Conditions the study is for
- Acute Myelogenous Leukemia
- What is being tested?
- Decitabine, Vorinostat and Filgrastim (G-CSF)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 37 participants
- Where
- 33 sitesin 3 countries
- Study dates
- 11 Jul 2017to 10 Feb 2022
- Phase
- Phase 1
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 year to 25 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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).
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- 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 enrollment.
- Female patients with infants must agree not to breastfeed their infants while on this study.
- 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.
Who cannot join
- 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)
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- 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
Trial locations and contacts
33 sites in 3 countries.
33 sites in 3 countries
United States28 sites
C.S. Mott Children's Hospital
Ann Arbor, Michigan, 48109-0914
CS Mott Children's Hospital, Ann Arbor
Ann Arbor, Michigan, 48109
Children's Healthcare of Atlanta, Emory University
Atlanta, Georgia, 30322
The Children's Hospital, University of Colorado
Aurora, Colorado, 80045
Johns Hopkins University
Baltimore, Maryland, 21231
Sidney Kimmel Cancer Center at Johns Hopkins
Baltimore, Maryland, 21231
National Cancer Institute, Pediatric Oncology Branch
Bethesda, Maryland, 20892
Dana-Farber Cancer Institute
Boston, Massachusetts, 02215
Levine Children's Hospital
Charlotte, North Carolina, 28203
Lurie Children's Hospital of Chicago
Chicago, Illinois, 60611
Cincinnati Children's Hospital
Cincinnati, Ohio, 45229
Nationwide Children's Hospital
Columbus, Ohio, 43205
Cook Children's Medical Center
Fort Worth, Texas, 76104
Texas Children's Cancer Center, Baylor
Houston, Texas, 77030
Children's Hospital Los Angeles
Los Angeles, California, 90027
University of Miami
Miami, Florida, 33136
Medical College of Wisconsin
Milwaukee, Wisconsin, 53226
Children's Hospitals and Clinics of Minnesota
Minneapolis, Minnesota, 55404
New York University Medical Center
New York, New York, 10016
Children's Hospital New York-Presbyterian
New York, New York, 10032
Children's Hospital Orange County
Orange, California, 92868
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, 19104
Oregon Health and Science University
Portland, Oregon, 97239
Primary Children's Hospital
Salt Lake City, Utah, 84113
UCSF School of Medicine
San Francisco, California, 94158
Seattle Children's Hospital
Seattle, Washington, 98105
All Children's Hospital
St. Petersburg, Florida, 33701
Children's National Medical Center
Washington D.C., District of Columbia, 20010
Canada3 sites
Sainte Justine University Hospital
Montreal, Quebec
Hospital for Sick Children
Toronto, Ontario, M5G 1X8
British Columbia Children's Hospital
Vancouver, British Columbia, V6H 3V4
Australia2 sites
Sydney Children's Hospital
Randwick, New South Wales, 2031
Children's Hospital at Westmead
Westmead
About this study
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
This is a pilot study using decitabine and vorinostat before and during chemotherapy with fludarabine, cytarabine and G-CSF (FLAG).
Read the 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.
- Conditions
- Acute Myelogenous Leukemia
- Being tested
- Decitabine, Vorinostat, Filgrastim (G-CSF), Fludarabine, Cytarabine
- Keywords
- Relapse, Myelogenous, Leukemia, Refractory, Acute, Pediatric
- Medical subject headings
- Leukemia, Myeloid, Acute, Recurrence, Leukemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DecitabineDrug
Also called Dacogen
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
VorinostatDrug
Also called Zolinza, SAHA, suberoylanilide acid
Age <18: 180 mg/m2/day once daily PO. Age≥18: 200 mg twice daily PO.
Filgrastim (G-CSF)Drug
Also called G-CSF, neupogen
Given on days 5 until evidence of ANC recovery (>500/µL)5µg/kg/dose IV or SQ (starting at hour 0)
FludarabineDrug
Also called Fludara
30 mg/m2/day IV over 30 minutes (starting at Hour 0 - Immediately after G-CSF)
CytarabineDrug
Also called Cytosine arabinoside, Ara-C, Cytosar
2000 mg/m2/day (Starting at Hour 0.5),IV over 3 hours, days 6-10
| Study group | Role | What they receive |
|---|---|---|
| Other | Other | decitabine, vorinostat, fludarabine, high dose cytarabine, filgrastim (G-CSF) Receives: Drug: Decitabine; Drug: Vorinostat; Drug: Filgrastim (G-CSF); Drug: Fludarabine; Drug: Cytarabine |
What is being measured
The primary outcome is the main question the study is designed to answer.
The Dose of Decitabine That Can be Safely Given With Vorinostat, Fludarabine, High Dose Cytarabine and G-CSF (FLAG)
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
Measured: during course 1 DLT evaluation period, approx 9 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Aug 2017
- Study start11 Jul 2017
- Primary completion9 Jul 2020
- Study completion10 Feb 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Acute Myelogenous LeukemiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 37 participants (actual)
Sponsor and investigators
- Lead sponsor
- Therapeutic Advances in Childhood Leukemia Consortium
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03263936
- Sponsor's protocol ID
- T2016-003
- Status last verified
- May 2023
- First submitted
- 21 Aug 2017
- Last updated
- 16 Oct 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Undecided