Epigenetic Reprogramming in Relapse/Refractory AML

NCT ID: NCT03263936

Last Updated: 2025-10-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 37 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-07-11
• Study Completion Date: 2022-02-10

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.

Conditions

Acute Myelogenous Leukemia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Other

decitabine, vorinostat, fludarabine, high dose cytarabine, filgrastim (G-CSF)

Group Type: OTHER

Decitabine

Intervention Type: DRUG

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

Vorinostat

Intervention Type: DRUG

Age \<18: 180 mg/m2/day once daily PO. Age≥18: 200 mg twice daily PO.

Filgrastim (G-CSF)

Intervention Type: DRUG

Given on days 5 until evidence of ANC recovery (\>500/µL)5µg/kg/dose IV or SQ (starting at hour 0)

Fludarabine

Intervention Type: DRUG

30 mg/m2/day IV over 30 minutes (starting at Hour 0 - Immediately after G-CSF)

Cytarabine

Intervention Type: DRUG

2000 mg/m2/day (Starting at Hour 0.5),IV over 3 hours, days 6-10

Interventions

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

Intervention Type: DRUG

Vorinostat

Age \<18: 180 mg/m2/day once daily PO. Age≥18: 200 mg twice daily PO.

Intervention Type: 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)

Intervention Type: DRUG

Fludarabine

30 mg/m2/day IV over 30 minutes (starting at Hour 0 - Immediately after G-CSF)

Intervention Type: DRUG

Cytarabine

2000 mg/m2/day (Starting at Hour 0.5),IV over 3 hours, days 6-10

Intervention Type: DRUG

Other Intervention Names

Dacogen; Zolinza, SAHA, suberoylanilide acid; G-CSF, neupogen; Fludara; Cytosine arabinoside, Ara-C, Cytosar

Eligibility Criteria

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

• Minimum Eligible Age: 1 Year
• Maximum Eligible Age: 25 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Therapeutic Advances in Childhood Leukemia Consortium

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Children's Hospital Los Angeles

Los Angeles, California, United States

Children's Hospital Orange County

Orange, California, United States

UCSF School of Medicine

San Francisco, California, United States

The Children's Hospital, University of Colorado

Aurora, Colorado, United States

Children's National Medical Center

Washington D.C., District of Columbia, United States

University of Miami

Miami, Florida, United States

All Children's Hospital

St. Petersburg, Florida, United States

Children's Healthcare of Atlanta, Emory University

Atlanta, Georgia, United States

Lurie Children's Hospital of Chicago

Chicago, Illinois, United States

Johns Hopkins University

Baltimore, Maryland, United States

Sidney Kimmel Cancer Center at Johns Hopkins

Baltimore, Maryland, United States

National Cancer Institute, Pediatric Oncology Branch

Bethesda, Maryland, United States

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

C.S. Mott Children's Hospital

Ann Arbor, Michigan, United States

CS Mott Children's Hospital, Ann Arbor

Ann Arbor, Michigan, United States

Children's Hospitals and Clinics of Minnesota

Minneapolis, Minnesota, 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

Levine Children's Hospital

Charlotte, North Carolina, United States

Cincinnati Children's Hospital

Cincinnati, Ohio, United States

Nationwide Children's Hospital

Columbus, Ohio, United States

Oregon Health and Science University

Portland, Oregon, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Cook Children's Medical Center

Fort Worth, Texas, United States

Texas Children's Cancer Center, Baylor

Houston, Texas, United States

Primary Children's Hospital

Salt Lake City, Utah, United States

Seattle Children's Hospital

Seattle, Washington, United States

Medical College of Wisconsin

Milwaukee, Wisconsin, United States

Sydney Children's Hospital

Randwick, New South Wales, Australia

Children's Hospital at Westmead

Westmead, , Australia

British Columbia Children's Hospital

Vancouver, British Columbia, Canada

Hospital for Sick Children

Toronto, Ontario, Canada

Sainte Justine University Hospital

Montreal, Quebec, Canada

Countries

United States; Australia; Canada

Provided Documents

Document Type: Study Protocol, Statistical Analysis Plan, and Informed Consent Form

View Document

Other Identifiers

T2016-003

Identifier Type: -

Identifier Source: org_study_id