Epigenetic Reprogramming in Relapse AML

Stopped early · Phase 1

Conditions studied: Leukemia, Acute Myeloid

In brief

Successful treatment for children and young adults with relapsed acute myeloid leukemia (AML) continues to be a significant challenge. Despite relative improvements in survival for patients with newly diagnosed AML, an estimated 40-60% will relapse with the majority eventually dying of their relapsed disease. Attaining a subsequent remission in patients who relapse is the initial critical step toward achieving a potential cure. As chemotherapy resistance is one of the primary drivers of poor treatment response and subsequent relapse in AML, identifying methods to reverse this resistance are desperately needed. This clinical trial is aimed at improving the remission re-Induction rates for children and adults with relapsed or refractory AML through epigenetic modifying agents that have the ability to reverse chemotherapy resistance. Decitabine, a DNA methyltransferase inhibitor (DNMTi) and Vorinostat, a histone deacetylase inhibitor (HDACi), are two epigenetic modifying drugs that act on the methylation of proximal promoter regions of genes and on proteins involved in the wrapping of DNA around histones, respectively. Both processes play a critical role in regulating gene expression, and frequently these genes are involved in chemotherapy resistance. These agents are FDA-approved for treatment in adult hematologic malignancies, making this an opportune time to begin testing these novel therapies in pediatric leukemia trials. This study will investigate chemotherapy priming of relapsed/refractory AML using Decitabine and Vorinostat given for 5 days prior to standard re-Induction with Fludarabine, Cytarabine and G-CSF for children and adults.

Key facts

Study ID

NCT02412475

Run by

Michael Burke

People needed

3

Starts

2015-02-21

Expected to finish

2017-06-21

Last updated by the study team

2019-01-24

Who can join

Age: 1 and older, up to 25. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

• The eligibility criteria listed below are interpreted literally and cannot be waived.
• Age: Patients must be ≥ 1 and ≤ 25 years of age when originally diagnosed with AML.
• Diagnosis:
• o Patients must have a diagnosis of AML with > 5% blast in the bone marrow and fall into one of the categories listed below:
• Any patient in 1st or greater relapse OR Patients failed to go into remission after first or greater relapse OR Patients failed to go into remission from original diagnosis after two or more induction attempts.
• o Patients with CNS 1 or CNS 2 leukemia are eligible
• Performance Level: (See Appendix 2 for Performance Scales)
• o Karnofsky Performance Status ≥ 50% for patients 16 years and older
• o Lansky Play Score ≥ 50 for patients under 16 years of age
• Life Expectancy:
• o Patients must have a life expectancy ≥ 8 weeks as determined by the enrolling investigator.
• Prior Therapy:
• o Cytotoxic Therapy: At least 7 days must have elapsed from prior chemotherapy with the exception of hydroxyurea which can be used up to 24 hours of starting this protocol therapy.
• o Hematopoietic Stem Cell Transplant (HSCT): Patients who have experienced their relapse after a HSCT are eligible, provided they have no evidence of active Graft-versus-Host Disease (GVHD).
• o Prior Demethylating and/or HDAC Inhibitor Therapy: Patients who have received prior DNMTi (e.g. decitabine) and/or HDACi (e.g. vorinostat) are eligible to participate in this Phase 1 study.
• o 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
• o 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 type of immunotherapy, e.g. tumor vaccines.
• XRT: > 14 days for local palliative XRT for CNS chloromas; No washout period is necessary for other chloromas; > 30 days must have elapsed if prior TBI, craniospinal XRT.
• Organ Function:
• Patients must have acceptable organ function as defined within 7 days of study registration
• Renal: creatinine clearance ≥ 60 mL/min/1.73 m2 or serum creatinine based on age and gender as follows:
• Maximum Serum Creatinine (mg/dL) Age Male Female 1 month to < 6 months 0.4 0.4 6 months to < 1 year 0.5 0.5
• year to < 2 years 0.6 0.6
• years to < 6 years 0.8 0.8

You may not qualify if…

• Patients will be excluded if they meet any of the following criteria
• They are unable to swallow Vorinostat capsules or take oral solution.
• 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 Down syndrome are excluded.
• 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.

Where it is running

• Children's Hospitals and Clinics of Minnesota — Minneapolis, Minnesota, United States
• Children's Hospital of Wisconsin — Milwaukee, Wisconsin, United States

Full record on ClinicalTrials.gov

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